The Interplay of Axonal Energy Homeostasis and Mitochondrial Trafficking and Anchoring.

Mitochondria are key cellular power plants essential for neuronal growth, survival, function, and regeneration after injury. Given their unique morphological features, neurons face exceptional challenges in maintaining energy homeostasis at distal synapses and growth cones where energy is in high demand. Efficient regulation of mitochondrial trafficking and anchoring is critical for neurons to meet altered energy requirements. Mitochondrial dysfunction and impaired transport have been implicated in several major neurological disorders. Thus, research into energy-mediated regulation of mitochondrial recruitment and redistribution is an important emerging frontier. In this review, I discuss new insights into the mechanisms regulating mitochondrial trafficking and anchoring, and provide an updated overview of how mitochondrial motility maintains energy homeostasis in axons, thus contributing to neuronal growth, regeneration, and synaptic function.

[1]  G. Hajnóczky,et al.  Control of mitochondrial motility and distribution by the calcium signal , 2004, The Journal of cell biology.

[2]  K. Zinsmaier,et al.  Drosophila Miro Is Required for Both Anterograde and Retrograde Axonal Mitochondrial Transport , 2009, The Journal of Neuroscience.

[3]  A. Sagasti,et al.  WldS and PGC-1α Regulate Mitochondrial Transport and Oxidation State after Axonal Injury , 2013, The Journal of Neuroscience.

[4]  Groeneweg,et al.  Supplemental Information Mitochondrial Dynamics in Visual Cortex Are Limited In Vivo and Not Affected by Axonal Structural Plasticity , 2016 .

[5]  Pierre J Magistretti,et al.  Brain energy metabolism: focus on astrocyte-neuron metabolic cooperation. , 2011, Cell metabolism.

[6]  E. Schon,et al.  Mitochondria: The Next (Neurode)Generation , 2011, Neuron.

[7]  Haifa Qiao,et al.  Motile axonal mitochondria contribute to the variability of presynaptic strength. , 2013, Cell reports.

[8]  D. Chan,et al.  Mitochondrial dynamics–fusion, fission, movement, and mitophagy–in neurodegenerative diseases , 2009, Human molecular genetics.

[9]  G. López-Doménech,et al.  Mitochondrial trafficking in neurons and the role of the Miro family of GTPase proteins. , 2013, Biochemical Society transactions.

[10]  Rebecca L. Frederick,et al.  Yeast Miro GTPase, Gem1p, regulates mitochondrial morphology via a novel pathway , 2004, The Journal of cell biology.

[11]  K. Pozo,et al.  Mapping the GRIF-1 Binding Domain of the Kinesin, KIF5C, Substantiates a Role for GRIF-1 as an Adaptor Protein in the Anterograde Trafficking of Cargoes* , 2006, Journal of Biological Chemistry.

[12]  Cuiling Li,et al.  Docking of Axonal Mitochondria by Syntaphilin Controls Their Mobility and Affects Short-Term Facilitation , 2008, Cell.

[13]  C. Hoogenraad,et al.  TRAK/Milton Motor-Adaptor Proteins Steer Mitochondrial Trafficking to Axons and Dendrites , 2013, Neuron.

[14]  J. Bourne,et al.  Mitochondrial support of persistent presynaptic vesicle mobilization with age-dependent synaptic growth after LTP , 2016, eLife.

[15]  Qian Cai,et al.  Spatial Parkin Translocation and Degradation of Damaged Mitochondria via Mitophagy in Live Cortical Neurons , 2012, Current Biology.

[16]  N. Bonini,et al.  A Novel Drosophila Model of Nerve Injury Reveals an Essential Role of Nmnat in Maintaining Axonal Integrity , 2012, Current Biology.

[17]  S. Pulst,et al.  Loss of Miro1-directed mitochondrial movement results in a novel murine model for neuron disease , 2014, Proceedings of the National Academy of Sciences.

[18]  P. Hollenbeck,et al.  The axonal transport of mitochondria , 2005, Journal of Cell Science.

[19]  F. Polleux,et al.  Terminal Axon Branching Is Regulated by the LKB1-NUAK1 Kinase Pathway via Presynaptic Mitochondrial Capture , 2013, Cell.

[20]  D. Kerschensteiner,et al.  Dendritic mitochondria reach stable positions during circuit development , 2016, eLife.

[21]  Huan Ma,et al.  KIF5B Motor Adaptor Syntabulin Maintains Synaptic Transmission in Sympathetic Neurons , 2009, The Journal of Neuroscience.

[22]  S. Laughlin,et al.  An Energy Budget for Signaling in the Grey Matter of the Brain , 2001, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[23]  D. Attwell,et al.  Synaptic Energy Use and Supply , 2012, Neuron.

[24]  I. Forsythe,et al.  Presynaptic Mitochondrial Calcium Sequestration Influences Transmission at Mammalian Central Synapses , 2002, The Journal of Neuroscience.

[25]  P. Rakic,et al.  AMP-Activated Protein Kinase Regulates Neuronal Polarization by Interfering with PI 3-Kinase Localization , 2011, Science.

[26]  C. Krarup,et al.  Acute energy restriction triggers Wallerian degeneration in mouse , 2008, Experimental Neurology.

[27]  K. Medler,et al.  Mitochondrial Ca(2+) buffering regulates synaptic transmission between retinal amacrine cells. , 2002, Journal of neurophysiology.

[28]  N. Matsuki,et al.  AMP‐activated protein kinase mediates activity‐dependent axon branching by recruiting mitochondria to axon , 2014, Developmental neurobiology.

[29]  R. Burke,et al.  Clinical progression in Parkinson disease and the neurobiology of axons , 2010, Annals of neurology.

[30]  H. Peng,et al.  The function of mitochondria in presynaptic development at the neuromuscular junction. , 2008, Molecular biology of the cell.

[31]  V. Choubey,et al.  Mitochondrial biogenesis is required for axonal growth , 2016, Development.

[32]  A. Ruusala,et al.  Atypical Rho GTPases Have Roles in Mitochondrial Homeostasis and Apoptosis* , 2003, The Journal of Biological Chemistry.

[33]  S. Miroňov Complexity of mitochondrial dynamics in neurons and its control by ADP produced during synaptic activity. , 2009, The international journal of biochemistry & cell biology.

[34]  C. Lively,et al.  Kinesin-1 and Dynein are the primary motors for fast transport of mitochondria in Drosophila motor axons. , 2006, Molecular biology of the cell.

[35]  Ken Nakamura,et al.  Energy Failure , 2013, Annals of neurology.

[36]  B. Locke,et al.  The effects of temperature, pH, and magnesium on the diffusion coefficient of ATP in solutions of physiological ionic strength. , 1996, Biochimica et biophysica acta.

[37]  Marc Hammarlund,et al.  Mitochondria Localize to Injured Axons to Support Regeneration , 2016, Neuron.

[38]  Qian Cai,et al.  Syntabulin-mediated anterograde transport of mitochondria along neuronal processes , 2005, The Journal of cell biology.

[39]  T. Schwarz Mitochondrial trafficking in neurons. , 2013, Cold Spring Harbor perspectives in biology.

[40]  D. Attwell,et al.  Miro1 Is a Calcium Sensor for Glutamate Receptor-Dependent Localization of Mitochondria at Synapses , 2009, Neuron.

[41]  Xiao Liu,et al.  Quantitative imaging of energy expenditure in human brain , 2012, NeuroImage.

[42]  H. Roš,et al.  Loss of Dendritic Complexity Precedes Neurodegeneration in a Mouse Model with Disrupted Mitochondrial Distribution in Mature Dendrites , 2016, Cell reports.

[43]  Z. Sheng,et al.  Kinesin-1–syntaphilin coupling mediates activity-dependent regulation of axonal mitochondrial transport , 2013, The Journal of cell biology.

[44]  G. Shepherd,et al.  Three-Dimensional Structure and Composition of CA3→CA1 Axons in Rat Hippocampal Slices: Implications for Presynaptic Connectivity and Compartmentalization , 1998, The Journal of Neuroscience.

[45]  H. Horvitz,et al.  Axons Degenerate in the Absence of Mitochondria in C. elegans , 2014, Current Biology.

[46]  I. Reynolds,et al.  Mitochondrial Trafficking to Synapses in Cultured Primary Cortical Neurons , 2006, The Journal of Neuroscience.

[47]  M. Molinari,et al.  Acute focal brain damage alters mitochondrial dynamics and autophagy in axotomized neurons , 2014, Cell Death and Disease.

[48]  P. Verstreken,et al.  Synaptic Mitochondria Are Critical for Mobilization of Reserve Pool Vesicles at Drosophila Neuromuscular Junctions , 2005, Neuron.

[49]  Z. Sheng,et al.  Facilitation of axon regeneration by enhancing mitochondrial transport and rescuing energy deficits , 2016, The Journal of cell biology.

[50]  E. Barrett,et al.  Mitochondrial Ca2+ uptake prevents desynchronization of quantal release and minimizes depletion during repetitive stimulation of mouse motor nerve terminals , 2003, The Journal of physiology.

[51]  P. Hollenbeck,et al.  Nerve Growth Factor Signaling Regulates Motility and Docking of Axonal Mitochondria , 2004, Current Biology.

[52]  J. Twiss,et al.  Mitochondria coordinate sites of axon branching through localized intra-axonal protein synthesis. , 2013, Cell reports.

[53]  Xinnan Wang,et al.  The Mechanism of Ca2+-Dependent Regulation of Kinesin-Mediated Mitochondrial Motility , 2009, Cell.

[54]  Frank Bradke,et al.  Assembly of a new growth cone after axotomy: the precursor to axon regeneration , 2012, Nature Reviews Neuroscience.

[55]  A. MacAskill,et al.  Control of mitochondrial transport and localization in neurons. , 2010, Trends in cell biology.

[56]  J. Gilley,et al.  Endogenous Nmnat2 Is an Essential Survival Factor for Maintenance of Healthy Axons , 2010, PLoS biology.

[57]  Prashant Mishra,et al.  Metabolic regulation of mitochondrial dynamics , 2016, The Journal of cell biology.

[58]  Dimitrios Kapogiannis,et al.  Disrupted energy metabolism and neuronal circuit dysfunction in cognitive impairment and Alzheimer's disease , 2011, The Lancet Neurology.

[59]  F. Stephenson,et al.  Trafficking Kinesin Protein (TRAK)-mediated Transport of Mitochondria in Axons of Hippocampal Neurons* , 2011, The Journal of Biological Chemistry.

[60]  Rebecca L. Frederick,et al.  Moving Mitochondria: Establishing Distribution of an Essential Organelle , 2007, Traffic.

[61]  Attila Losonczy,et al.  Progressive Decrease of Mitochondrial Motility during Maturation of Cortical Axons In Vitro and In Vivo , 2016, Current Biology.

[62]  Gulcin Pekkurnaz,et al.  Glucose Regulates Mitochondrial Motility via Milton Modification by O-GlcNAc Transferase , 2014, Cell.

[63]  M. Charlton,et al.  The GTPase dMiro Is Required for Axonal Transport of Mitochondria to Drosophila Synapses , 2005, Neuron.

[64]  T. A. Ryan,et al.  Activity-Driven Local ATP Synthesis Is Required for Synaptic Function , 2014, Cell.

[65]  I. Reynolds,et al.  Mitochondrial trafficking and morphology in healthy and injured neurons , 2006, Progress in Neurobiology.

[66]  Sergej L Mironov,et al.  ADP regulates movements of mitochondria in neurons. , 2007, Biophysical journal.

[67]  G. Kress,et al.  Glutamate Decreases Mitochondrial Size and Movement in Primary Forebrain Neurons , 2003, The Journal of Neuroscience.

[68]  J. Gilley,et al.  Wallerian degeneration: an emerging axon death pathway linking injury and disease , 2014 .

[69]  M. Mattson,et al.  Mitochondria in Neuroplasticity and Neurological Disorders , 2008, Neuron.

[70]  Kai-Fenp Liu,et al.  Neuronal intrinsic mechanisms of axon regeneration. , 2011, Annual review of neuroscience.

[71]  Qian Cai,et al.  Mitochondrial transport in neurons: impact on synaptic homeostasis and neurodegeneration , 2012, Nature Reviews Neuroscience.

[72]  Martin D. Brand,et al.  The Role of Mitochondrially Derived ATP in Synaptic Vesicle Recycling*♦ , 2015, The Journal of Biological Chemistry.

[73]  L. Mucke,et al.  Dynamin-related protein 1 is required for normal mitochondrial bioenergetic and synaptic function in CA1 hippocampal neurons , 2015, Cell Death and Disease.

[74]  S. Budd,et al.  Mitochondria and neuronal survival. , 2000, Physiological reviews.

[75]  G. Hajnóczky,et al.  Bidirectional Ca2+-dependent control of mitochondrial dynamics by the Miro GTPase , 2008, Proceedings of the National Academy of Sciences.

[76]  Michael P. Sheetz,et al.  Axonal mitochondrial transport and potential are correlated , 2004, Journal of Cell Science.

[77]  Z. Sheng,et al.  Mitochondrial trafficking and anchoring in neurons: New insight and implications , 2014, The Journal of cell biology.

[78]  Yosuke Tanaka,et al.  Molecular Motors in Neurons: Transport Mechanisms and Roles in Brain Function, Development, and Disease , 2010, Neuron.

[79]  G. Brewer,et al.  Mitoenergetic failure in Alzheimer disease. , 2007, American journal of physiology. Cell physiology.

[80]  Manuel B. Graeber,et al.  PGC-1α, A Potential Therapeutic Target for Early Intervention in Parkinson’s Disease , 2010, Science Translational Medicine.

[81]  E. Barrett,et al.  Inhibition of mitochondrial Ca2+ uptake affects phasic release from motor terminals differently depending on external [Ca2+]. , 2003, Journal of neurophysiology.

[82]  T. Misgeld,et al.  CNS Axons Globally Increase Axonal Transport after Peripheral Conditioning , 2014, The Journal of Neuroscience.