Information

C4. An Overview of Mitochondrial Electron Transport - Biology

C4.  An Overview of Mitochondrial Electron Transport - Biology



We are searching data for your request:

Forums and discussions:
Manuals and reference books:
Data from registers:
Wait the end of the search in all databases.
Upon completion, a link will appear to access the found materials.

The main oxidizing agent used during aerobic metabolism is NAD+ (although FAD is used in one step) which get converted to NADH. Unless the NAD+ can be regenerated, glycolysis and the Kreb's cycle will grind to a halt. The enzymes of the Kreb's cycle and electron transport are localized in mitochondria.

Figure: mitochondria

By analogy to the coupling mechanism under anaerobic conditions, it would be useful from a biological perspective if this electron transport from NADH to dioxygen, a thermodynamically favorable reaction (as you calculated in the last study guide - a value of about -55 kcal/mol), were coupled to ATP synthesis. It is! For years scientist tried to find a high energy phosphorylated intermediate, similar to that formed by glyceraldehyde-3-phosphate dehydrogenase in glycolysis, which could drive ATP synthesis (which likewise occurs in the mitochondria). None could be found. A startling hypothesis was put forward by Peter Mitchell, which was proven correct and for which he was awarded the Nobel Prize in Chemistry in 1978. The immediate source of energy to drive ATP synthesis was shown to come not from a phosphorylated intermediate, but a proton gradient across the mitochondrial inner membrane. All the enzymes complexes in electron transport are in the inner membrane of the mitochondria, as opposed to the cytoplasmic enzymes of glycolysis. A pH gradient is formed across the inner membrane occurs in respiring mitochondria. In electron transport, electrons are passed from mobile electron carriers through membrane complexes back to another mobile carrier. Initially, NADH shuttles electrons (2 electron oxidation, characteristic of NAD+/NADH), to a flavin derivative, FMN, covalently attached to Complex I. The reduced form of FMN then passes electrons in single electron steps (characteristic of FAD-like molecules, which can undergo 1 or 2 electrons transfers) through the complex to the lipophilic electron carrier, ubiquinone, UQ.

Figure: lipophilic electron carrier, ubiquinone, UQ

This then passes electrons through Complex III to another mobile electron carrier, a small protein, cytochrome C. Then cytochrome C passes electrons through complex IV, cytochrome C oxidase, to dioxygen to form water. At each step electrons are passed to better and better oxidizing agents, as reflected in their increasing positive standard reduction potential. Hence the oxidation at each complex is thermodynamically favored.

Jmol: Updated Cytochrome C Oxidase Jmol14 (Java) | JSMol (HTML5)

Complex II (also called succinate:quinone oxidoreductase) is a Kreb cycle enzyme that catalyzes the oxidation of succinate to fumarate by bound FAD (hence its other name: succinate dehydrogenase). It is not involved in flow of electrons from NADH to dioxygen described above but passes electrons from the reduced succinate to ubiquinone to form fumarate and reduced ubiquone which then can transfer electrons to cytochrome C through Complex III. The crystal structure of this complex has recently been solved by Yankovskaya et al. who have shown that the arrangement of the redox-active sites in the complex minimizes potential oxidation of bound FADH2 by dioxygen, minimizing production of harmful reactive oxygen species like superoxide.

Animation of electron transport in mitochondria

Jmol: Updated Succinate Dehydrogenase (Complex II) Jmol14 (Java) | JSMol (HTML5)

At each complex, the energy released by the oxidative event is used to drive protons through each complex from the matrix to the intermembrane space of the mitochondria, and is not used to form a high energy mixed anhydride as we saw in the glyceraldehyde-3-phosphate dehydrogenase reaction. The actual mechanism of proton transfer is unclear.

Figure: ELECTRON TRANSPORT AND PROTON GRADIENT FORMATION IN THE MITOCHONDRIA


Molecular and Cellular Regulation of Adaptation to Exercise

6.2 Mitochondrial Biogenesis

Mitochondrial biogenesis is a major adaption of skeletal muscle to exercise training and is induced by a complex interplay between numerous signaling pathways that respond to metabolic, mechanical, and hypoxic stresses that are generated within the myocyte during contraction. Adipocytes are highly plastic and mitochondrial biogenesis can be induced by pharmacological interventions in both isolated cells and free-living animals. Currently, there is a paucity of data describing the effects of exercise on mitochondrial biogenesis and its relevance for adipocyte function. Swim training in mice increases the mRNA/protein levels of key transcriptional regulators of mitochondrial biogenesis and increases mitochondrial DNA content in subcutaneous adipose tissue. 93 In support of these findings, the expression of genes involved in oxidative phosphorylation was increased following 6 months of endurance training, but notably, mitochondrial mass and function were not assessed. 94 We are aware of only one study to directly examine exercise training on adipocyte mitochondrial biogenesis in humans. Camera et al. 95 reported no change in adipose tissue citrate synthase activity, mitochondrial volume, or expression of genes that predict increased oxidative capacity after 10 days of endurance training in untrained men. While the length of the training program might explain differences between these human studies, the actual requirement for adipocyte mitochondrial biogenesis with exercise training is uncertain because ATP turnover (oxygen uptake) is not actually increased during acute exercise. 26 At present, there is much to be learned about the magnitude of mitochondrial biogenesis in adipocytes, the potential drivers of this process (most likely endocrine related), and even the requirement for biogenesis in sustaining metabolic functions after exercise training.

A major issue faced with examining adipocyte adaptations is the marked heterogeneity of cells in adipose tissue. Hence, a measure of a cellular or molecular response in adipose tissue cannot be regarded as a change in adipocyte function per se and caution must be taken when interpreting studies of molecular adaptation in adipose tissue.


Mitochondria are thought to have evolved from free-living bacteria that developed into a symbiotic relationship with a prokaryotic cell, providing it energy in return for a safe place to live. It eventually became an organelle, a specialized structure within the cell, the presence of which are used to distinguish eukaryotic cells from prokaryotic cells. This occurred over a long process of millions of years, and now the mitochondria inside the cell cannot live separately from it. The idea that mitochondria evolved this way is called endosymbiotic theory.

Endosymbiotic theory has multiple forms of evidence. For example, mitochondria have their own DNA that is separate from the DNA in the cell’s nucleus. It is called mitochondrial DNA or mtDNA, and it is only passed down through females because sperm do not have mitochondria. You received your mtDNA from your mother, and you can only pass it on if you are a female who has a child. It is also circular, like bacterial DNA. Another form of evidence is the way new mitochondria are created in the cell. New mitochondria only arise from binary fission, or splitting, which is the same way that bacteria asexually reproduce. If all of the mitochondria are removed from a cell, it can’t make new ones because there are no existing mitochondria there to split. Also, the genome of mitochondria and Rickettsia bacteria (bacteria that can cause spotted fever and typhus) have been compared, and the sequence is so similar that it suggests that mitochondria are closely related to Rickettsia.

Chloroplasts, the organelles in plants where photosynthesis occurs, are also thought to have evolved from endosymbiotic bacteria for similar reasons: they have separate, circular DNA, a double membrane structure, and split through binary fission.

1. Which is a function of mitochondria?
A. Regulating metabolism
B. Producing ATP
C. Storing calcium
D. All of the above

2. Which is NOT a reason why mitochondria are thought to have evolved from free-living bacteria?
A. Mitochondria have their own DNA.
B. Mitochondria reproduce through binary fission.
C. Mitochondrial DNA is inherited matrilineally.
D. The genome is similar to that of bacterial DNA.

3. Where is the mitochondrial matrix located?
A. Within the inner membrane
B. Between the inner and outer membrane
C. Inside the mtDNA
D. In the intermembrane space


Mitochondrial Dysfunction and Fatigue

Mitochondrial dysfunction is directly related to excess fatigue. Fatigue is considered a multidimensional sensation that is perceived to be a loss of overall energy and an inability to perform even simple tasks without exertion.53,54 Although mild fatigue can be caused by a number of conditions, including depression and other psychological conditions, moderate to severe fatigue involves cellular energy systems.53,54 At the cellular level, moderate to severe fatigue is related to loss of mitochondrial function and diminished production of ATP.54� Intractable fatigue lasting more than 6 months that is not reversed by sleep (chronic fatigue) is the most common complaint of patients seeking general medical care.53,57 Chronic fatigue is also an important secondary condition in many clinical diagnoses, often preceding patients’ primary diagnoses.57,58

As a result of aging and chronic diseases, oxidative damage to mitochondrial membranes impairs mitochondrial function.59� As an example, individuals with chronic fatigue syndrome present with evidence of oxidative damage to DNA and lipids,61,62 such as oxidized blood markers63 and oxidized membrane lipids,64 that is indicative of excess oxidative stress. These individuals also have sustained, elevated levels of peroxynitrite caused by excess nitric oxide, which can also result in lipid peroxidation and loss of mitochondrial function as well as changes in cytokine levels that exert a positive feedback on nitric oxide production.65


Mitochondrion Function

Mitochondria are involved in breaking down sugars and fats into energy through aerobic respiration (cellular respiration). This metabolic process creates ATP, the energy source of a cell, through a series of steps that require oxygen. Cellular respiration involves three main stages.


The figure shows an overview of cellular respiration. Glycolysis takes place in the cytosol while the Krebs cycle and oxidative phosphorylation occur in the mitochondria.

Glycolysis

Glycolysis occurs in the cytosol, splitting glucose into two smaller sugars which are then oxidized to form pyruvate. Glycolysis can be either anaerobic or aerobic, and as such is not technically part of cellular respiration, although it is often included. It produces a small amount of ATP.

During glycolysis the starting glucose molecule is phosphorylated (using one ATP molecule), forming glucose-6-phosphate, which then rearranges to its isomer fructose-6-phosphate. The molecule is again phosphorylated (using a second ATP molecule), this time forming fructose-1,6-bisphosphate. Fructose-1,6-bisphosphate is then split into two 3-carbon sugars which are converted to pyruvate molecules through a redox reaction, which produces two NADH molecules, and substrate-level phosphorylation, which releases four molecules of ATP. Glycolysis produces a net two ATP molecules.

Citric Acid Cycle

In the presence of oxygen, the pyruvate molecules produced in glycolysis enter the mitochondrion. The citric acid cycle, or Krebs cycle, occurs in the mitochondrial matrix. This process breaks down pyruvate into carbon dioxide in an oxidation reaction. The citric acid cycle results in the formation of NADH (from NAD + ) which transports electrons to the final stage of cellular respiration. The citric acid cycle produces two ATP molecules.

Pyruvate enters the mitochondrion and is converted into acetyl coenzyme A. This conversion is catalyzed by enzymes, produces NADH, and releases CO2. The acetyl group then enters the citric acid cycle, a series of eight enzyme-catalyzed steps that begins with citrate and ends in oxaloacetate. The addition of the acetyl group to oxaloacetate forms citrate and the cycle repeats. The breakdown of citrate into oxaloacetate releases a further two CO2 molecules and one molecule of ATP (through substrate-level phosphorylation). The majority of the energy is in the reduced coenzymes NADH and FADH2. These molecules are then transported to the electron transport chain.


The figure shows the conversion of pyruvate into acetyl coenzyme A and its progression through the citric acid cycle.

Oxidative Phosphorylation

Oxidative phosphorylation consists of two parts: the electron transport chain and chemiosmosis. It is this final stage that produces the bulk of the ATP in the respiration process. The electron transport chain uses the electrons carried forward from the previous two steps (as NADH and FADH2) to form water molecules through combination with oxygen and hydrogen ions. Oxidative phosphorylation occurs in the inner membrane of the mitochondrion.

The electron transport chain is made up of five multi-protein complexes (I to IV) that are repeated hundreds to thousands of times in the cristae of the inner membrane. The complexes are made up of electron carriers that transport the electrons released from NADH and FADH2 through a series of redox reactions. Many of the proteins found in the electron transport chain are cytochromes, proteins that are encoded for in part by mitochondrial DNA. As the electrons move along the chain they are passed to increasingly more electronegative molecules. The final step is the transfer of the electron to an oxygen atom which combines with two hydrogen ions to form a water molecule. The electron transport chain itself does not produce ATP.

ATP is produced via chemiosmosis, a process that also occurs in the inner membrane of the mitochondrion. Chemiosmosis involves the transmembrane protein ATP synthase which produces ATP from ADP and inorganic phosphate. ATP synthase uses the concentration gradient of hydrogen ions to drive the formation of ATP. As the electrons move through the electron transport chain, hydrogen ions are pushed out into the intermembrane space, producing a higher concentration of H + outside the membrane. The consumption of H + through incorporation into water molecules further increases the concentration gradient. The hydrogen ions then try to re-enter the mitochondrial matrix to equalize the concentrations the only place they can cross the membrane is through the ATP synthase. The flow of H + through the enzyme results in conformational changes that provide catalytic active sites for ADP and inorganic phosphate. When these two molecules bind to the ATP synthase they are connected and catalyzed to form ATP.

Oxidative phosphorylation produces between 32 and 34 ATP molecules from each initial glucose molecule, accounting for

89% of the energy produced in cellular respiration.

1. Which step of cellular respiration produces the most ATP?
A. Krebs cycle
B. Glycolysis
C. Citric acid cycle
D. Chemiosmosis

89% of the ATP in cellular respiration.

2. Where does oxidative phosphorylation occur?
A. Mitochondrial matrix
B. Outer membrane
C. Inner membrane
D. Intermembrane space

3. What organisms do not contain mitochondria?
A. Plants
B. Animals
C. Bacteria
D. Fungi


The Electron Transport System of Mitochondria

Embedded in the inner membrane are proteins and complexes of molecules that are involved in the process called electron transport. The electron transport system (ETS), as it is called, accepts energy from carriers in the matrix and stores it to a form that can be used to phosphorylate ADP. Two energy carriers are known to donate energy to the ETS, namely nicotine adenine dinucleotide (NAD) and flavin adenine dinucleotide (FAD). Reduced NAD carries energy to complex I (NADH-Coenzyme Q Reductase) of the electron transport chain. FAD is a bound part of the succinate dehydrogenase complex (complex II).

It is reduced when the substrate succinate binds the complex.

What happens when NADH binds to complex I? It binds to a prosthetic group called flavin mononucleotide (FMN), and is immediately re-oxidized to NAD. NAD is"recycled," acting as an energy shuttle. What happens to the hydrogen atom that comes off the NADH? FMN receives the hydrogen from the NADH and two electrons. It also picks up a proton from the matrix. In this reduced form, it passes the electrons to iron-sulfur clusters that are part of the complex, and forces two protons into the intermembrane space.

The obligatory forcing of protons into the intermembrane space is a key concept. Electrons cannot pass through complex I without accomplishing proton translocation. If you prevent the proton translocation, you prevent electron transport. If you prevent electron transport, you prevent proton translocation. The events must happen together or not at all.

Electron transport carriers are specific, in that each carrier accepts electrons (and associated free energy) from a specific type of preceeding carrier. Electrons pass from complex I to a carrier (Coenzyme Q) embedded by itself in the membrane. From Coenzyme Q electrons are passed to a complex III which is associated with another proton translocation event. Note that the path of electrons is from Complex I to Coenzyme Q to Complex III. Complex II, the succinate dehydrogenase complex, is a separate starting point, and is not a part of the NADH pathway.

From Complex III the pathway is to cytochrome c then to a Complex IV (cytochrome oxidase complex). More protons are translocated by Complex IV, and it is at this site that oxygen binds, along with protons, and using the electron pair and remaining free energy, oxygen is reduced to water. Since molecular oxygen is diatomic, it actually takes two electron pairs and two cytochrome oxidase complexes to complete the reaction sequence for the reduction of oxygen. This last step in electron transport serves the critical function of removing electrons from the system so that electron transport can operate continuously.

The reduction of oxygen is not an end in itself. Oxygen serves as an electron acceptor, clearing the way for carriers in the sequence to be reoxidized so that electron transport can continue. In your mitochondria, in the absence of oxygen, or in the presence of a poison such as cyanide, there is no outlet for electrons. All carriers remain reduced and Krebs products become out of balance because some Krebs reactions require NAD or FAD and some do not. However, you don't really care about that because you are already dead. The purpose of electron transport is to conserve energy in the form of a chemiosmotic gradient. The gradient, in turn, can be exploited for the phosphorylation of ADP as well as for other purposes. With the cessation of aerobic metabolism cell damage is immediate and irreversible.

From succinate, the sequence is Complex II to Coenzyme Q to Complex III to cytochrome c to Complex IV. Thus there is a common electron transport pathway beyond the entry point, either Complex I or Complex II. Protons are not translocated at Complex II. There isn't sufficient free energy available from the succinate dehydrogenase reaction to reduce NAD or to pump protons at more than two sites.

Is the ETS a sequence?

Before the development of the fluid mosaic model of membranes, the ETS was pictured as a chain, in which each complex was fixed in position relative to the next. Now it is accepted that while the complexes form 'islands' in the fluid membrane, they move independently of one another, and exchange electrons when they are in mutual proximity. Textbooks necessarily show the ETS as a physical sequence of complexes and carriers. This has the unintentional effect of implying that they are all locked in place. The fluid nature of membranes allows electron exchange to take place in a test tube containing membrane fragments.

The location of ETS complexes on the inner membrane has two major consequences. By floating in two-dimensional space, the likelihood of carriers making an exchange is much higher than if they were in solution in the three dimensional space of the matrix. They are exposed to the matrix side of the membrane, of course, for access to succinate and NADH, but have limited mobility. Second, the location of the ETS on the inner membrane enables them to establish a chemiosmotic gradient.

Electron pathways and inhibition

Electron transport inhibitors act by binding one or more electron carriers, preventing electron transport directly. Changes in the rate of dissipation of the chemiosmotic gradient have no effect on the rate of electron transport with such inhibition. In fact, if electron transport is blocked the chemiosmotic gradient cannot be maintained. No matter what substrate is used to fuel electron transport, only two entry points into the electron transport system are known to be used by mitochondria. A consequence of having separate pathways for entry of electrons is that an ETS inhibitor can affect one part of a pathway without interfering with another part. Respiration can still occur depending on choice of substrate.

An inhibitor may competely block electron transport by irreversibly binding to a binding site. For example, cyanide binds cytochrome oxidase so as to prevent the binding of oxygen. Electron transport is reduced to zero. Breathe all you want - you can't use any of the oxygen you take in. Rotenone, on the other hand, binds competitively, so that a trickle of electron flow is permitted. However, the rate of electron transport is too slow for maintenance of a gradient.


Footnotes

Published by the Royal Society under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/4.0/, which permits unrestricted use, provided the original author and source are credited.

References

Newmeyer DD, Ferguson-Miller S

. 2003 Mitochondria: releasing power for life and unleashing the machineries of death . Cell 112, 481–490. (doi:10.1016/S0092-8674(03)00116-8) Crossref, PubMed, Google Scholar

. 2012 Mitochondria: in sickness and in health . Cell 148, 1145–1159. (doi:10.1016/j.cell.2012.02.035) Crossref, PubMed, ISI, Google Scholar

Rizzuto R, De Stefani D, Raffaello A, Mammucari C

. 2012 Mitochondria as sensors and regulators of calcium signalling . Nat. Rev. Mol. Cell Biol . 13, 566–578. (doi:10.1038/nrm3412) Crossref, PubMed, ISI, Google Scholar

. 2013 The role of mitochondria in cellular iron-sulfur protein biogenesis: mechanisms, connected processes, and diseases . Cold Spring Harb. Perspect. Biol . 5, a011312. (doi:10.1101/cshperspect.a011312) Crossref, PubMed, ISI, Google Scholar

. 2014 Mitochondrial form and function . Nature 505, 335–343. (doi:10.1038/nature12985) Crossref, PubMed, ISI, Google Scholar

Tatsuta T, Scharwey M, Langer T

. 2014 Mitochondrial lipid trafficking . Trends Cell Biol . 24, 44–52. (doi:10.1016/j.tcb.2013.07.011) Crossref, PubMed, Google Scholar

Dolezal P, Likic V, Tachezy J, Lithgow T

. 2006 Evolution of the molecular machines for protein import into mitochondria . Science 313, 314–318. (doi:10.1126/science.1127895) Crossref, PubMed, ISI, Google Scholar

2016 A eukaryote without a mitochondrial organelle . Curr. Biol . 26, 1274–1284. (doi:10.1016/j.cub.2016.03.053) Crossref, PubMed, ISI, Google Scholar

. 2016 Late acquisition of mitochondria by a host with chimaeric prokaryotic ancestry . Nature 531, 101–104. (doi:10.1038/nature16941) Crossref, PubMed, ISI, Google Scholar

. 2005 A mitochondrial paradigm of metabolic and degenerative diseases, aging, and cancer: a dawn for evolutionary medicine . Annu. Rev. Genet . 39, 359–407. (doi:10.1146/annurev.genet.39.110304.095751) Crossref, PubMed, ISI, Google Scholar

. 1952 The fine structure of mitochondria . Anat. Rec . 114, 427–451. (doi:10.1002/ar.1091140304) Crossref, PubMed, Google Scholar

. 2013 Mitochondrial dynamics in the regulation of nutrient utilization and energy expenditure . Cell Metab . 17, 491–506. (doi:10.1016/j.cmet.2013.03.002) Crossref, PubMed, Google Scholar

2014 Uniform nomenclature for the mitochondrial contact site and cristae organizing system . J. Cell Biol . 204, 1083–1086. (doi:10.1083/jcb.201401006) Crossref, PubMed, ISI, Google Scholar

. 2016 Mito-morphosis: mitochondrial fusion, fission, and cristae remodeling as key mediators of cellular function . Annu. Rev. Physiol . 78, 505–531. (doi:10.1146/annurev-physiol-021115-105011) Crossref, PubMed, Google Scholar

2003 The proteome of Saccharomyces cerevisiae mitochondria . Proc. Natl Acad. Sci. USA 100, 13 207–13 212. (doi:10.1073/pnas.2135385100) Crossref, Google Scholar

Calvo SE, Clauser KR, Mootha VK

. 2016 MitoCarta2.0: an updated inventory of mammalian mitochondrial proteins . Nucleic Acids Res . 44, D1251–D1257. (doi:10.1093/nar/gkv1003) Crossref, PubMed, ISI, Google Scholar

. 2014 Making proteins in the powerhouse . Cell Metab . 20, 226–240. (doi:10.1016/j.cmet.2014.07.001) Crossref, PubMed, ISI, Google Scholar

Lightowlers RN, Rozanska A, Chrzanowska-Lightowlers ZM

. 2014 Mitochondrial protein synthesis: figuring the fundamentals, complexities and complications, of mammalian mitochondrial translation . FEBS Lett . 588, 2496–2503. (doi:10.1016/j.febslet.2014.05.054) Crossref, PubMed, Google Scholar

. 2007 Translocation of proteins into mitochondria . Annu. Rev. Biochem . 76, 723–749. (doi:10.1146/annurev.biochem.76.052705.163409) Crossref, PubMed, ISI, Google Scholar

. 2011 Structural insight into the mitochondrial protein import system . Biochim. Biophys. Acta 1808, 955–970. (doi:10.1016/j.bbamem.2010.07.018) Crossref, PubMed, Google Scholar

Dudek J, Rehling P, van der Laan M

. 2013 Mitochondrial protein import: common principles and physiological networks . Biochim. Biophys. Acta 1833, 274–285. (doi:10.1016/j.bbamcr.2012.05.028) Crossref, PubMed, Google Scholar

Harbauer AB, Zahedi RP, Sickmann A, Pfanner N, Meisinger C

. 2014 The protein import machinery of mitochondria—a regulatory hub in metabolism, stress, and disease . Cell Metab . 19, 357–372. (doi:10.1016/j.cmet.2014.01.010) Crossref, PubMed, ISI, Google Scholar

Wasilewski M, Chojnacka K, Chacinska A

. 2016 Protein trafficking at the crossroads to mitochondria . Biochim. Biophys. Acta 1864, 125–137. (doi:10.1016/j.bbamcr.2016.10.019) Crossref, Google Scholar

Straub SP, Stiller SB, Wiedemann N, Pfanner N

. 2016 Dynamic organization of the mitochondrial protein import machinery . Biol. Chem . 397, 1097–1114. (doi:10.1515/hsz-2016-0145) Crossref, PubMed, Google Scholar

. 2012 Mitochondrial quality control: a matter of life and death for neurons . EMBO J . 31, 1336–1349. (doi:10.1038/emboj.2012.38) Crossref, PubMed, Google Scholar

. 2013 Chaperone-protease networks in mitochondrial protein homeostasis . Biochim. Biophys. Acta 1833, 388–399. (doi:10.1016/j.bbamcr.2012.06.005) Crossref, PubMed, Google Scholar

Soubannier V, McLelland GL, Zunino R, Braschi E, Rippstein P, Fon EA, McBride HM

. 2012 A vesicular transport pathway shuttles cargo from mitochondria to lysosomes . Curr. Biol . 22, 135–141. (doi:10.1016/j.cub.2011.11.057) Crossref, PubMed, ISI, Google Scholar

Sugiura A, McLelland GL, Fon EA, McBride HM

. 2014 A new pathway for mitochondrial quality control: mitochondrial-derived vesicles . EMBO J . 33, 2142–2156. (doi:10.15252/embj.201488104) Crossref, PubMed, ISI, Google Scholar

Hughes AL, Hughes CE, Henderson KA, Yazvenko N, Gottschling DE

. 2016 Selective sorting and destruction of mitochondrial membrane proteins in aged yeast . Elife 5, e13943. (doi:10.7554/eLife.13943) Crossref, PubMed, Google Scholar

Groll M, Bajorek M, Kohler A, Moroder L, Rubin DM, Huber R, Glickman MH, Finley D

. 2000 A gated channel into the proteasome core particle . Nat. Struct. Biol . 7, 1062–1067. (doi:10.1038/80992) Crossref, PubMed, Google Scholar

Besche HC, Peth A, Goldberg AL

. 2009 Getting to first base in proteasome assembly . Cell 138, 25–28. (doi:10.1016/j.cell.2009.06.035) Crossref, PubMed, Google Scholar

Livneh I, Cohen-Kaplan V, Cohen-Rosenzweig C, Avni N, Ciechanover A

. 2016 The life cycle of the 26S proteasome: from birth, through regulation and function, and onto its death . Cell Res . 26, 869–885. (doi:10.1038/cr.2016.86) Crossref, PubMed, Google Scholar

. 2009 Recognition and processing of ubiquitin-protein conjugates by the proteasome . Annu. Rev. Biochem . 78, 477–513. (doi:10.1146/annurev.biochem.78.081507.101607) Crossref, PubMed, ISI, Google Scholar

. 2014 The complexity of recognition of ubiquitinated substrates by the 26S proteasome . Biochim. Biophys. Acta 1843, 86–96. (doi:10.1016/j.bbamcr.2013.07.007) Crossref, PubMed, Google Scholar

. 2016 Ubiquitin chain diversity at a glance . J. Cell Sci . 129, 875–880. (doi:10.1242/jcs.183954) Crossref, PubMed, ISI, Google Scholar

Stewart MD, Ritterhoff T, Klevit RE, Brzovic PS

. 2016 E2 enzymes: more than just middle men . Cell Res . 26, 423–440. (doi:10.1038/cr.2016.35) Crossref, PubMed, ISI, Google Scholar

2012 The size of the proteasomal substrate determines whether its degradation will be mediated by mono- or polyubiquitylation . Mol Cell 48, 87–97. (doi:10.1016/j.molcel.2012.07.011) Crossref, PubMed, Google Scholar

Nijman SM, Luna-Vargas MP, Velds A, Brummelkamp TR, Dirac AM, Sixma TK, Bernards R

. 2005 A genomic and functional inventory of deubiquitinating enzymes . Cell 123, 773–786. (doi:10.1016/j.cell.2005.11.007) Crossref, PubMed, ISI, Google Scholar

Peng J, Schwartz D, Elias JE, Thoreen CC, Cheng D, Marsischky G, Roelofs J, Finley D, Gygi SP

. 2003 A proteomics approach to understanding protein ubiquitination . Nat. Biotechnol . 21, 921–926. (doi:10.1038/nbt849) Crossref, PubMed, Google Scholar

Matsumoto M, Hatakeyama S, Oyamada K, Oda Y, Nishimura T, Nakayama KI

. 2005 Large-scale analysis of the human ubiquitin-related proteome . Proteomics 5, 4145–4151. (doi:10.1002/pmic.200401280) Crossref, PubMed, Google Scholar

Jeon HB, Choi ES, Yoon JH, Hwang JH, Chang JW, Lee EK, Choi HW, Park ZY, Yoo YJ

. 2007 A proteomics approach to identify the ubiquitinated proteins in mouse heart . Biochem. Biophys. Res. Commun . 357, 731–736. (doi:10.1016/j.bbrc.2007.04.015) Crossref, PubMed, Google Scholar

. 2005 Role of essential genes in mitochondrial morphogenesis in Saccharomyces cerevisiae . Mol. Biol. Cell 16, 5410–5417. (doi:10.1091/mbc.E05-07-0678) Crossref, PubMed, Google Scholar

Fritz S, Weinbach N, Westermann B

. 2003 Mdm30 is an F-box protein required for maintenance of fusion-competent mitochondria in yeast . Mol. Biol. Cell 14, 2303–2313. (doi:10.1091/mbc.E02-12-0831) Crossref, PubMed, Google Scholar

. 2003 The yeast deubiquitinating enzyme Ubp16 is anchored to the outer mitochondrial membrane . FEBS Lett . 549, 135–140. (doi:10.1016/S0014-5793(03)00801-9) Crossref, PubMed, Google Scholar

Nakamura N, Kimura Y, Tokuda M, Honda S, Hirose S

. 2006 MARCH-V is a novel mitofusin 2- and Drp1-binding protein able to change mitochondrial morphology . EMBO Rep . 7, 1019–1022. (doi:10.1038/sj.embor.7400790) Crossref, PubMed, Google Scholar

2006 A novel mitochondrial ubiquitin ligase plays a critical role in mitochondrial dynamics . EMBO J . 25, 3618–3626. (doi:10.1038/sj.emboj.7601249) Crossref, PubMed, Google Scholar

Karbowski M, Neutzner A, Youle RJ

. 2007 The mitochondrial E3 ubiquitin ligase MARCH5 is required for Drp1 dependent mitochondrial division . J. Cell Biol . 178, 71–84. (doi:10.1083/jcb.200611064) Crossref, PubMed, Google Scholar

Li W, Bengtson MH, Ulbrich A, Matsuda A, Reddy VA, Orth A, Chanda SK, Batalov S, Joazeiro CA

. 2008 Genome-wide and functional annotation of human E3 ubiquitin ligases identifies MULAN, a mitochondrial E3 that regulates the organelle's dynamics and signaling . PLoS ONE 3, e1487. (doi:10.1371/journal.pone.0001487) Crossref, PubMed, ISI, Google Scholar

. 2008 Regulation of mitochondrial morphology by USP30, a deubiquitinating enzyme present in the mitochondrial outer membrane . Mol. Biol. Cell 19, 1903–1911. (doi:10.1091/mbc.E07-11-1103) Crossref, PubMed, Google Scholar

2008 GIDE is a mitochondrial E3 ubiquitin ligase that induces apoptosis and slows growth . Cell Res . 18, 900–910. (doi:10.1038/cr.2008.75) Crossref, PubMed, Google Scholar

Cohen MM, Amiott EA, Day AR, Leboucher GP, Pryce EN, Glickman MH, McCaffery JM, Shaw JM, Weissman AM

. 2011 Sequential requirements for the GTPase domain of the mitofusin Fzo1 and the ubiquitin ligase SCFMdm30 in mitochondrial outer membrane fusion . J. Cell Sci . 124, 1403–1410. (doi:10.1242/jcs.079293) Crossref, PubMed, ISI, Google Scholar

2013 Mutations in FBXL4 cause mitochondrial encephalopathy and a disorder of mitochondrial DNA maintenance . Am. J. Hum. Genet . 93, 471–481. (doi:10.1016/j.ajhg.2013.07.017) Crossref, PubMed, ISI, Google Scholar

2013 Mutations in FBXL4, encoding a mitochondrial protein, cause early-onset mitochondrial encephalomyopathy . Am. J. Hum. Genet . 93, 482–495. (doi:10.1016/j.ajhg.2013.07.016) Crossref, PubMed, Google Scholar

Cilenti L, Ambivero CT, Ward N, Alnemri ES, Germain D, Zervos AS

. 2014 Inactivation of Omi/HtrA2 protease leads to the deregulation of mitochondrial Mulan E3 ubiquitin ligase and increased mitophagy . Biochim. Biophys. Acta 1843, 1295–1307. (doi:10.1016/j.bbamcr.2014.03.027) Crossref, PubMed, Google Scholar

Narendra D, Tanaka A, Suen DF, Youle RJ

. 2008 Parkin is recruited selectively to impaired mitochondria and promotes their autophagy . J. Cell Biol . 183, 795–803. (doi:10.1083/jcb.200809125) Crossref, PubMed, Google Scholar

2011 SCF(FBW7) regulates cellular apoptosis by targeting MCL1 for ubiquitylation and destruction . Nature 471, 104–109. (doi:10.1038/nature09732) Crossref, PubMed, Google Scholar

Tang F, Wang B, Li N, Wu Y, Jia J, Suo T, Chen Q, Liu YJ, Tang J

. 2011 RNF185, a novel mitochondrial ubiquitin E3 ligase, regulates autophagy through interaction with BNIP1 . PLoS ONE 6, e24367. (doi:10.1371/journal.pone.0024367) Crossref, PubMed, Google Scholar

2013 The Parkinson's disease-linked proteins Fbxo7 and Parkin interact to mediate mitophagy . Nat. Neurosci . 16, 1257–1265. (doi:10.1038/nn.3489) Crossref, PubMed, Google Scholar

Benard G, Neutzner A, Peng G, Wang C, Livak F, Youle RJ, Karbowski M

. 2010 IBRDC2, an IBR-type E3 ubiquitin ligase, is a regulatory factor for Bax and apoptosis activation . EMBO J . 29, 1458–1471. (doi:10.1038/emboj.2010.39) Crossref, PubMed, Google Scholar

Lehmann G, Ziv T, Braten O, Admon A, Udasin RG, Ciechanover A

. 2016 Ubiquitination of specific mitochondrial matrix proteins . Biochem. Biophys. Res. Commun . 475, 13–18. (doi:10.1016/j.bbrc.2016.04.150) Crossref, PubMed, Google Scholar

. 2016 Doa1 targets ubiquitinated substrates for mitochondria-associated degradation . J. Cell Biol . 213, 49–63. (doi:10.1083/jcb.201510098) Crossref, PubMed, Google Scholar

Nakagawa T, Shirane M, Iemura S, Natsume T, Nakayama KI

. 2007 Anchoring of the 26S proteasome to the organellar membrane by FKBP38 . Genes Cells 12, 709–719. (doi:10.1111/j.1365-2443.2007.01086.x) PubMed, Google Scholar

. 2010 Degradation of an intramitochondrial protein by the cytosolic proteasome . J. Cell Sci . 123, 578–585. (doi:10.1242/jcs.060004) Crossref, PubMed, Google Scholar

Chan NC, Salazar AM, Pham AH, Sweredoski MJ, Kolawa NJ, Graham RL, Hess S, Chan DC

. 2011 Broad activation of the ubiquitin-proteasome system by Parkin is critical for mitophagy . Hum. Mol. Genet . 20, 1726–1737. (doi:10.1093/hmg/ddr048) Crossref, PubMed, Google Scholar

Yoshii SR, Kishi C, Ishihara N, Mizushima N

. 2011 Parkin mediates proteasome-dependent protein degradation and rupture of the outer mitochondrial membrane . J. Biol. Chem . 286, 19 630–19 640. (doi:10.1074/jbc.M110.209338) Crossref, Google Scholar

Heinemeyer W, Trondle N, Albrecht G, Wolf DH

. 1994 PRE5 and PRE6, the last missing genes encoding 20S proteasome subunits from yeast? Indication for a set of 14 different subunits in the eukaryotic proteasome core . Biochemistry 33, 12 229–12 237. (doi:10.1021/bi00206a028) Crossref, Google Scholar

2006 MMI1 (YKL056c, TMA19), the yeast orthologue of the translationally controlled tumor protein (TCTP) has apoptotic functions and interacts with both microtubules and mitochondria . Biochim. Biophys. Acta 1757, 631–638. (doi:10.1016/j.bbabio.2006.05.022) Crossref, PubMed, Google Scholar

Cohen MM, Leboucher GP, Livnat-Levanon N, Glickman MH, Weissman AM

. 2008 Ubiquitin-proteasome-dependent degradation of a mitofusin, a critical regulator of mitochondrial fusion . Mol. Biol. Cell 19, 2457–2464. (doi:10.1091/mbc.E08-02-0227) Crossref, PubMed, Google Scholar

Ziviani E, Tao RN, Whitworth AJ

. 2010 Drosophila parkin requires PINK1 for mitochondrial translocation and ubiquitinates mitofusin . Proc. Natl Acad. Sci. USA 107, 5018–5023. (doi:10.1073/pnas.0913485107) Crossref, PubMed, Google Scholar

Park YY, Lee S, Karbowski M, Neutzner A, Youle RJ, Cho H

. 2010 Loss of MARCH5 mitochondrial E3 ubiquitin ligase induces cellular senescence through dynamin-related protein 1 and mitofusin 1 . J. Cell Sci . 123, 619–626. (doi:10.1242/jcs.061481) Crossref, PubMed, Google Scholar

2013 MITOL regulates endoplasmic reticulum-mitochondria contacts via Mitofusin2 . Mol. Cell 51, 20–34. (doi:10.1016/j.molcel.2013.04.023) Crossref, PubMed, Google Scholar

2016 Mitochondrial E3 ubiquitin ligase MARCH5 controls mitochondrial fission and cell sensitivity to stress-induced apoptosis through regulation of MiD49 protein . Mol. Biol. Cell 27, 349–359. (doi:10.1091/mbc.E15-09-0678) Crossref, PubMed, Google Scholar

2014 Proteasomes associated with the Blm10 activator protein antagonize mitochondrial fission through degradation of the fission protein Dnm1 . J. Biol. Chem . 289, 12 145–12 156. (doi:10.1074/jbc.M114.554105) Crossref, Google Scholar

Schmidt M, Haas W, Crosas B, Santamaria PG, Gygi SP, Walz T, Finley D

. 2005 The HEAT repeat protein Blm10 regulates the yeast proteasome by capping the core particle . Nat. Struct. Mol. Biol . 12, 294–303. (doi:10.1038/nsmb914) Crossref, PubMed, Google Scholar

Blickwedehl J, Agarwal M, Seong C, Pandita RK, Melendy T, Sung P, Pandita TK, Bangia N

. 2008 Role for proteasome activator PA200 and postglutamyl proteasome activity in genomic stability . Proc. Natl Acad. Sci. USA 105, 16 165–16 170. (doi:10.1073/pnas.0803145105) Crossref, Google Scholar

. 2013 PINK1 is degraded through the N-end rule pathway . Autophagy 9, 1758–1769. (doi:10.4161/auto.24633) Crossref, PubMed, Google Scholar

Jin SM, Lazarou M, Wang C, Kane LA, Narendra DP, Youle RJ

. 2010 Mitochondrial membrane potential regulates PINK1 import and proteolytic destabilization by PARL . J. Cell Biol . 191, 933–942. (doi:10.1083/jcb.201008084) Crossref, PubMed, ISI, Google Scholar

. 2013 The accumulation of misfolded proteins in the mitochondrial matrix is sensed by PINK1 to induce PARK2/Parkin-mediated mitophagy of polarized mitochondria . Autophagy 9, 1750–1757. (doi:10.4161/auto.26122) Crossref, PubMed, Google Scholar

2012 PINK1 is activated by mitochondrial membrane potential depolarization and stimulates Parkin E3 ligase activity by phosphorylating Serine 65 . Open Biol . 2, 120080. (doi:10.1098/rsob.120080) Link, Google Scholar

Kane LA, Lazarou M, Fogel AI, Li Y, Yamano K, Sarraf SA, Banerjee S, Youle RJ

. 2014 PINK1 phosphorylates ubiquitin to activate Parkin E3 ubiquitin ligase activity . J. Cell Biol . 205, 143–153. (doi:10.1083/jcb.201402104) Crossref, PubMed, ISI, Google Scholar

2014 Parkin is activated by PINK1-dependent phosphorylation of ubiquitin at Ser65 . Biochem. J . 460, 127–139. (doi:10.1042/BJ20140334) Crossref, PubMed, ISI, Google Scholar

2014 Ubiquitin is phosphorylated by PINK1 to activate parkin . Nature 510, 162–166. (doi:10.1038/nature13392) Crossref, PubMed, ISI, Google Scholar

2014 Phosphorylation of mitochondrial polyubiquitin by PINK1 promotes Parkin mitochondrial tethering . PLoS Genet . 10, e1004861. (doi:10.1371/journal.pgen.1004861) Crossref, PubMed, Google Scholar

Rose CM, Isasa M, Ordureau A, Prado MA, Beausoleil SA, Jedrychowski MP, Finley DJ, Harper JW, Gygi SP

. 2016 Highly multiplexed quantitative mass spectrometry analysis of ubiquitylomes . Cell Syst . 3, 395–403e394. (doi:10.1016/j.cels.2016.08.009) Crossref, PubMed, Google Scholar

2014 Quantitative proteomics reveal a feedforward mechanism for mitochondrial PARKIN translocation and ubiquitin chain synthesis . Mol. Cell 56, 360–375. (doi:10.1016/j.molcel.2014.09.007) Crossref, PubMed, ISI, Google Scholar

Tanaka A, Cleland MM, Xu S, Narendra DP, Suen DF, Karbowski M, Youle RJ

. 2010 Proteasome and p97 mediate mitophagy and degradation of mitofusins induced by Parkin . J. Cell Biol . 191, 1367–1380. (doi:10.1083/jcb.201007013) Crossref, PubMed, Google Scholar

2011 PINK1 and Parkin target Miro for phosphorylation and degradation to arrest mitochondrial motility . Cell 147, 893–906. (doi:10.1016/j.cell.2011.10.018) Crossref, PubMed, Google Scholar

2015 The E3 ubiquitin ligase parkin is recruited to the 26 S proteasome via the proteasomal ubiquitin receptor Rpn13 . J. Biol. Chem . 290, 7492–7505. (doi:10.1074/jbc.M114.614925) Crossref, PubMed, Google Scholar

Cunningham CN, Baughman JM, Phu L, Tea JS, Yu C, Coons M, Kirkpatrick DS, Bingol B, Corn JE

. 2015 USP30 and parkin homeostatically regulate atypical ubiquitin chains on mitochondria . Nat. Cell Biol. 17, 160–169. (doi:10.1038/ncb3097) Crossref, PubMed, Google Scholar

Akabane S, Matsuzaki K, Yamashita S, Arai K, Okatsu K, Kanki T, Matsuda N, Oka T

. 2016 Constitutive activation of PINK1 protein leads to proteasome-mediated and non-apoptotic cell death independently of mitochondrial autophagy . J. Biol. Chem . 291, 16 162–16 174. (doi:10.1074/jbc.M116.714923) Crossref, Google Scholar

. 2011 Regulating mitochondrial outer membrane proteins by ubiquitination and proteasomal degradation . Curr. Opin. Cell Biol . 23, 476–482. (doi:10.1016/j.ceb.2011.05.007) Crossref, PubMed, Google Scholar

. 2011 Mitochondrial quality control by the ubiquitin-proteasome system . Biochem. Soc. Trans . 39, 1509–1513. (doi:10.1042/BST0391509) Crossref, PubMed, Google Scholar

. 2005 Endoplasmic reticulum-associated degradation . Annu. Rev. Cell Dev. Biol . 21, 435–456. (doi:10.1146/annurev.cellbio.21.012704.133250) Crossref, PubMed, Google Scholar

. 2002 Retro-translocation of proteins from the endoplasmic reticulum into the cytosol . Nat. Rev. Mol. Cell Biol . 3, 246–255. (doi:10.1038/nrm780) Crossref, PubMed, Google Scholar

Hirsch C, Gauss R, Horn SC, Neuber O, Sommer T

. 2009 The ubiquitylation machinery of the endoplasmic reticulum . Nature 458, 453–460. (doi:10.1038/nature07962) Crossref, PubMed, Google Scholar

2010 A stress-responsive system for mitochondrial protein degradation . Mol. Cell 40, 465–480. (doi:10.1016/j.molcel.2010.10.021) Crossref, PubMed, Google Scholar

Xu S, Peng G, Wang Y, Fang S, Karbowski M

. 2011 The AAA-ATPase p97 is essential for outer mitochondrial membrane protein turnover . Mol. Biol. Cell 22, 291–300. (doi:10.1091/mbc.E10-09-0748) Crossref, PubMed, Google Scholar

Heo JM, Nielson JR, Dephoure N, Gygi SP, Rutter J

. 2013 Intramolecular interactions control Vms1 translocation to damaged mitochondria . Mol. Biol. Cell 24, 1263–1273. (doi:10.1091/mbc.E13-02-0072) Crossref, PubMed, Google Scholar

. 2012 Cdc48p/p97-mediated regulation of mitochondrial morphology is Vms1p-independent . J. Struct. Biol . 179, 112–120. (doi:10.1016/j.jsb.2012.04.017) Crossref, PubMed, Google Scholar

Cherok E, Xu S, Li S, Das S, Meltzer WA, Zalzman M, Wang C, Karbowski M

. 2016 Novel regulatory roles of Mff and Drp1 in E3 ubiquitin ligase MARCH5-dependent degradation of MiD49 and Mcl1 and control of mitochondrial dynamics . Mol. Biol. Cell 28, 396–410. (doi:10.1091/mbc.E16-04-0208) Crossref, PubMed, Google Scholar

Chen YC, Umanah GK, Dephoure N, Andrabi SA, Gygi SP, Dawson TM, Dawson VL, Rutter J

. 2014 Msp1/ATAD1 maintains mitochondrial function by facilitating the degradation of mislocalized tail-anchored proteins . EMBO J . 33, 1548–1564. (doi:10.15252/embj.201487943) Crossref, PubMed, Google Scholar

. 2014 The conserved AAA-ATPase Msp1 confers organelle specificity to tail-anchored proteins . Proc. Natl Acad. Sci. USA 111, 8019–8024. (doi:10.1073/pnas.1405755111) Crossref, PubMed, Google Scholar

Benischke AS, Hemion C, Flammer J, Neutzner A

. 2014 Proteasome-mediated quality control of S-nitrosylated mitochondrial proteins . Mitochondrion 17, 182–186. (doi:10.1016/j.mito.2014.04.001) Crossref, PubMed, Google Scholar

Margineantu DH, Emerson CB, Diaz D, Hockenbery DM

. 2007 Hsp90 inhibition decreases mitochondrial protein turnover . PLoS ONE 2, e1066. (doi:10.1371/journal.pone.0001066) Crossref, PubMed, Google Scholar

Radke S, Chander H, Schafer P, Meiss G, Kruger R, Schulz JB, Germain D

. 2008 Mitochondrial protein quality control by the proteasome involves ubiquitination and the protease Omi . J. Biol. Chem . 283, 12 681–12 685. (doi:10.1074/jbc.C800036200) Crossref, Google Scholar

Bragoszewski P, Gornicka A, Sztolsztener ME, Chacinska A

. 2013 The ubiquitin-proteasome system regulates mitochondrial intermembrane space proteins . Mol. Cell. Biol . 33, 2136–2148. (doi:10.1128/MCB.01579-12) Crossref, PubMed, ISI, Google Scholar

Quan EM, Kamiya Y, Kamiya D, Denic V, Weibezahn J, Kato K, Weissman JS

. 2008 Defining the glycan destruction signal for endoplasmic reticulum-associated degradation . Mol. Cell 32, 870–877. (doi:10.1016/j.molcel.2008.11.017) Crossref, PubMed, Google Scholar

Carvalho P, Stanley AM, Rapoport TA

. 2010 Retrotranslocation of a misfolded luminal ER protein by the ubiquitin-ligase Hrd1p . Cell 143, 579–591. (doi:10.1016/j.cell.2010.10.028) Crossref, PubMed, Google Scholar

Azzu V, Mookerjee SA, Brand MD

. 2010 Rapid turnover of mitochondrial uncoupling protein 3 . Biochem. J. 426, 13–17. (doi:10.1042/BJ20091321) Crossref, PubMed, Google Scholar

. 2011 Characteristics of the turnover of uncoupling protein 3 by the ubiquitin proteasome system in isolated mitochondria . Biochim. Biophys. Acta 1807, 1474–1481. (doi:10.1016/j.bbabio.2011.07.011) Crossref, PubMed, Google Scholar

Bragoszewski P, Wasilewski M, Sakowska P, Gornicka A, Bottinger L, Qiu J, Wiedemann N, Chacinska A

. 2015 Retro-translocation of mitochondrial intermembrane space proteins . Proc. Natl Acad. Sci. USA 112, 7713–7718. (doi:10.1073/pnas.1504615112) Crossref, PubMed, ISI, Google Scholar

Stojanovski D, Bragoszewski P, Chacinska A

. 2012 The MIA pathway: a tight bond between protein transport and oxidative folding in mitochondria . Biochim. Biophys. Acta 1823, 1142–1150. (doi:10.1016/j.bbamcr.2012.04.014) Crossref, PubMed, ISI, Google Scholar

. 2013 The mitochondrial intermembrane space: a hub for oxidative folding linked to protein biogenesis . Antioxid. Redox Signal 19, 54–62. (doi:10.1089/ars.2012.4855) Crossref, PubMed, Google Scholar

Gornicka A, Bragoszewski P, Chroscicki P, Wenz LS, Schulz C, Rehling P, Chacinska A

. 2014 A discrete pathway for the transfer of intermembrane space proteins across the outer membrane of mitochondria . Mol. Biol. Cell 25, 3999–4009. (doi:10.1091/mbc.E14-06-1155) Crossref, PubMed, ISI, Google Scholar

2009 Global analysis of the mitochondrial N-proteome identifies a processing peptidase critical for protein stability . Cell 139, 428–439. (doi:10.1016/j.cell.2009.07.045) Crossref, PubMed, Google Scholar

. 2011 The N-end rule pathway and regulation by proteolysis . Protein Sci . 20, 1298–1345. (doi:10.1002/pro.666) Crossref, PubMed, Google Scholar

Duttler S, Pechmann S, Frydman J

. 2013 Principles of cotranslational ubiquitination and quality control at the ribosome . Mol. Cell 50, 379–393. (doi:10.1016/j.molcel.2013.03.010) Crossref, PubMed, Google Scholar

Wang F, Durfee LA, Huibregtse JM

. 2013 A cotranslational ubiquitination pathway for quality control of misfolded proteins . Mol. Cell 50, 368–378. (doi:10.1016/j.molcel.2013.03.009) Crossref, PubMed, Google Scholar

Schubert U, Anton LC, Gibbs J, Norbury CC, Yewdell JW, Bennink JR

. 2000 Rapid degradation of a large fraction of newly synthesized proteins by proteasomes . Nature 404, 770–774. (doi:10.1038/35008096) Crossref, PubMed, Google Scholar

. 1997 Differential ubiquitin-dependent degradation of the yeast apo-cytochrome c isozymes . J. Biol. Chem . 272, 31 829–31 836. (doi:10.1074/jbc.272.50.31829) Crossref, Google Scholar

Itakura E, Zavodszky E, Shao S, Wohlever ML, Keenan RJ, Hegde RS

. 2016 Ubiquilins chaperone and triage mitochondrial membrane proteins for degradation . Mol. Cell 63, 21–33. (doi:10.1016/j.molcel.2016.05.020) Crossref, PubMed, Google Scholar

2011 Regulation of mitochondrial protein import by cytosolic kinases . Cell 144, 227–239. (doi:10.1016/j.cell.2010.12.015) Crossref, PubMed, Google Scholar

2014 Mitochondria. Cell cycle-dependent regulation of mitochondrial preprotein translocase . Science 346, 1109–1113. (doi:10.1126/science.1261253) Crossref, PubMed, Google Scholar

Ciryam P, Kundra R, Morimoto RI, Dobson CM, Vendruscolo M

. 2015 Supersaturation is a major driving force for protein aggregation in neurodegenerative diseases . Trends Pharmacol. Sci . 36, 72–77. (doi:10.1016/j.tips.2014.12.004) Crossref, PubMed, Google Scholar

Ciryam P, Kundra R, Freer R, Morimoto RI, Dobson CM, Vendruscolo M

. 2016 A transcriptional signature of Alzheimer's disease is associated with a metastable subproteome at risk for aggregation . Proc. Natl Acad. Sci. USA 113, 4753–4758. (doi:10.1073/pnas.1516604113) Crossref, PubMed, Google Scholar

Sung MK, Reitsma JM, Sweredoski MJ, Hess S, Deshaies RJ

. 2016 Ribosomal proteins produced in excess are degraded by the ubiquitin-proteasome system . Mol. Biol. Cell 27, 2642–2652. (doi:10.1091/mbc.E16-05-0290) Crossref, PubMed, Google Scholar

Cenini G, Rub C, Bruderek M, Voos W

. 2016 Amyloid beta-peptides interfere with mitochondrial preprotein import competence by a coaggregation process . Mol. Biol. Cell 27, 3257–3272. (doi:10.1091/mbc.E16-05-0313) Crossref, PubMed, Google Scholar

Young JC, Hoogenraad NJ, Hartl FU

. 2003 Molecular chaperones Hsp90 and Hsp70 deliver preproteins to the mitochondrial import receptor Tom70 . Cell 112, 41–50. (doi:10.1016/S0092-8674(02)01250-3) Crossref, PubMed, Google Scholar

Hessa T, Sharma A, Mariappan M, Eshleman HD, Gutierrez E, Hegde RS

. 2011 Protein targeting and degradation are coupled for elimination of mislocalized proteins . Nature 475, 394–397. (doi:10.1038/nature10181) Crossref, PubMed, Google Scholar

Rodrigo-Brenni MC, Gutierrez E, Hegde RS

. 2014 Cytosolic quality control of mislocalized proteins requires RNF126 recruitment to Bag6 . Mol. Cell 55, 227–237. (doi:10.1016/j.molcel.2014.05.025) Crossref, PubMed, Google Scholar

2016 UBQLN2 mediates autophagy-independent protein aggregate clearance by the proteasome . Cell 166, 935–949. (doi:10.1016/j.cell.2016.07.001) Crossref, PubMed, Google Scholar

2014 Organelle-based aggregation and retention of damaged proteins in asymmetrically dividing cells . Cell 159, 530–542. (doi:10.1016/j.cell.2014.09.026) Crossref, PubMed, Google Scholar

Sung MK, Porras-Yakushi TR, Reitsma JM, Huber FM, Sweredoski MJ, Hoelz A, Hess S, Deshaies RJ

. 2016 A conserved quality-control pathway that mediates degradation of unassembled ribosomal proteins . Elife 5, e19105. (doi:10.7554/eLife.19105) Crossref, PubMed, Google Scholar

. 1999 In vivo mitochondrial import. A comparison of leader sequence charge and structural relationships with the in vitro model resulting in evidence for co-translational import . J. Biol. Chem . 274, 12 685–12 691. (doi:10.1074/jbc.274.18.12685) Crossref, Google Scholar

Marc P, Margeot A, Devaux F, Blugeon C, Corral-Debrinski M, Jacq C

. 2002 Genome-wide analysis of mRNAs targeted to yeast mitochondria . EMBO Rep . 3, 159–164. (doi:10.1093/embo-reports/kvf025) Crossref, PubMed, ISI, Google Scholar

Williams CC, Jan CH, Weissman JS

. 2014 Targeting and plasticity of mitochondrial proteins revealed by proximity-specific ribosome profiling . Science 346, 748–751. (doi:10.1126/science.1257522) Crossref, PubMed, Google Scholar

Pechmann S, Willmund F, Frydman J

. 2013 The ribosome as a hub for protein quality control . Mol. Cell 49, 411–421. (doi:10.1016/j.molcel.2013.01.020) Crossref, PubMed, Google Scholar

. 2016 Ribosome-associated protein quality control . Nat. Struct. Mol. Biol . 23, 7–15. (doi:10.1038/nsmb.3147) Crossref, PubMed, Google Scholar

. 2017 The ribosome as a platform for mRNA and nascent polypeptide quality control . Trends Biochem. Sci . 42, 5–15. (doi:10.1016/j.tibs.2016.09.005) Crossref, PubMed, Google Scholar

von der Malsburg K, Shao S, Hegde RS

. 2015 The ribosome quality control pathway can access nascent polypeptides stalled at the Sec61 translocon . Mol. Biol. Cell 26, 2168–2180. (doi:10.1091/mbc.E15-01-0040) Crossref, PubMed, Google Scholar

Izawa T, Tsuboi T, Kuroha K, Inada T, Nishikawa S, Endo T

. 2012 Roles of dom34:hbs1 in nonstop protein clearance from translocators for normal organelle protein influx . Cell Rep . 2, 447–453. (doi:10.1016/j.celrep.2012.08.010) Crossref, PubMed, Google Scholar

Huang Q, Wang H, Perry SW, Figueiredo-Pereira ME

. 2013 Negative regulation of 26S proteasome stability via calpain-mediated cleavage of Rpn10 subunit upon mitochondrial dysfunction in neurons . J. Biol. Chem . 288, 12 161–12 174. (doi:10.1074/jbc.M113.464552) Crossref, Google Scholar

Geng Q, Romero J, Saini V, Baker TA, Picken MM, Gamelli RL, Majetschak M

. 2009 A subset of 26S proteasomes is activated at critically low ATP concentrations and contributes to myocardial injury during cold ischemia . Biochem. Biophys. Res. Commun . 390, 1136–1141. (doi:10.1016/j.bbrc.2009.10.067) Crossref, PubMed, Google Scholar

2010 Physiological levels of ATP negatively regulate proteasome function . Cell Res . 20, 1372–1385. (doi:10.1038/cr.2010.123) Crossref, PubMed, Google Scholar

2003 Role of the proteasome in protein oxidation and neural viability following low-level oxidative stress . FEBS Lett . 546, 228–232. (doi:10.1016/S0014-5793(03)00582-9) Crossref, PubMed, Google Scholar

Aiken CT, Kaake RM, Wang X, Huang L

. 2011 Oxidative stress-mediated regulation of proteasome complexes . Mol. Cell. Proteomics 10, R110006924. (doi:10.1074/mcp.M110.006924) Crossref, PubMed, Google Scholar

2014 Pathogenesis of human mitochondrial diseases is modulated by reduced activity of the ubiquitin/proteasome system . Cell Metab . 19, 642–652. (doi:10.1016/j.cmet.2014.01.016) Crossref, PubMed, Google Scholar

Wang X, Yen J, Kaiser P, Huang L

. 2010 Regulation of the 26S proteasome complex during oxidative stress . Sci. Signal . 3, ra88. (doi:10.1126/scisignal.2001232) Crossref, Google Scholar

Grune T, Catalgol B, Licht A, Ermak G, Pickering AM, Ngo JK, Davies KJ

. 2011 HSP70 mediates dissociation and reassociation of the 26S proteasome during adaptation to oxidative stress . Free Radic. Biol. Med . 51, 1355–1364. (doi:10.1016/j.freeradbiomed.2011.06.015) Crossref, PubMed, Google Scholar

2014 Reversible 26S proteasome disassembly upon mitochondrial stress . Cell Rep . 7, 1371–1380. (doi:10.1016/j.celrep.2014.04.030) Crossref, PubMed, Google Scholar

Haratake K, Sato A, Tsuruta F, Chiba T

. 2016 KIAA0368-deficiency affects disassembly of 26S proteasome under oxidative stress condition . J. Biochem . 159, 609–618. (doi:10.1093/jb/mvw006) Crossref, PubMed, Google Scholar

Pickering AM, Linder RA, Zhang H, Forman HJ, Davies KJ

. 2012 Nrf2-dependent induction of proteasome and Pa28alphabeta regulator are required for adaptation to oxidative stress . J. Biol. Chem . 287, 10 021–10 031. (doi:10.1074/jbc.M111.277145) Crossref, Google Scholar

Pickering AM, Staab TA, Tower J, Sieburth D, Davies KJ

. 2013 A conserved role for the 20S proteasome and Nrf2 transcription factor in oxidative stress adaptation in mammals, Caenorhabditis elegans and Drosophila melanogaster . J. Exp. Biol . 216, 543–553. (doi:10.1242/jeb.074757) Crossref, PubMed, Google Scholar

. 2001 Degradation of oxidized proteins by the 20S proteasome . Biochimie 83, 301–310. (doi:10.1016/S0300-9084(01)01250-0) Crossref, PubMed, Google Scholar

Kisselev AF, Kaganovich D, Goldberg AL

. 2002 Binding of hydrophobic peptides to several non-catalytic sites promotes peptide hydrolysis by all active sites of 20 S proteasomes: evidence for peptide-induced channel opening in the alpha-rings . J. Biol. Chem . 277, 22 260–22 270. (doi:10.1074/jbc.M112360200) Crossref, Google Scholar

Livnat-Levanon N, Glickman MH

. 2011 Ubiquitin–proteasome system and mitochondria—reciprocity . Biochim. Biophys. Acta 1809, 80–87. (doi:10.1016/j.bbagrm.2010.07.005) Crossref, PubMed, Google Scholar

. 2015 Double-edged alliance: mitochondrial surveillance by the UPS and autophagy . Curr. Opin. Cell Biol . 37, 18–27. (doi:10.1016/j.ceb.2015.08.004) Crossref, PubMed, Google Scholar

Raynes R, Pomatto LC, Davies KJ

. 2016 Degradation of oxidized proteins by the proteasome: distinguishing between the 20S, 26S, and immunoproteasome proteolytic pathways . Mol. Aspects Med . 50, 41–55. (doi:10.1016/j.mam.2016.05.001) Crossref, PubMed, Google Scholar

. 2006 Mitochondrial retrograde signaling . Annu. Rev. Genet . 40, 159–185. (doi:10.1146/annurev.genet.40.110405.090613) Crossref, PubMed, ISI, Google Scholar

. 2010 The mitochondrial UPR—protecting organelle protein homeostasis . J. Cell Sci . 123, 3849–3855. (doi:10.1242/jcs.075119) Crossref, PubMed, ISI, Google Scholar

. 2015 A cytosolic network suppressing mitochondria-mediated proteostatic stress and cell death . Nature 524, 481–484. (doi:10.1038/nature14859) Crossref, PubMed, ISI, Google Scholar

2015 Mistargeted mitochondrial proteins activate a proteostatic response in the cytosol . Nature 524, 485–488. (doi:10.1038/nature14951) Crossref, PubMed, ISI, Google Scholar

2015 Widespread proteome remodeling and aggregation in aging C. elegans . Cell 161, 919–932. (doi:10.1016/j.cell.2015.03.032) Crossref, PubMed, ISI, Google Scholar

Vilchez D, Morantte I, Liu Z, Douglas PM, Merkwirth C, Rodrigues AP, Manning G, Dillin A

. 2012 RPN-6 determines C. elegans longevity under proteotoxic stress conditions . Nature 489, 263–268. (doi:10.1038/nature11315) Crossref, PubMed, ISI, Google Scholar

Houtkooper RH, Mouchiroud L, Ryu D, Moullan N, Katsyuba E, Knott G, Williams RW, Auwerx J

. 2013 Mitonuclear protein imbalance as a conserved longevity mechanism . Nature 497, 451–457. (doi:10.1038/nature12188) Crossref, PubMed, ISI, Google Scholar


Enzymes and energetics

In order to understand the role of mitochondria in cells, you will need some very basic concepts concerning how cells store and transfer energy. All molecules contain energy, stored in the molecular structure itself. A portion of that energy, called free energy, can be used to do work. A chemical reaction that adds free energy to a molecule is said to reduce the molecule. Removing free energy from a molecule is called oxidation. When a reaction results in transfer of free energy from one molecule to another we call it an oxidation/reduction, or redox reaction. In a redox reaction one or more molecules is reduced (gains energy) while one or more molecules is oxidized (loses energy).

In cells, enzymes are responsible for reactions that transfer free energy from one molecule to another. A typical enzyme is extremely selective for its substrates (the reactants). Enzymes bind substrates in such a way that they are brought in to positions favoring a particular reaction, greatly lowering the activation energy for the reaction. By controlling enzyme activity a cell can control what reactions take place, because the types of reactions catalyzed by enzymes are extremely unlikely to occur spontaneously.

The second law of thermodynamics states that spontaneous reactions occur in directions that increase the overall disorder of the universe. A consequence is that with each energy transfer some energy is lost to the chaotic motion of molecules that we measure as temperature. While enzymes are designed to conserve free energy, some energy is always 'wasted' with each process (although endotherms use the 'wasted' energy to maintain body temperature). The stepwise oxidation of substrates by enzymes can be thought of as a 'controlled burn,' in which much of the available free energy is retained in a useful form.


Mitochondrial Structure-Function Correlation

Mitochondria contain two membranes, separated by a space. Both are the typical "unit membrane" (railroad track) in structure. Inside the space enclosed by the inner membrane is the matrix. This appears moderately dense and one may find strands of DNA, ribosomes, or small granules in the matrix. The mitochondria are able to code for part of their proteins with these molecular tools. The above cartoon shows the diagram of the mitochondrial membranes and the enclosed compartments. Return to Menu

The food we eat is oxidized to produce high-energy electrons that are converted to stored energy. This energy is stored in high energy phosphate bonds in a molecule called adenosine triphosphate, or ATP. ATP is converted from adenosine diphosphate by adding the phosphate group with the high-energy bond. Various reactions in the cell can either use energy (whereby the ATP is converted back to ADP, releasing the high energy bond) or produce it (whereby the ATP is produced from ADP).

Mitochondria are the cells' power sources. They are distinct organelles with two membranes. Usually they are rod-shaped, however they can be round. The outer membrane limits the organelle. The inner membrane is thrown into folds or shelves that project inward. These are called "cristae mitochondriales". The above electron micrograph taken from Fawcett, A Textbook of Histology, Chapman and Hall, 12th edition, 1994, shows the organization of the two membranes.

For the discussion session, read the following pages in your text: pp 653-676 and 569-672. Alberts et al, Molecular Biology of the Cell, Garland Publishing, Third Edition, 1994

Steps from glycolysis to the electron transport chain. Why are mitochondria important?

Lets break down each of the steps so you can see how food turns into ATP energy packets and water. The food we eat must first be converted to basic chemicals that the cell can use. Some of the best energy supplying foods contain sugars or carbohydrates . bread, for example. Using this as an example, the sugars are broken down by enzymes that split them into the simplest form of sugar which is called glucose. Then, glucose enters the cell by special molecules in the membrane called “glucose transporters”.

Once inside the cell, glucose is broken down to make ATP in two pathways. The first pathway requires no oxygen and is called anaerobic metabolism. This pathway is called glycolysis and it occurs in the cytoplasm outside the mitochondria. During glycolysis, glucose is broken down into pyruvate. Other foods like fats can also be broken down for use as fuel (see following cartoon). Each reaction is designed to produce some hydrogen ions (electrons) that can be used to make energy packets (ATP). However, only 4 ATP molecules can be made by one molecule of glucose run through this pathway. That is why mitochondria and oxygen are so important. We need to continue the breakdown process with the Kreb’s cycle inside the mitochondria in order to get enough ATP to run all the cell functions.

The events that occur inside and outside mitochondria are diagrammed in the above cartoon. Pyruvate is carried into the mitochondria and there it is converted into Acetyl Co-A which enters the Kreb's cycle. This first reaction produces carbon dioxide because it involves the removal of one carbon from the pyruvate.

How does the Krebs cycle work?

The whole idea behind respiration in the mitochondria is to use the Krebs cycle (also called the citric acid cycle) to get as many electrons out of the food we eat as possible. These electrons (in the form of hydrogen ions) are then used to drive pumps that produce ATP. The energy carried by ATP is then used for all kinds of cellular functions like movement, transport, entry and exit of products, division, etc. The following explanation is very simple and focuses on only the pathway from pyruvate through the cycle. However, it illustrates the process and its functions.

To run the Krebs cycle, you need several important molecules in addition to all the enzymes. Consult your text for details about the enzymes themselves. This presentation will focus on the electron donors, carriers and acceptors. First, you need pyruvate, which is made by glycolysis from glucose. Next, you need some carrier molecules for the electrons. There are two types of these: one is called nicotinamide adenine dinucleotide (NAD+) and the other is called flavin adenine dinucleotide (FAD+). The third molecule, of course, is oxygen.

Pyruvate is a 3 carbon molecule. After it enters the mitochondria, it is broken down to a 2 carbon molecule by a special enzyme (see text for more details about the biochemistry of each step). This releases carbon dioxide. The 2 carbon molecule is called Acetyl CoA and it enters the Kreb’s cycle by joining to a 4 carbon molecule called oxaloacetate. Once the two molecules are joined, they make a 6 carbon molecule called citric acid (2 carbons + 4 carbons = 6 carbons). That is where the Citric acid cycle got its name. from that first reaction that makes citric acid. Citric acid is then broken down and modified in a stepwise fashion (see text for details) and, as this happens, hydrogen ions and carbon molecules are released. The carbon molecules are used to make more carbon dioxide and the hydrogen ions are picked up by NAD and FAD (see below). Eventually, the process produces the 4 carbon oxaloacetate again. The reason the process is called a cycle, is because it ends up always where it started. with oxaloacetate available to combine with more acetyl coA.

What is “oxidative phosphorylation”?

First, some basic definitions. When you take hydrogen ions or electrons away from a molecule, you “oxidize” that molecule. When you give hydrogen ions or electrons to a molecule, you “reduce” that molecule. When you give phosphate molecules to a molecule, you “phosphorylate” that molecule. So, oxidative phosphorylation (very simply) means the process that couples the removal of hydrogen ions from one molecule and giving phosphate molecules to another molecule. How does this apply to mitochondria?

As the Krebs cycle runs, hydrogen ions (or electrons) are donated to the two carrier molecules in 4 of the steps. They are picked up by either NAD or FAD and these carrier molecules become NADH and FADH (because they now are carrying a hydrogen ion). The following cartoon shows what happens next.

These electrons are carried chemically to the respiratory or electron transport chain found in the mitochondrial cristae (see cartoons above and below this paragraph). The NADH and FADH essentially serve as a ferry in the lateral plane of the membrane diffusing from one complex to the next. At each site is a hydrogen (or proton) pump which transfers hydrogen from one side of the membrane to the other. This creates a gradient across the inner membrane with a higher concentration of Hydrogen ions in the intercristae space (this is the space between the inner and outer membranes).

The following cartoon shows the individual complexes in the electron transport chain. The electrons are carried from complex to complex by ubiquinone and cycochrome C.

The third pump in the series catalyzes the transfer of the electrons to oxygen to make water. This chemiosmotic pumping creates an electrochemical proton gradient across the membrane which is used to drive the "energy producing machine". the ATP synthase. This molecule is found in small elementary particles that project from the cristae. The cartoon below shows an elementary particle. Also see its projection from the inner membrane in the previous figure showing the overview of the cristae.

As stated above, this process requires oxygen which is why it is called "aerobic metabolism". The ATP synthase uses the energy of the hydrogen ion (also called proton) gradient to form ATP from ADP and Phosphate. It also produces water from the hydrogen and the oxygen. Thus, each compartment in the mitochondrion is specialized for one phase of these reactions.

This is how oxidation is coupled to phosphorylation:

To review: NAD and FAD remove the electrons that are donated during some of the steps of the Kreb's or Citric acid cycle. Then, they carry the electrons to the electron transport pumps and donate them to the pumps. So, NAD and FAD are “oxidized” because they lose the hydrogen ions to the pumps. The pumps then transport the hydrogens ions to the space between the two membranes where they accumulate in a high enough concentration to fuel the ATP pumps. With sufficient fuel, they “phosphorylate” the ADP. That is how “oxidation” is coupled to “phosphorylation”.

The hydrogens that get pumped back into the matrix by the ATP pump then combine with the oxygen to make water. And that is very important because, without oxygen, they will accumulate and the concentration gradient needed to run the ATP pumps will not allow the pumps to work.

So, why do we need mitochondria?

The whole idea behind this process is to get as much ATP out of glucose (or other food products) as possible. If we have no oxygen, we get only 4 molecules of ATP energy packets for each glucose molecule (in glycolysis). However, if we have oxygen, then we get to run the Kreb’s cycle to produce many more hydrogen ions that can run those ATP pumps. From the Kreb’s cycle we get 24-28 ATP molecules out of one molecule of glucose converted to pyruvate (plus the 4 molecules we got out of glycolysis). So, you can see how much more energy we can get out of a molecule of glucose if our mitochondria are working and if we have oxygen.

You can now appreciate the importance of the cristae. not only do they contain and organize the electron transport chain and the ATP pumps, they also serve to separate the matrix from the space that will contain the hydrogen ions, allowing the gradient needed to drive the pump. When the discussion focuses on how mitochondria move proteins into the matrix, you will see another reason why this hydrogen ion (proton) gradient is so important!

As shown in the above cartoons, the molecules in the electron transport chain are found as a cluster organized in the cristae. These membrane shelves may be more numerous in mitochondria that are more active in the production of ATP. Thus, they may increase the density of these membranes as the need arises. The flight muscle of a hummingbird has many cristae in each mitochondrion, because the need is so great.
Return to Menu

Mitochondria can be separated and the inner and outer membrane can be dissociated. This will result in a fraction containing only the inner membrane and the matrix. These have been called "mitoplasts". They are functional and have helped us learn more about the compartmentation of mitochondria. One can open mitoplasts and view the inside membrane surface after negatively staining the membranes. This deposits stain around any surface projections. With this method, one can see the elementary particles projecting from the inner surface of the cristae. These are the ATP synthase molecules (or elementary particles) discussed in the previous section.

The cartoons in the previous section showed cytochrome C lying just outside the inner membrane. It is a loosely attached peripheral protein lying in the space contained by the cristae. In fact, if the outer membrane is removed, often the cytochrome C is lost and must be replaced to promote function of the mitoplast.

How do cytochemists know that cytochrome C is on the inner membrane? We can do cytochemical tests for this cytochrome and the results are shown in this figure. Note that the enzyme reaction product is confined to the cristae and in fact delineates the cristae. Unfortunately, as is the case with most enzyme cytochemistry, the reaction product spreads and it looks like it fills the inter-membrane space. This reflects the orientation of cytochrome C. It is found in space inbetween cristae membranes which suggests it is next to the outer leaflet of the cristae membrane, rather than the inner leaflet (opposite to that of the elementary particles, or ATP synthetase).


Significance of mitochondria on cardiometabolic syndromes

Metabolic syndromes (MS) are a cluster of disorders such as obesity, hypertension, dyslipidemia, and diabetes. Cardiometabolic syndrome (CMS), a branch of MS, is a group of diseases affecting cardiovascular, renal, metabolic, prothrombotic, and inflammatory abnormalities due to defects in energy metabolism. Since the emergence of molecular biology and the discovery of pathogenic mitochondrial DNA defect in the 1980s, research advances have revealed a number of common human diseases involving mitochondrial dysfunction. One of the major defects in CMS and its associated diseases is excess cellular oxidative stress and oxidative damage to mitochondrial components. In this study, we overview specific aspects of mitochondrial biology that have contributed and likely will continue enhance the progress of development of therapeutics for CMS. During the last decade, however, increasing evidence has emerged supporting the role of mitochondrial functional parameters in the genesis of various metabolism-related disorders. The biochemical pathways which modulate various mitochondrial functional indicators such as mitochondrial biogenesis, mitochondrial membrane potential, electron transport chain and ATP synthesis, intramitochondrial oxidative stress, and mitochondria-mediated cell death have been recognized in diagnosis and prognosis of various disorders associated with energy metabolism and heart function.

Keywords: FOXO3a calcium cardiolipins mitochondria reactive oxygen species thioredoxin.


Watch the video: Electron Transport Chain Oxidative Phosphorylation (August 2022).