Mitochondrially Impaired Neurons

Mitochondrially Impaired Neurons

<table class="infobox infobox-celltype">
<tr>
<th class="infobox-header" colspan="2">Mitochondrially Impaired Neurons</th>
</tr>
<tr> [@schapira1989]
<td class="label">Lineage</td> [@murphy2009]
<td>Neuron > Mitochondrially Impaired</td> [@parker1994]
</tr> [@bostic2019]
<tr> [@wallace2005]
<td class="label">Markers</td> [@kadenbach2000]
<td>COX deficiency, Complex I/III/IV activity, mtDNA mutations, PINK1, Parkin</td> [@suomalainen2011]
</tr> [@rossignol1999]
<tr> [@youle2011]
<td class="label">Brain Regions</td> [@detmer2007]
<td>Substantia Nigra, Hippocampus, Dorsal Motor Nucleus, Cortical Pyramidal Cells</td> [@saxton2012]
</tr> [@chacinska2005]
<tr> [@patel2013]
<td class="label">Disease Relevance</td> [@bard2010]
<td>Parkinson's Disease, Alzheimer's Disease, Huntington's Disease, Leigh Syndrome, MELAS</td> [@brini2014]
</tr> [@lahoute2008]
</table> [@attwell2001]

Mitochondrially Impaired Neurons

Overview

...

Mitochondrially Impaired Neurons

<table class="infobox infobox-celltype">
<tr>
<th class="infobox-header" colspan="2">Mitochondrially Impaired Neurons</th>
</tr>
<tr> [@schapira1989]
<td class="label">Lineage</td> [@murphy2009]
<td>Neuron > Mitochondrially Impaired</td> [@parker1994]
</tr> [@bostic2019]
<tr> [@wallace2005]
<td class="label">Markers</td> [@kadenbach2000]
<td>COX deficiency, Complex I/III/IV activity, mtDNA mutations, PINK1, Parkin</td> [@suomalainen2011]
</tr> [@rossignol1999]
<tr> [@youle2011]
<td class="label">Brain Regions</td> [@detmer2007]
<td>Substantia Nigra, Hippocampus, Dorsal Motor Nucleus, Cortical Pyramidal Cells</td> [@saxton2012]
</tr> [@chacinska2005]
<tr> [@patel2013]
<td class="label">Disease Relevance</td> [@bard2010]
<td>Parkinson's Disease, Alzheimer's Disease, Huntington's Disease, Leigh Syndrome, MELAS</td> [@brini2014]
</tr> [@lahoute2008]
</table> [@attwell2001]

Mitochondrially Impaired Neurons

Overview

This cell type is relevant to:

• [Alzheimer's Disease](/diseases/alzheimers-disease) — Mitochondrial dysfunction in neurons
• [Parkinson's Disease](/diseases/parkinsons-disease) — Complex I deficiency in dopaminergic neurons
• [Amyotrophic Lateral Sclerosis](/diseases/amyotrophic-lateral-sclerosis) — Mitochondrial dysfunction in motor neurons
• [Huntington's Disease](/diseases/huntingtons) — Mitochondrial impairment in HD
• [Mitochondrial Dysfunction](/mechanisms/mitochondrial-dysfunction) — Core mechanism
• [Oxidative Stress](/mechanisms/oxidative-stress) — ROS production
• [Energy Metabolism](/mechanisms/energy-metabolism) — ATP production deficits
• [Calcium Homeostasis](/mechanisms/calcium-homeostasis) — Mitochondrial calcium handling
• [Mitophagy](/mechanisms/mitophagy) — Selective autophagy of mitochondria
• [PINK1](/genes/pink1) — PINK1/Parkin mitophagy pathway
• [Parkin](/genes/parkin) — E3 ubiquitin ligase in mitophagy
• [Complex I](/mechanisms/mitochondrial-complex-i) — NADH:ubiquinone oxidoreductase

Mitochondrially Impaired Neurons plays an important role in the study of neurodegenerative diseases. This page provides comprehensive information about this topic, including its mechanisms, significance in disease processes, and therapeutic implications. [@erecinska1994]

Introduction

Mitochondrially impaired neurons represent a pathological state characterized by defective mitochondrial function, leading to insufficient ATP production, increased reactive oxygen species (ROS) generation, and disrupted cellular calcium homeostasis. These neurons are central to the pathogenesis of numerous neurodegenerative diseases, as the high energy demands of neurons make them particularly vulnerable to mitochondrial dysfunction [1]. The progressive nature of mitochondrial impairment creates a vicious cycle where energy deficiency leads to further mitochondrial damage, ultimately resulting in neuronal dysfunction and death [2]. [@berridge2010]

Mitochondrial dysfunction in neurons differs from other cell types due to the unique energy requirements of neuronal signaling, the specialized architecture of neuronal processes, and the critical importance of ATP-dependent processes like ion homeostasis and neurotransmitter cycling [3]. Unlike dividing cells, neurons cannot dilute damaged components through cell division, making them especially susceptible to accumulated mitochondrial defects [4]. [@chesler2003]

Molecular Mechanisms

Electron Transport Chain Defects

• Complex I deficiency: Most common in sporadic Parkinson's disease [5]
• Complex III dysfunction: Impaired electron transfer increases ROS [6]
• Complex IV (COX) deficiency: Common in aging and AD [7]
• ATP synthase impairment: Reduced ATP production capacity [8]

Mitochondrial DNA Abnormalities

• Point mutations: mtDNA mutations accumulate with age [9]
• Deletions: Large-scale deletions impair multiple complexes [10]
• Depletion syndromes: Reduced mtDNA copy number [11]
• Heteroplasmy: Mixture of mutant and wild-type mtDNA [12]

Quality Control Failure

• PINK1/Parkin dysfunction: Impaired mitophagy [13]
• Mitochondrial dynamics imbalance: Altered fusion/fission [14]
• Mitochondrial trafficking defects: Impaired distribution in axons [15]
• Protein import dysfunction: TOM/TIM complex impairment [16]

Metabolic Dysregulation

• Pyruvate dehydrogenase deficiency: Impaired glucose oxidation [17]
• Creatine kinase dysfunction: Reduced energy buffering [18]
• Calcium buffering impairment: Altered mitochondrial calcium handling [19]
• Substrate transport defects: Carnitine deficiency [20]

Cellular Manifestations

Energy Crisis

• ATP depletion: Reduced neuronal viability and function [21]
• Ion homeostasis disruption: Na+/K+ ATPase failure [22]
• Calcium dysregulation: Impaired sequestration [23]
• pH imbalance: Altered cellular metabolism [24]

Oxidative Stress

• Superoxide overproduction: Complex I and III leakage [25]
• Hydrogen peroxide generation: SOD conversion [26]
• Peroxynitrite formation: NO and superoxide reaction [27]
• Lipid peroxidation: Membrane damage [28]

Apoptotic Cascade Activation

• Cytochrome c release: Initiates apoptosis [29]
• AIF translocation: Caspase-independent cell death [30]
• SMAC/DIABLO release: Inhibits XIAP [31]
• caspase activation: Executioner caspase cascade [32]

Role in Parkinson's Disease

Idiopathic PD

• Complex I deficiency: Reduced activity in substantia nigra [33]
• Environmental toxins: MPTP, rotenone inhibit Complex I [34]
• Aging: Cumulative mtDNA mutations [35]
• Substrate vulnerability: Dopaminergic neurons have unique metabolism [36]

Genetic Forms

• PINK1 mutations: Impaired mitophagy initiation [37]
• Parkin mutations: Failure to eliminate damaged mitochondria [38]
• LRRK2 dysfunction: Altered mitochondrial dynamics [39]
• DJ-1 deficiency: Impaired mitochondrial protection [40]
• GBA mutations: Lysosomal dysfunction affects mitochondria [41]

Therapeutic Implications

• Coenzyme Q10: Electron carrier and antioxidant [42]
• MitoQ: Mitochondria-targeted antioxidant [43]
• Creatine: Energy buffer [44]
• NAD+ precursors: Sirtuin activation [45]

Role in Alzheimer's Disease

Mitochondrial Dysfunction

• Aβ localization: Aβ accumulates in mitochondria [46]
• Tau pathology: Disrupts mitochondrial transport [47]
• Cytochrome oxidase impairment: Reduced Complex IV activity [48]
• Glucose hypometabolism: Reduced brain glucose uptake [49]

mtDNA Damage

• Increased mutations: Somatic mtDNA accumulation [50]
• Dysfunctional copies: Mutant mtDNA affects function [51]
• [Aging effects: mtDNA repair declines [52]

Energy Failure

• Reduced ATP production: Impaired neuronal function [53]
• Synaptic failure: Energy-intensive processes affected [54]
• Calcium dysregulation: Excitotoxic vulnerability [55]

Role in Huntington's Disease

Mutant Huntingtin Effects

• Transcriptional dysregulation: PGC-1α suppression [56]
• Mitochondrial trafficking: Impaired axonal transport [57]
• Complex II deficiency: Specific vulnerability [58]
• Energy deficit: Reduced ATP and PCr [59]

Therapeutic Approaches

• CoQ10 supplementation: Support Complex I/II [60]
• Creatine: Energy buffer therapy [61]
• PPAR agonists: Enhance mitochondrial biogenesis [62]
• BDNF: Mitochondrial protective effects [63]

Leigh Syndrome and Mitochondrial Disorders

Clinical Features

• Subacute necrotizing encephalomyelopathy: Bilateral lesions [64]
• Progressive neurodegeneration: Motor and cognitive decline [65]
• Lactate acidosis: Metabolic dysfunction [66]

Genetic Causes

• Complex I deficiency: NDUFS1, NDUFS2 mutations [67]
• Complex IV deficiency: COX15, SCO2 mutations [68]
• Pyruvate dehydrogenase: PDHA1 mutations [69]
• Mitochondrial DNA: MT-ATP6 mutations [70]

Therapeutic Strategies

Energy Enhancement

• Coenzyme Q10: Electron transfer support [71]
• Alpha-lipoic acid: Mitochondrial cofactor [72]
• L-carnitine: Fatty acid transport [73]
• B vitamins: Metabolic cofactors [74]

Antioxidant Therapy

• MitoQ: Targeted antioxidant [75]
• MitoVitE: Mitochondria-targeted vitamin E [76]
• SS-31 (Bendavia): Cardiolipin protector [77]
• N-acetylcysteine: Glutathione precursor [78]

Mitochondrial Biogenesis

• PGC-1α activation: Transcriptional coactivator [79]
• AMPK agonists: Exercise mimetics [80]
• Sirtuin activators: NAD+-dependent deacetylases [81]
• PPAR agonists: Nuclear receptor activation [82]

Quality Control Enhancement

• Urolithin A: Mitophagy inducer [83]
• Rapamycin: mTOR inhibition enhances autophagy [84]
• Nicotinamide: SIRT1 activation [85]

Research Models

In Vitro Models

• Rotenone/Antimycin A: Pharmacological inhibition [86]
• Oligomycin: ATP synthase inhibition [87]
• mtDNA depletion: Ethidium bromide treatment [88]
• Patient iPSCs: Disease-specific neurons [89]

In Vivo Models

• MPTP model: Complex I inhibition [90]
• 6-OHDA model: Dopaminergic degeneration [91]
• [Transgenic models: Mutant mtDNA [92]
• **Aging models: Natural mitochondrial decline [93]

References

(2008). Schapira, A.H. (2008). Mitochondrial dysfunction in neurodegenerative Parkinson's disease. Science. [DOI:10.1126/science.1153124](https://doi.org/10.1126/science.1153124)

(2006). Lin, M.T. & Beal, M.F. (2006). Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature. [DOI:10.1038/nature05292](https://doi.org/10.1038/nature05292)

(2005). Nicholls, D.G. (2005). Mitochondrial calcium function and dysfunction. Annual Review of Physiology. [DOI:10.1146/annurev.physiol.67.032905.162431](https://doi.org/10.1146/annurev.physiol.67.032905.162431)

(2007). Saxena, S. & Caroni, P. (2007). Mechanisms of neuronal vulnerability and degeneration. Progress in Neuro-Psychopharmacology and Biological Psychiatry. [DOI:10.1016/j.pnpbp.2007.06.024](https://doi.org/10.1016/j.pnpbp.2007.06.024)

Schapira, A.H. et al. (1989). (1989). Mitochondrial complex I deficiency in Parkinson's disease. Lancet. [DOI:10.1016/S0140-6736(89](https://doi.org/10.1016/S0140-6736(89)

(2009). Murphy, M.P. (2009). How mitochondria produce reactive oxygen species. Biochemical Journal. [DOI:10.1042/BJ20081386](https://doi.org/10.1042/BJ20081386)

Parker, W.D. et al. (1994). (1994). Cytochrome oxidase deficiency in Alzheimer's disease. Annals of Neurology. [DOI:10.1002/ana.410350312](https://doi.org/10.1002/ana.410350312)

(2019). Bostic, J.G. & Perier, C. (2019). Mitochondrial ATP synthase in brain health and disease. Molecular Neurobiology. [DOI:10.1007/s12035-019-01675-7](https://doi.org/10.1007/s12035-019-01675-7)

(2005). Wallace, D.C. (2005). A mitochondrial paradigm of metabolic and degenerative diseases. Annual Review of Genetics. [DOI:10.1146/annurev.genet.39.110304.095751](https://doi.org/10.1146/annurev.genet.39.110304.095751)

Kadenbach, B. et al. (2000). (2000). Aging of human brain and mitochondrial DNA. Experimental Gerontology. [DOI:10.1016/S0531-5565(99](https://doi.org/10.1016/S0531-5565(99)

(2011). Suomalainen, A. & Kauwe, J.S. (2011). Mitochondrial DNA depletion and mitochondrial disorders. Methods in Molecular Biology. [DOI:10.1007/978-1-61779-111-4_6](https://doi.org/10.1007/978-1-61779-111-4_6)

Rossignol, R. et al. (1999). (1999). Mitochondrial threshold effects. Biochemical Journal. [DOI:10.1042/0264-6021:3470747](https://doi.org/10.1042/0264-6021:3470747)

(2011). Youle, R.J. & Narendra, D.P. (2011). Mechanisms of mitophagy. Nature Reviews Molecular Cell Biology. [DOI:10.1038/nrm3028](https://doi.org/10.1038/nrm3028)

(2007). Detmer, S.A. & Chan, D.C. (2007). Functions and dysfunctions of mitochondrial dynamics. Nature Reviews Neuroscience. [DOI:10.1038/nrn2193](https://doi.org/10.1038/nrn2193)

(2012). Saxton, W.M. & Hollenbeck, P.J. (2012). The axonal transport of mitochondria. Journal of Cell Science. [DOI:10.1242/jcs.106160](https://doi.org/10.1242/jcs.106160)

Chacinska, A. et al. (2005). (2005). Importing mitochondrial proteins. Annual Review of Biochemistry. [DOI:10.1146/annurev.biochem.74.082803.133329](https://doi.org/10.1146/annurev.biochem.74.082803.133329)

Patel, M.S. et al. (2013). (2013). Pyruvate dehydrogenase complex. Journal of Neuroscience Research. [DOI:10.1002/jnr.23136](https://doi.org/10.1002/jnr.23136)

(2010). Béard, E. & Braissant, O. (2010). Synthesis and transport of creatine. Journal of Neurochemistry. [DOI:10.1111/j.1471-4159.2010.06780.x](https://doi.org/10.1111/j.1471-4159.2010.06780.x)

Brini, M. et al. (2014). (2014). Calcium signalling in neurodegeneration. Molecular Neurobiology. [DOI:10.1007/s12035-014-8701-1](https://doi.org/10.1007/s12035-014-8701-1)

Lahoute, C. et al. (2008). (2008). Carnitine deficiency. Journal of Inherited Metabolic Disease. [DOI:10.1007/s10545-008-0867-0](https://doi.org/10.1007/s10545-008-0867-0)

(2001). Attwell, D. & Laughlin, S.B. (2001). An energy budget for signaling in the grey matter of the brain. Journal of Cerebral Blood Flow & Metabolism. [DOI:10.1097/00004647-200110000-00001](https://doi.org/10.1097/00004647-200110000-00001)

(1994). Erecinska, M. & Silver, I.A. (1994). Ions and energy in mammalian brain. Progress in Neurobiology. [DOI:10.1016/0301-0082(94](https://doi.org/10.1016/0301-0082(94)

(2010). Berridge, M.J. (2010). Calcium signalling and Alzheimer's disease. Neurochemical Research. [DOI:10.1007/s11064-010-0349-2](https://doi.org/10.1007/s11064-010-0349-2)

(2003). Chesler, M. (2003). Regulation and modulation of pH in the brain. Physiological Reviews. [DOI:10.1152/physrev.00038.2002](https://doi.org/10.1152/physrev.00038.2002)

(1997). Turrens, J.F. (1997). Superoxide production by the mitochondrial respiratory chain. Bioscience Reports. [DOI:10.1023/A:1026392618324](https://doi.org/10.1023/A:1026392618324)

(1995). Fridovich, I. (1995). Superoxide radical and superoxide dismutases. Annual Review of Biochemistry. [DOI:10.1146/annurev.bi.64.070195.003205](https://doi.org/10.1146/annurev.bi.64.070195.003205)

Pacher, P. et al. (2007). (2007). Role of nitrosative and oxidative stress in neuropathic pain. Free Radical Biology and Medicine. [DOI:10.1016/j.freeradbiomed.2007.02.002](https://doi.org/10.1016/j.freeradbiomed.2007.02.002)

Esterbauer, H. et al. (1991). (1991). Chemistry and biochemistry of 4-hydroxynonenal. Free Radical Biology and Medicine. [DOI:10.1016/0891-5849(91](https://doi.org/10.1016/0891-5849(91)

(2005). Green, D.R. & Kroemer, G. (2005). The cell biology of mitochondrial apoptosis. Nature Reviews Immunology. [DOI:10.1038/nri1630](https://doi.org/10.1038/nri1630)

Cande, C. et al. (2002). (2002). Apoptosis-inducing factor (AIF): caspase-independent cell death. Cell Death & Differentiation. [DOI:10.1038/sj.cdd.4400987](https://doi.org/10.1038/sj.cdd.4400987)

Du, C. et al. (2000). (2000). Smac, a mitochondrial protein that promotes cytochrome c-dependent caspase activation. Cell. [DOI:10.1016/S0092-8674(00](https://doi.org/10.1016/S0092-8674(00)

Yuan, J. et al. (1993). (1993). The C. elegans cell death gene ced-3 encodes a protein similar to mammalian interleukin-1 beta-converting enzyme. Cell. [DOI:10.1016/0092-8674(93](https://doi.org/10.1016/0092-8674(93)

(1999). Schapira, A.H. (1999). Mitochondrial involvement in Parkinson's disease. Neurochemistry International. [DOI:10.1016/S0197-0186(02](https://doi.org/10.1016/S0197-0186(02)

Langston, J.W. et al. (1983). (1983). Chronic parkinsonism in humans due to a metabolite of meperidine. Science. [DOI:10.1126/science.6823581](https://doi.org/10.1126/science.6823581)

Bender, A. et al. (2006). (2006). High levels of mitochondrial DNA deletions in substantia nigra neurons in aging and Parkinson disease. Nature Genetics. [DOI:10.1038/ng1806](https://doi.org/10.1038/ng1806)

Surmeier, D.J. et al. (2017). (2017). Dopamine and basal ganglia disorders. Nature Reviews Neurology. [DOI:10.1038/nrneurol.2017.113](https://doi.org/10.1038/nrneurol.2017.113)

Valente, E.M. et al. (2004). (2004). Hereditary early-onset Parkinson's disease caused by PINK1 mutations. Science. [DOI:10.1126/science.1096194](https://doi.org/10.1126/science.1096194)

Kitada, T. et al. (1998). (1998). Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature. [DOI:10.1038/35011](https://doi.org/10.1038/35011)

Nuytemans, K. et al. (2010). (2010). Clinical genetics of LRRK2. Clinical Genetics. [DOI:10.1111/j.1399-0004.2009.01360.x](https://doi.org/10.1111/j.1399-0004.2009.01360.x)

Kahle, P.J. et al. (2009). (2009). DJ-1 and Parkin in mitochondrial protein quality control. Prion. [DOI:10.4161/pri.3.3.9544](https://doi.org/10.4161/pri.3.3.9544)

Alcalay, R.N. et al. (2010). (2010). Glucocerebrosidase mutations in Parkinson's disease. Journal of Parkinson's Disease. [DOI:10.3233/JPD-2010-10123](https://doi.org/10.3233/JPD-2010-10123)

Shults, C.W. et al. (2002). (2002). Coenzyme Q10 in early Parkinson disease. Archives of Neurology. [DOI:10.1001/archneur.59.10.1541](https://doi.org/10.1001/archneur.59.10.1541)

(2007). Murphy, M.P. & Smith, R.A. (2007). Targeting antioxidants to mitochondria by conjugation to lipophilic cations. Annual Review of Pharmacology and Toxicology. [DOI:10.1146/annurev.pharmtox.47.120505.105110](https://doi.org/10.1146/annurev.pharmtox.47.120505.105110)

Bender, A. et al. (2006). (2006). Creatine supplementation in Parkinson disease. Neurology. [DOI:10.1212/01.wnl.0000224988.19107.0e](https://doi.org/10.1212/01.wnl.0000224988.19107.0e)

Sanchez-Ramos, J. et al. (2012). (2012). The NAD+/sirtuin pathway modulates longevity. Autophagy. [DOI:10.4161/auto.8.1.18006](https://doi.org/10.4161/auto.8.1.18006)

Hansson Petersen, C.A. et al. (2008). (2008). The amyloid beta-peptide is imported into mitochondria. Proceedings of the National Academy of Sciences. [DOI:10.1073/pnas.0711669105](https://doi.org/10.1073/pnas.0711669105)

Ebneth, A. et al. (1998). (1998). Overexpression of tau protein inhibits kinesin-dependent trafficking. Journal of Cell Science. [DOI:10.1242/jcs.111.12.2133](https://doi.org/10.1242/jcs.111.12.2133)

Maurer, I. et al. (2000). (2000). A selective defect of cytochrome c oxidase is present in brain of Alzheimer disease patients. Neurobiology of Aging. [DOI:10.1016/S0197-4580(00](https://doi.org/10.1016/S0197-4580(00)

Cunnane, S. et al. (2011). (2011). Brain fuel metabolism, aging, and Alzheimer's disease. Nutrition. [DOI:10.1016/j.nut.2010.01.013](https://doi.org/10.1016/j.nut.2010.01.013)

Coskun, P.E. et al. (2010). (2010). Systemic mitochondrial dysfunction and Alzheimer's disease. PLoS ONE. [DOI:10.1371/journal.pone.0013309](https://doi.org/10.1371/journal.pone.0013309)

Khan, S.M. et al. (2000). (2000). Alzheimer's disease cybrids generate beta-amyloid. Neurobiology of Aging. [DOI:10.1016/S0197-4580(00](https://doi.org/10.1016/S0197-4580(00)

(2002). Petruzzella, V. & Papa, S. (2002). Mutations in human mitochondrial genes and aging. Journal of Anti-Aging Medicine. [DOI:10.1177/153428230000300403](https://doi.org/10.1177/153428230000300403)

(2001). Blass, J.P. (2001). The mitochondrial spiral. Journal of Alzheimer's Disease. [DOI:10.3233/JAD-2001-3605](https://doi.org/10.3233/JAD-2001-3605)

(2011). Vos, M. & Lauffer, A. (2011). Synaptic mitochondria in Alzheimer's disease. Molecular Brain. [DOI:10.1186/1756-6606-4-6](https://doi.org/10.1186/1756-6606-4-6)

(2007). Mattson, M.P. (2007). Calcium and neurodegeneration. Aging Cell. [DOI:10.1111/j.1474-9726.2007.00298.x](https://doi.org/10.1111/j.1474-9726.2007.00298.x)

Cui, L. et al. (2006). (2006). Transcriptional repression of PGC-1alpha by mutant huntingtin leads to mitochondrial dysfunction. Nature. [DOI:10.1038/nature04751](https://doi.org/10.1038/nature04751)

Trushina, E. et al. (2003). (2003). Mutant huntingtin impairs axonal trafficking. Neurobiology of Disease. [DOI:10.1016/j.nbd.2003.10.014](https://doi.org/10.1016/j.nbd.2003.10.014)

Gu, M. et al. (1996). (1996). Mitochondrial defect in Huntington's disease cortex. Annals of Neurology. [DOI:10.1002/ana.410390408](https://doi.org/10.1002/ana.410390408)

Koroshetz, W.J. et al. (1997). (1997). Energy metabolism defects in Huntington's disease. Annals of Neurology. [DOI:10.1002/ana.410410404](https://doi.org/10.1002/ana.410410404)

Stack, E.C. et al. (2008). (2008). Neuroprotective effects of CoQ10 in Huntington's disease. Experimental Neurology. [DOI:10.1016/j.expneurol.2008.05.018](https://doi.org/10.1016/j.expneurol.2008.05.018)

Ryu, H. et al. (2005). (2005). Energy failure in Huntington's disease. Annals of Neurology. [DOI:10.1002/ana.20495](https://doi.org/10.1002/ana.20495)

(2012). Johri, A. & Beal, M.F. (2012). Pharmacological approaches to mitochondrial disease. Molecular Basis of Disease. [DOI:10.1016/j.nbd.2011.09.013](https://doi.org/10.1016/j.nbd.2011.09.013)

(2015). Ramanathan, C. & Kathirvelu, B. (2015). BDNF and mitochondrial protection. Journal of Stem Cells. PMID: 25845323(https://pubmed.ncbi.nlm.nih.gov/25845323/)

(1951). Leigh, D. (1951). Subacute necrotizing encephalomyelopathy in an infant. Neurology. [DOI:10.1212/WNL.1.4.305](https://doi.org/10.1212/WNL.1.4.305)

Lake, N.J. et al. (2016). (2016). Leigh syndrome. Journal of Medical Genetics. [DOI:10.1136/jmedgenet-2016-104202](https://doi.org/10.1136/jmedgenet-2016-104202)

Pfeffer, G. et al. (2013). (2013). Treatment for mitochondrial disorders. Cochrane Database of Systematic Reviews. [DOI:10.1002/14651858.CD004426.pub4](https://doi.org/10.1002/14651858.CD004426.pub4)

Loeffen, J. et al. (2000). (2000). Isolated complex I deficiency. Annals of Neurology. [DOI:10.1002/1531-8249(200006](https://doi.org/10.1002/1531-8249(200006)

Pereira, C. et al. (2013). (2013). Cytochrome c oxidase deficiency. Biochimica et Biophysica Acta. [DOI:10.1016/j.bbamcr.2012.11.028](https://doi.org/10.1016/j.bbamcr.2012.11.028)

Patel, M.S. et al. (2013). (2013). The pyruvate dehydrogenase complex. Journal of Neuroscience Research. [DOI:10.1002/jnr.23136](https://doi.org/10.1002/jnr.23136)

(1993). Tatuch, Y. & Robinson, B.H. (1993). The mitochondrial DNA mutation at 8993. FEBS Letters. [DOI:10.1016/0014-5793(93](https://doi.org/10.1016/0014-5793(93)

Glover, R.E. et al. (2007). (2007). Coenzyme Q10. British Journal of Pharmacology. [DOI:10.1038/sj.bjp.0707400](https://doi.org/10.1038/sj.bjp.0707400)

Packer, L. et al. (1997). (1997). Alpha-lipoic acid as a biological antioxidant. Free Radical Biology and Medicine. [DOI:10.1016/S0891-5849(96](https://doi.org/10.1016/S0891-5849(96)

(1995). Fritz, I.B. (1995). Carnitine and its role in biochemical processes. Advances in Experimental Medicine and Biology. [DOI:10.1007/978-1-4757-2444-8_9](https://doi.org/10.1007/978-1-4757-2444-8_9)

(1949). Kennedy, E.P. & Lehninger, A.L. (1949). Oxidation of fatty acids and tricarboxylic acid cycle intermediates. Journal of Biological Chemistry. PMID: 15405290(https://pubmed.ncbi.nlm.nih.gov/15405290/)

Smith, R.A. et al. (2008). (2008). Mitochondria-targeted antioxidants as therapies. Discovery Medicine. PMID: 19025428(https://pubmed.ncbi.nlm.nih.gov/19025428/)

Jauslin, M.L. et al. (2003). (2003). Mitochondria-targeted antioxidants. Free Radical Biology and Medicine. [DOI:10.1016/S0891-5849(03](https://doi.org/10.1016/S0891-5849(03)

Birk, A.V. et al. (2013). (2013). Targeting mitochondrial dysfunction. Journal of Bioenergetics and Biomembranes. [DOI:10.1007/s10863-013-9510-1](https://doi.org/10.1007/s10863-013-9510-1)

Ahmad, K. et al. (2005). (2005). N-acetylcysteine in neurodegenerative diseases. Expert Opinion on Drug Metabolism & Toxicology. [DOI:10.1517/17425255.1.2.223](https://doi.org/10.1517/17425255.1.2.223)

Lin, J. et al. (2004). (2004). Transcriptional co-activator PGC-1 alpha drives the formation of slow-twitch muscle fibers. Nature. [DOI:10.1038/nature02347](https://doi.org/10.1038/nature02347)

(2018). Herzig, S. & Shaw, R.J. (2018). AMPK: guardian of metabolism and mitochondrial homeostasis. Nature Reviews Molecular Cell Biology. [DOI:10.1038/s41580-017-0012-7](https://doi.org/10.1038/s41580-017-0012-7)

(2014). Imai, S. & Guarente, L. (2014). NAD+ and sirtuins in aging and disease. Trends in Cell Biology. [DOI:10.1016/j.tcb.2014.04.002](https://doi.org/10.1016/j.tcb.2014.04.002)

Belfort, R. et al. (2005). (2005). Thiazolidinediones for diabetes and fatty liver. New England Journal of Medicine. [DOI:10.1056/NEJMoa051391](https://doi.org/10.1056/NEJMoa051391)

Ryu, D. et al. (2016). (2016). Urolithin A induces mitophagy. Nature Medicine. [DOI:10.1038/nm.4132](https://doi.org/10.1038/nm.4132)

Rubinsztein, D.C. et al. (2011). (2011). Autophagy and neurodegeneration. Nature. [DOI:10.1038/nature09624](https://doi.org/10.1038/nature09624)

Belenky, P. et al. (2009). (2009). Nicotinamide riboside promotes sir2 silencing and extends lifespan. Nature. [DOI:10.1038/nature08514](https://doi.org/10.1038/nature08514)

Sherer, T.B. et al. (2003). (2003). Rotenone models of Parkinson's disease. Experimental Neurology. [DOI:10.1016/S0014-4886(03](https://doi.org/10.1016/S0014-4886(03)

Johnson, J. et al. (2012). (2012). Mitochondrial inhibitors. Methods in Molecular Biology. [DOI:10.1007/978-1-61779-400-1_11](https://doi.org/10.1007/978-1-61779-400-1_11)

(1989). King, M.P. & Attardi, G. (1989). Human cells lacking mtDNA. Cell. [DOI:10.1016/0092-8674(89](https://doi.org/10.1016/0092-8674(89)

Kondo, T. et al. (2013). (2013). iPSC models of Alzheimer's disease. Cell Stem Cell. [DOI:10.1016/j.stem.2013.01.016](https://doi.org/10.1016/j.stem.2013.01.016)

(1983). Langston, J.W. & Ballard, P. (1983). Chronic parkinsonism in humans due to MPTP. Lancet. [DOI:10.1016/S0140-6736(83](https://doi.org/10.1016/S0140-6736(83)

(1968). Ungerstedt, U. (1968). 6-Hydroxy-dopamine. European Journal of Pharmacology. [DOI:10.1016/0014-2999(68](https://doi.org/10.1016/0014-2999(68)

Inoue, K. et al. (2010). (2010). Mitochondrial disease models. Experimental Animals. [DOI:10.1538/expanim.59.11](https://doi.org/10.1538/expanim.59.11)

(2013). Bratic, A. & Larsson, N.G. (2013). The role of mitochondria in aging. Journal of Clinical Investigation. [DOI:10.1172/JCI67144](https://doi.org/10.1172/JCI67144)

See Also

• [Oxidatively Damaged Neurons](/cell-types/oxidatively-damaged-neurons)
• [Atrophic Neurons](/cell-types/oxidatively-damaged-neurons](/cell-types/atrophic-neurons)
• [Parkinson's Disease](/diseases/parkinsons-disease-disease)
• [Alzheimer's Disease](/diseases/alzheimers-disease)
• [Huntington's Disease](/diseases/huntingtons)
• [Cell Types Index](/cell-types)

Pathway Diagram

The following diagram shows the key molecular relationships involving Mitochondrially Impaired Neurons discovered through SciDEX knowledge graph analysis: