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Recently an interesting study has reported. Zhou et al., 2016. J. Cell Biol. http://dx.doi.org/10… 3/jcb.201605101
According to this study, enhancing anterograde axon transport of mitochondria is essential for regeneration of injured axons.
Neurons need a large amount of energy provided by ATP to extend their axons when they are injured. Mitochondria transported to axons produces ATP which is necessary for that.
This study shows that in mature neurons, the motility of mitochondria is reduced and the reduced mitochondrial motility might be the cause of the deficit in regrowth capacity of mature neurons. Moreover, this study found that enhancing mitochondria transport enables mature neurons to recover their regrowth capacity.
It is said that mature neurons typically arrest their cell cycle and fail to proliferate and regrow. However, considering the fact that only enhancing mitochondria transport enables mature neuron to recover their regrowth capacity, I can't help but doubt the commonly accepted theory.
Do mature neurons actually not arrest their cell cycle？
What do you think of this finding ？
Axons grow but that is not same as cell is proceeding through cell cycle. Cell grows in size but there is no cell division. It is still arrested. However during this process some growth related genes are upregulated which are also upregulated in actively dividing cells.
Mitochondria's role in neurodegenerative diseases clearer thanks to mouse study
A new study by researchers at the University of Utah School of Medicine sheds light on a longstanding question about the role of mitochondria in debilitating and fatal motor neuron diseases and resulted in a new mouse model to study such illnesses.
Researchers led by Janet Shaw, Ph.D., professor of biochemistry, found that when healthy, functioning mitochondria was prevented from moving along axons -- nerve fibers that conduct electricity away from neurons -- mice developed symptoms of neurodegenerative diseases. In a study in the Proceedings of the National Academy of Sciences, Shaw and her research colleagues said their findings indicate that motor neuron diseases might result from poor distribution of mitochondria along the spinal cord and axons. First author Tammy T. Nguyen, is a student in the U medical school's M.D./Ph.D. program, which aims to produce physicians with outstanding clinical skills and rigorous scientific training to bridge the worlds of clinical medicine and basic research to improve health care.
"We've known for a long time of the link between mitochondrial function and distribution and neural disease," Shaw says. "But we haven't been able to tell if the defect occurs because mitochondria aren't getting to the right place or because they're not functioning correctly."
Mitochondria are organelles -- compartments contained inside cells -- that serve several functions, including making ATP, a nucleotide that cells convert into chemical energy to stay alive. For this reason mitochondria often are called "cellular power plants." They also play a critical role in preventing too much calcium from building up in cells, which can cause apoptosis, or cell death.
For mitochondria to perform its functions, it must be distributed to cells throughout the body, which is accomplished with the help of small protein "motors" that transport the organelles along axons. For the motors to transport mitochondria, enzymes known as Mitochondrial Rho (Miro1) GTPases act to attach mitochondria to the motors. To study how the movement of mitochondria is related to motor neuron disease, Nguyen developed two mouse models in which the gene that makes Miro1 was knocked out. In one model, mice lacked Miro1 during the embryonic stage. A second model lacked the enzyme in the cerebral cortex, spinal cord and hippocampus.
The researchers observed that mice lacking Miro1 during the embryonic stage had motor neuron defects that prevented them from taking a single breath once born. After examining the mice, Nguyen, Shaw and their colleagues discovered that neurons required for breathing after birth were missing from the upper half of the mice's brain stems. The phrenic nerve, also important for breathing, was not fully developed, either.
"We believe the physical difficulties in the mice indicated there were motor neuron defects," Shaw says.
Conversely, the mice without Miro1 in their brain and spinal cord were fine at birth but soon developed signs of neurological problems, such as hunched spines, difficulty moving and clasping their hind paws together, and died around 35 days after birth. Those symptoms appeared similar to motor neuron disease, according to Shaw.
"The mitochondrial function in the cells appeared to be fine, and calcium levels were normal," she says. "This shows for the first time that restricting mitochondrial movement and distribution could cause neuronal disease."
Stefan M. Pulst, M.D., Dr. med, professor and chair of the University's neurology department and a co-author on the study, says the mitochondrial transport process is important not just for motor neurons but other neurons as well. "The Miro1 proteins and the respective animal models represent a breakthrough for studying ALS (Lou Gehrig's disease) and other neurodegenerative diseases."
Although much more research must be done, the study opens the possibility of developing new drugs to partially correct the mitochondrial distribution defects to slow the progression of motor neuron diseases. First, Shaw wants to generate a model to knock out the Miro1 gene in adult mice to see if the results mimic neurological diseases.
Emerging roles of mitochondria in synaptic transmission and neurodegeneration
Neuronal mitochondria show compartment-specific morphology in dendrites and axons.
Genetically-encoded tools allow for monitoring of many mitochondrial functions in neurons.
Dendritic ER and mitochondria are functionally connected.
Mitochondrial dysfunction play critical roles in multiple neurodegenerative diseases.
Mitochondria play numerous critical physiological functions in neurons including ATP production, Ca 2+ regulation, lipid synthesis, ROS signaling, and the ability to trigger apoptosis. Recently developed technologies, including in vivo 2-photon imaging in awake behaving mice revealed that unlike in the peripheral nervous system (PNS), mitochondrial transport decreases strikingly along the axons of adult neurons of the central nervous system (CNS). Furthermore, the improvements of genetically-encoded biosensors have enabled precise monitoring of the spatial and temporal impact of mitochondria on Ca 2+ , ATP and ROS homeostasis in a compartment-specific manner. Here, we discuss recent findings that begin to unravel novel physiological and pathophysiological properties of neuronal mitochondria at synapses. We also suggest new directions in the exploration of mitochondrial function in synaptic transmission, plasticity and neurodegeneration.
Huntington's Disease and Mitochondria
Huntington's disease (HD) as an inherited neurodegenerative disorder leads to neuronal loss in striatum. Progressive motor dysfunction, cognitive decline, and psychiatric disturbance are the main clinical symptoms of the HD. This disease is caused by expansion of the CAG repeats in exon 1 of the huntingtin which encodes Huntingtin protein (Htt). Various cellular and molecular events play role in the pathology of HD. Mitochondria as important organelles play crucial roles in the most of neurodegenerative disorders like HD. Critical roles of the mitochondria in neurons are ATP generation, Ca 2+ buffering, ROS generation, and antioxidant activity. Neurons as high-demand energy cells closely related to function, maintenance, and dynamic of mitochondria. In the most neurological disorders, mitochondrial activities and dynamic are disrupted which associate with high ROS level, low ATP generation, and apoptosis. Accumulation of mutant huntingtin (mHtt) during this disease may evoke mitochondrial dysfunction. Here, we review recent findings to support this hypothesis that mHtt could cause mitochondrial defects. In addition, by focusing normal huntingtin functions in neurons, we purpose mitochondria and Huntingtin association in normal condition. Moreover, mHtt affects various cellular signaling which ends up to mitochondrial biogenesis. So, it could be a potential candidate to decline ATP level in HD. We conclude how mitochondrial biogenesis plays a central role in the neuronal survival and activity and how mHtt affects mitochondrial trafficking, maintenance, integrity, function, dynamics, and hemostasis and makes neurons vulnerable to degeneration in HD.
Keywords: Huntingtin Huntington’s disease Mitochondria Mitochondrial biogenesis Striatum.
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The aggregation of mitochondria is a prominent feature of the nerve terminal. Previous studies have revealed the role of synaptic mitochondria in modulating the efficacy and plasticity of mature synapses (Alnaes and Rahamimoff, 1975 Herrera et al., 1985 Nguyen et al., 1997 Li et al., 2004). At the developing NMJ, our recent study has shown that mitochondria become coclustered with SVs at developing presynaptic specializations within minutes upon presentation of synaptogenic stimulus to spinal neurons. The results of the present study have indicated an essential role of localized mitochondrial activity in presynaptic differentiation.
The Regulation of Presynaptic Development by Mitochondrial ΔΨm Manipulators
JC-1 provided us with a simple probe for monitoring ΔΨm in live neurons. This dye has been extensively used as a semiquantitative indicator of neuronal mitochondrial ΔΨm (Ankarcrona et al., 1995 White and Reynolds, 1996 Buckman and Reynolds, 2001). We provided evidence that ΔΨm in cultured neurons could be reversibly modulated by creatine or FCCP and such manipulation affected mitochondria's axonal mobility and SV clustering. Creatine phosphate modulates ATP production by donating its high-energy phosphate in converting ADP to ATP (Ishida et al., 1994). Exogenous creatine therefore acts as a temporal and spatial buffer of energy which enhances the conversion rate of ATP from ADP. On the other hand, FCCP, an ionophore for proton, increases the permeabilization of inner mitochondrial membrane to protons and consequently depolarizes this membrane, therefore reducing ATP production (Nicholls and Budd, 2000). The relatively long latency in the effect of creatine on ΔΨm is likely due to the fact that its entry into the cell is rate-limited by a transporter-mediated process compared with the direct passage of FCCP (Moller and Hamprecht, 1989). Moreover, there is a possibility that the increase in SV clusters by creatine treatment involves transcriptional regulation of SV proteins.
In cultured neurons, axonal transport of mitochondria is bidirectional along microtubules or actin filaments by different motor proteins (Morris and Hollenbeck, 1993, 1995). Labeling the nerve-muscle or bead-nerve cocultures with JC-1 revealed that mitochondria with higher ΔΨm are preferentially located at the synaptic sites along the axon (Lee and Peng, 2006). This suggests that even during development, there is a requirement for high, local ATP production to support presynaptic development. Consistent with this, the present study showed that mitochondria were localized near the sites of local ATP consumption as a result of presynaptic differentiation induced by bFGF beads (Figure 5). The mechanism for targeting mitochondria to the presynaptic nerve terminal is likely mediated by the protein milton and syntabulin in Drosophila NMJs and in rat hippocampal synapses, respectively (Stowers et al., 2002 Cai et al., 2005). A previous study showed that a mitochondrial uncoupler CCCP blocks the bidirectional mitochondrial movements, whereas an inhibitor of the electron transport chain antimycin causes higher retrograde mitochondrial movement in neurons (Miller and Sheetz, 2004). In agreement with that study, our present results showed that depolarization by FCCP completely abolished mitochondrial translocation in both anterograde and retrograde directions along the axon, presumably due to the fact that ATP hydrolysis powers the microtubule motor proteins, such as kinesin and dynein, for anterograde and retrograde translocation, respectively. Like antimycin, inhibition of mitochondrial ATP production by oligomycin caused an increase in retrograde (slow) and a decrease in anterograde (slow) movements of mitochondria. An increase in retrograde mitochondrial transport may drive mitochondria with low ATP production away from the axon toward the soma. Because mitochondrial clustering induced by beads was not affected by oligomycin treatment, the docking of mitochondria to the synaptic sites is likely independent on the direction of mitochondrial movement.
The Role of F-Actin in the Formation of SV Clusters
The clustering, mobilization, fusion and recycling of SVs are vital to neurotransmitter release at the nerve terminal. The F-actin cytoskeleton is involved in regulating each one of these events (Dillon and Goda, 2005). At the mature nerve terminal, SVs are organized into two functional pools, the readily releasable pool (RRP) and the reserve pool (RP Rizzoli et al., 2003 Rizzoli and Betz, 2005). RRP is a population of vesicles docked at the active zone and primed for release, whereas RP is a cluster of vesicles residing distally from the active zone. Structural studies with electron microscopy and immunolabeling have shown that F-actin is associated with SV clusters within the nerve terminal (Hirokawa et al., 1989 Dai and Peng, 1996a Bloom et al., 2003). At Drosophila NMJs, F-actin disruption by cytochalasin D disrupts RP while leaving the RRP intact (Kuromi and Kidokoro, 1998). It is suggested that F-actin provides cytoskeletal tracks for SV replenishment as shown by the translocation of SVs from RP to RRP via an actin-based motor protein myosin V (Evans et al., 1998). In this study, polymerization of F-actin is locally induced at sites of synaptogenic induction in close association with mitochondrial clusters. These results further support that local actin polymerization is involved, at least in part, in the formation of presynaptic specialization.
The Importance of ATP Production in Actin-mediated Presynaptic Differentiation
The assembly of actin filaments requires ATP hydrolysis. In neurons, ∼50% of cellular ATP supply is utilized in cytoskeletal assembly (Bernstein and Bamburg, 2003). Thus, mitochondria that become localized at the nascent presynaptic region may serve as a local powerhouse in the assembly of F-actin and other presynaptic components, like SV clusters. With magnesium green as an ATP probe, our experiment has shown that depolarization of mitochondrial ΔΨm by FCCP significantly depleted the intracellular ATP content and this may account for the observed inhibition of presynaptic differentiation. ATP depletion by oligomycin similarly inhibited actin polymerization and SV clustering. Interestingly, although FCCP inhibited both SV and mitochondrial clustering, oligomycin only affected the former. A relatively low level of intracellular ATP may be sufficient for the function of motor proteins responsible for the synaptic targeting of mitochondria, a notion in agreement with our finding that mitochondrial translocation was not affected by oligomycin treatment (Supplementary Video 4). In agreement with our findings, mutant Drosophila NMJs lacking presynaptic mitochondria show a diffused, but not clustered, pattern of SV distribution in the nerve terminal, and this results in a reduction in the size of synaptic boutons (Guo et al., 2005). On the other hand, creatine, which enhanced presynaptic differentiation, did not cause an increase in intracellular ATP level. This may be due to the fact that creatine enhances local ATP resynthesis at sites of high metabolic activity but does not increase the overall ATP content in the neuron.
Because mitochondria also contribute to Ca 2+ buffering in cultured neurons, we also tested whether this function is involved in presynaptic differentiation with a Na + /Ca 2+ exchanger inhibitor CGP-37157. Our results showed that all three presynaptic events, SV and mitochondrial clustering as well as F-actin polymerization, were not affected by this compound. Thus, ATP production is specifically required for presynaptic differentiation. This conclusion is consistent with a study on Drosophila NMJs with a dynamin-related protein (Drp1) mutation that the mobilization of RP vesicles is inhibited in the absence of presynaptic mitochondria and this can be partially rescued by exogenous ATP (Verstreken et al., 2005). It remains unclear whether local ATP production by presynaptic mitochondria could regulate activity-dependent mobilization and release of SVs.
Taken together, this study shows that mitochondrial ATP production regulates presynaptic differentiation in an actin-dependent mechanism. The F-actin–based cytoskeleton may form the scaffold for the assembly of presynaptic organelles including SVs and mitochondria themselves.
Impaired Mitochondrial Recycling Drives Neuron Death in Parkinson’s, Study Indicates
Impaired recycling of mitochondria — the powerhouses of the cell — may drive the loss of the neurons at the heart of Parkinson’s disease, according to a new study.
Boosting the cell’s ability to remove old mitochondria and produce new ones then may prove an effective way to prevent the loss of those neurons.
Mitochondria are membrane-enclosed structures within cells that produce energy they suffer damage over the course of Parkinson’s disease.
Research has shown that mutations in the PRKN gene are linked both to a hereditary form of Parkinson’s disease and to clearing away damaged mitochondria — a process called mitophagy.
Other studies have shown that the accumulation of a protein called Parkin Interacting Substrate (PARIS) also drives the loss of dopamine-producing (dopaminergic) neurons in animals lacking the PARKIN protein that mimic Parkinson’s disease.
Dopamine is an important molecule used in passing information between neurons, coordinating movement, and regulating moods. The loss of dopaminergic neurons is a hallmark of Parkinson’s progression.
These past observations led researchers at Johns Hopkins University Medical School in Maryland to explore the role that defective mitochondrial recycling plays in dopaminergic neuron loss.
The researchers examined dopaminergic neurons that had mutations in the PRKN gene that they either derived from Parkinson’s patients or grew from embryonic stem cells.
These cells all showed declines in mitochondrial energy production, also called mitochondrial respiration, and an inability to clear away old and damaged mitochondria.
The investigators also noticed that cells lacking PARKIN protein had higher amounts of active PARIS, which is known to repress the activity of PGC-1alpha, a gene that regulates mitochondrial production and helps to manage the cell’s oxidative stress — an imbalance between the production of free radicals and the ability of cells to detoxify them, leading to cellular damage.
Cells lacking PARKIN and with higher active PARIS produced fewer mitochondria.
The researchers then examined the role of mitochondrial recycling in the survival of dopaminergic neurons by restoring healthy copies of the PRKN gene to cells with the lost or damaged version and by deleting PARIS from cells that also lacked PARKIN protein.
The two procedures produced different, but complementary, results.
Restoring healthy PRKN rescued the defects in mitophagy. Reducing PARIS levels restored the cells’ ability to produce new mitochondria, thereby also restoring mitochondrial respiration to healthy levels.
The results imply that mitochondrial deficits seen in dopaminergic neurons in Parkinson’s disease occur because the loss of PARKIN causes an increase in the amount of PARIS in the cell, which disrupts mitochondrial recycling.
Although these results do not preclude the possibility that other factors also influence that process, they do highlight the role that mitochondrial recycling plays in the survival of dopaminergic neurons.
They also point toward PARIS as a new potential therapeutic target to prevent the loss of dopaminergic neurons in Parkinson’s.
“Targeting PARIS with drugs to lower its protein levels may provide a new way to treat Parkinson’s disease,” Ted Dawson, MD, PhD, professor of neurology and the study’s senior author, said in a press release.
Mitochondria serve as axonal shuttle for Cox7c mRNA through mechanism that involves its mitochondrial targeting signal
Localized protein synthesis plays a key role in spatiotemporal regulation of the cellular proteome. Neurons, which extend axons over long distances, heavily depend on this process. However, the mechanisms by which axonal mRNAs are transported to protein target sites are not fully understood. Here, we describe a novel role for mitochondria in shuttling a nuclear encoded mRNA along axons. Fractionation analysis and smFISH revealed that the mRNA encoding Cox7c protein is preferentially associated with mitochondria from a neuronal cell line and from primary motor neuron axons. Live cell imaging of MS2-tagged Cox7c or Cryab control mRNA in primary motor neurons further confirmed the preferential colocalization of Cox7c mRNA with mitochondria. More importantly, Cox7c demonstrated substantial co-transport with mitochondria along axons. Intriguingly, the coding region, rather than the 3’UTR, was found to be the key domain for the co-transport. Furthermore, we show that puromycin treatment as well as hindering the synthesis of the mitochondrial targeting signal (MTS) reduced the co-localization. Overall, our results reveal a novel mRNA transport mode which exploits mitochondria as a shuttle and translation of the MTS as a recognition feature. Thus, mitochondria may play a role in spatial regulation of the axonal transcriptome and self-sustain their own proteome at distant neuronal sites.
Spinal muscular atrophy (SMA) is a monogenetic motor neuron disease on the verge of being redefined, largely due to notable therapeutic breakthroughs over the last decade. SMA is caused by mutations in the survival motor neuron 1 (SMN1) gene, leading to loss of its SMN protein product  (Fig. 1a). Due to a complex, highly repeated DNA sequence, the human genome contains an inverted duplication in the SMN region of chromosome 5, producing the near-identical duplicate gene, SMN2. A single nucleotide polymorphism in exon 7 of SMN2 leads to removal of exon 7 in 80–90% of transcripts this truncated transcript is unstable and quickly degraded [2, 3]. SMN2 is therefore unable to compensate for mutated SMN1 leading to suboptimal levels of SMN protein. Humans have variable copy numbers of the SMN2 gene (again due to the repeating nature of this region of chromosome 5), and increased copy numbers of SMN2 can partially compensate for SMN1 mutation. This is reflected in time of onset and severity of symptoms in patients .
Summary of the genetics of spinal muscular atrophy and their correlation to clinical symptoms. a Survival motor neuron (SMN)-1 encodes the SMN protein and is mutated in spinal muscular atrophy (SMA). SMN2 is a near-identical gene with a single nucleotide polymorphism (SNP) at the beginning of exon 7, leading to exon 7 exclusion in the majority of SMN2 mRNA transcripts. This truncated protein is quickly degraded. Three currently licenced therapies for SMA (shown in red) aim to increase SMN protein expression, either by introducing an exogenous copy of SMN1 (Zolgensma ® ) or promoting exon 7 inclusion in SMN2 transcripts (Spinraza ® and Evrysdi ® ), thereby producing full-length SMN. b As SMN2 copy number increases, full-length SMN protein expression increases and is inversely proportional to disease severity. Type 1 patients have one copy of SMN2, with copy numbers increasing until Type 4 patients, who have the mildest symptoms
Patients have traditionally been grouped into sub-types of SMA with disease severity and motor milestones influenced by SMN2 copy number  (Fig. 1b). Type 0 patients have one copy of SMN2, with prenatal motor weakness, paralysis, and death weeks after birth. Type 1 patients are more common, with two copies of SMN2 and obvious motor symptoms within the first few months of life as they do not develop head control. Untreated, Type 1 patients have a life expectancy of around 2 years. Patients with three copies of SMN2 are characterised as Type 2, with symptom onset between 6 months and 2 years and development of motor skills such as sitting and possibly standing. Type 3 patients develop motor symptoms after 18 months old, have three or four copies of SMN2, and are likely to reach the motor milestone of unassisted walking and have a normal lifespan . These SMA patient sub-types are based on the natural history of the disease. However, we have reached a new therapeutic era for SMA, with the approval and licencing of three genetic therapies: Spinraza ® is an antisense oligonucleotide that modulates splicing of SMN2 to increase SMN production  Zolgensma ® is a viral vector that introduces a second copy of SMN1 to boost SMN expression  and Evrysdi ® is a small molecule that also alters SMN2 splicing . Treatment with any one of these therapies significantly extends the time to invasive respiratory ventilation and life expectancy for many patients with SMA (most trials to date have been conducted in Type 1 patients). However, emerging evidence from patients treated with these “SMN-replacement” therapies reveals an ongoing loss of function and continued presence of neuromuscular symptoms . Children treated earlier, before motor symptoms develop, have the highest chance of achieving successive motor milestones, while children who are treated at a later disease time point continue to be at high risk of needing supported ventilation  and enteral feeding . The effect of these therapies in adults with Types 2/3 SMA is even less clear, not least because of the heterogeneity of clinical symptoms and small patient group sizes. Nevertheless, there is some evidence of stabilisation or even improvement in motor symptoms in adult patients . Thus, there is a growing body of evidence indicating that replacing SMN protein levels in patients can only go part-way to relieving symptoms due to affected tissues being too far down the degeneration pathway . SMN-independent therapies are therefore needed to act in concert with SMN-replacement and further benefit patients with SMA (e.g., “SMN + therapies” ).
As a multi-systemic disorder, SMA affects many cell types since SMN protein is ubiquitously expressed throughout the body . Undoubtedly though, motor neurons and muscle cells are a predominant site of cellular pathology. Neurons and muscle cells are in turn two of the most energy-dependent cells within the body therefore, as mitochondria are primarily known for their role in energy and metabolic pathways, it is not hard to envision their involvement in SMA based upon this role. Yet mitochondria are no longer viewed solely as the ‘powerhouse’ of the cell and are implicated in many other aspects of cellular function that intersect with the aetiology of SMA and known roles of the SMN protein. Initially, SMN protein was reported to function in transcriptional processes but is now known to also play roles in protein translation and related proteostatic mechanisms such as autophagy and ubiquitination . Dissecting these varied functions of SMN across a disease of heterogenous expression has been made possible through the development of animal models of varying severity (e.g., severe, intermediate, and mild mouse models, reflecting Types 1, 2, and 3/4 in patients, respectively) [18, 19]. By providing an overview of the mitochondrial dysfunction in SMA, our intention is to guide molecular mechanistic understanding and aid translational targeting of mitochondria, which offer many routes for complementary therapeutic interventions to current SMN-replacement therapies.
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Keywords: mitochondrial, mitochondrial dysfunction, mitochondrial-targeting molecules, chemical biology, chemical probe, nanomedicine
Citation: Wang H, Fang B, Peng B, Wang L, Xue Y, Bai H, Lu S, Voelcker NH, Li L, Fu L and Huang W (2021) Recent Advances in Chemical Biology of Mitochondria Targeting. Front. Chem. 9:683220. doi: 10.3389/fchem.2021.683220
Received: 20 March 2021 Accepted: 19 April 2021
Published: 03 May 2021.
Hongyan Sun, City University of Hong Kong, Hong Kong
Haibin Shi, Soochow University, China
Bogdan Olenyuk, Proteogenomics Research Institute for Systems Medicine, United States
Copyright © 2021 Wang, Fang, Peng, Wang, Xue, Bai, Lu, Voelcker, Li, Fu and Huang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Mitochodria's Role For Neuron Regrowth - Biology
Scientists have identified a protein in the brain that plays a key role in the function of mitochondria the part of the cell that supplies energy, supports cellular activity, and potentially wards off threats from disease. The discovery, which was reported today in the Journal of Cell Biology , may shed new light on how the brain recovers from stroke.
"Understanding the molecular machinery that helps distribute mitochondria to different parts of the cell has only recently begun to be understood," said University of Rochester Medical Center neurologist David Rempe, M.D., Ph.D., the lead author of the study. "We know that in some disease states that mitochondria function is modified, so understanding how their activity is modulated is important to understanding how the brain responds to a pathological state."
Mitochondria are cellular power plants that generate most of the cell's supply of adenosine triphosphate (ATP), which is used as a source of chemical energy. While mitochondria are present in all of the body's cells, some cells because of their size and purpose need to transport mitochondria to distant sites within the cell to maintain proper function. A prominent example is neurons which have a complex cellular structure that consist of a main cell body and dendrites and axons that project out from the cell core and transmit signals to adjoining cells via synapses at their terminus.
"Neurons are at a disadvantage in terms of their anatomy," said Rempe. "They put out enormous arms of axons and dendrites and they have to keep supplying nutrients and everything down these arms. The supply line is very long."
The supply line includes mitochondria which the cell must also push down the axons and dendrites to provide these parts of the cell with energy, help with the transmission of signals, and generally maintain cellular health. Mitochondria are constantly cycling throughout the neuron. Some are stationary while others are moving down the arms of the cell to assume their proper position. Additionally, for reasons not completely understood, at any given time about half of the mobile mitochondria in the neuron are in the process of returning to the cell body perhaps to be recycled or replenished in some form.
Rempe and his colleagues have discovered a protein that plays a critical role in regulating the movement or transport of mitochondria in neuron cells. The protein, which they dubbed hypoxia upregulated mitochondrial movement regulator (HUMMR), is produced in a state of low oxygen called hypoxia. HUMMR is induced by another protein called hypoxic inducible factor 1 alpha (HIF-1) which is responsible for triggering several processes in the cell that help it function in a low oxygen environment.
The primary role of HUMMR is to regulate the proper transport and distribution of mitochondria throughout the cell, essentially ensuring that they are in the correct position. One of the ways that the University of Rochester team was able to determine this is that when HUMMR was expressed at lower than normal levels, they observed that a greater number of the mitochondria began to abandon their posts along the cell's dendrites and axon and return to the cell body proper.
Understanding the mechanisms that regulate the movement of mitochondria may help scientists identify how the brain's cells ward off and potentially repair damage. An example is the role that mitochondria play as a calcium buffer. One of the mitochondria's functions is to help control the concentration of calcium in the cell, which the organelles can rapidly absorb and store. This capacity is important, particularly in instances when calcium levels in the cell spike during a stroke, a condition which contributes a cascading series of events that ultimately lead to a state called excitotoxicity and cell death.
One of the keys to identifying the function of HUMMR has been the appreciation in that the body operates at a relatively low oxygen level. While the air we breath consists of approximately 20% oxygen, the cells in the brain sit at somewhere between 2-5% oxygen. This creates a "normal" state of hypoxia in the brain.
However, the concentration of oxygen in the brain can drop even further in instances such as a stroke, when blood flow to a portion of the brain is cut off. This decrease in oxygen promotes the expression of HUMMR which, in turn, mobilizes mitochondria. More mitochondria in the correct position may mean the cell has a greater capacity to filter out toxic levels of calcium. Rempe and his colleagues are now investigating the role that HUMMR may play in stroke models, particularly whether or not this activity helps protect vulnerable cells that lie just outside the core areas of the brain that are damaged by stroke.
"Ultimately, these advances in our understanding of the molecular and cell biology of mitochondria have the potential to lead to novel approaches for the prevention and treatment of neurological disorders," said Rempe.