The Role of Mitochondrial Genes in Neurodegenerative Disorders

Mitochondrial disorders are clinically heterogeneous, resulting from nuclear gene and mitochondrial mutations that disturb the mitochondrial functions and dynamics. There is a lack of evidence linking mtDNA mutations to neurodegenerative disorders, mainly due to the absence of noticeable neuropathological lesions in postmortem samples. This review describes various gene mutations in Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, and stroke. These abnormalities, including PINK1, Parkin, and SOD1 mutations, seem to reveal mitochondrial dysfunctions due to either mtDNA mutation or deletion, the mechanism of which remains unclear in depth.

[1]  Hoon Kim,et al.  (Hetero-)(arylidene)arylhydrazides as Multitarget-Directed Monoamine Oxidase Inhibitors. , 2020, ACS combinatorial science.

[2]  D. G. Parambi,et al.  Exploring the Therapeutic Potentials of Highly Selective Oxygenated Chalcone Based MAO-B Inhibitors in a Haloperidol-Induced Murine Model of Parkinson’s Disease , 2020, Neurochemical Research.

[3]  T. Behl,et al.  Molecular mechanism of zinc neurotoxicity in Alzheimer’s disease , 2020, Environmental Science and Pollution Research.

[4]  N. Bresolin,et al.  The Role of Mitochondria in Neurodegenerative Diseases: the Lesson from Alzheimer’s Disease and Parkinson’s Disease , 2020, Molecular Neurobiology.

[5]  D. G. Parambi,et al.  Revisiting the blood-brain barrier: A hard nut to crack in the transportation of drug molecules , 2020, Brain Research Bulletin.

[6]  D. G. Parambi,et al.  Advancements in nanotherapeutics for Alzheimer’s disease: current perspectives , 2019, The Journal of pharmacy and pharmacology.

[7]  Nidhi Sharma,et al.  Mitochondrial DNA: Epigenetics and environment , 2019, Environmental and molecular mutagenesis.

[8]  Jong Seung Kim,et al.  Direct readout protonophore induced selective uncoupling and dysfunction of individual mitochondria within cancer cells. , 2019, Chemical communications.

[9]  F. Coppedè,et al.  Mitoepigenetics and Neurodegenerative Diseases , 2019, Front. Endocrinol..

[10]  A. Alexiou,et al.  Role of GTPases in the Regulation of Mitochondrial Dynamics in Alzheimer’s Disease and CNS-Related Disorders , 2018, Molecular Neurobiology.

[11]  S. Shaji,et al.  (I-3,II-3)-Biacacetin-mediated cell death involves mitochondria , 2018, Molecular and Cellular Biochemistry.

[12]  K. Wimalasena,et al.  Characteristics of the mitochondrial and cellular uptake of MPP+, as probed by the fluorescent mimic, 4'I-MPP+ , 2018, bioRxiv.

[13]  Faez Iqbal Khan,et al.  Mitochondrial Dynamics and Proteins Related to Neurodegenerative Diseases. , 2017, Current protein & peptide science.

[14]  J. Strosznajder,et al.  Sirtuins and Their Roles in Brain Aging and Neurodegenerative Disorders , 2016, Neurochemical Research.

[15]  Liu Yang,et al.  Aging-related 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurochemial and behavioral deficits and redox dysfunction: improvement by AK-7 , 2016, Experimental Gerontology.

[16]  M. Barrachina,et al.  Altered Mitochondrial DNA Methylation Pattern in Alzheimer Disease-Related Pathology and in Parkinson Disease. , 2016, The American journal of pathology.

[17]  M. Keogh,et al.  Mitochondrial DNA mutations in neurodegeneration. , 2015, Biochimica et biophysica acta.

[18]  J. Strosznajder,et al.  The Molecular Mechanism of Amyloid β42 Peptide Toxicity: The Role of Sphingosine Kinase-1 and Mitochondrial Sirtuins , 2015, PloS one.

[19]  Man Zhang,et al.  Mitochondrial Sirt3 Expression is Decreased in APP/PS1 Double Transgenic Mouse Model of Alzheimer’s Disease , 2015, Neurochemical Research.

[20]  M. Duchen,et al.  PPARγ and PGC-1α as Therapeutic Targets in Parkinson’s , 2014, Neurochemical Research.

[21]  Laura C. Greaves,et al.  Similar patterns of clonally expanded somatic mtDNA mutations in the colon of heterozygous mtDNA mutator mice and ageing humans , 2014, Mechanisms of Ageing and Development.

[22]  João Carneiro,et al.  Mitochondrial DNA Rearrangements in Health and Disease—A Comprehensive Study , 2014, Human mutation.

[23]  M. Lovell,et al.  Epigenetic changes in the progression of Alzheimer's disease , 2013, Mechanisms of Ageing and Development.

[24]  M. Elstner,et al.  Lewy body pathology is associated with mitochondrial DNA damage in Parkinson's disease , 2013, Neurobiology of Aging.

[25]  T. Prolla,et al.  Accumulation of mitochondrial DNA deletions within dopaminergic neurons triggers neuroprotective mechanisms. , 2013, Brain : a journal of neurology.

[26]  M. Chesselet,et al.  Mitochondrial dysfunction and oxidative stress in Parkinson's disease , 2013, Progress in Neurobiology.

[27]  David C. Samuels,et al.  Universal heteroplasmy of human mitochondrial DNA , 2012, Human molecular genetics.

[28]  Perry G. Ridge,et al.  Mitochondrial Genomic Analysis of Late Onset Alzheimer’s Disease Reveals Protective Haplogroups H6A1A/H6A1B: The Cache County Study on Memory in Aging , 2012, PloS one.

[29]  D. Bogenhagen Mitochondrial DNA nucleoid structure. , 2012, Biochimica et biophysica acta.

[30]  V. Petruzzella,et al.  Mitochondrial genome large rearrangements in the skeletal muscle of a patient with PMA , 2012, European journal of neurology.

[31]  Nick C Fox,et al.  No consistent evidence for association between mtDNA variants and Alzheimer disease , 2012, Neurology.

[32]  I. McKeith,et al.  Relationship between mitochondria and α-synuclein: a study of single substantia nigra neurons. , 2012, Archives of neurology.

[33]  L. Martin,et al.  Epigenetic Regulation of Motor Neuron Cell Death through DNA Methylation , 2011, The Journal of Neuroscience.

[34]  K. Khrapko The timing of mitochondrial DNA mutations in aging , 2011, Nature Genetics.

[35]  Trygve E Bakken,et al.  Association between mitochondrial DNA variations and Alzheimer's disease in the ADNI cohort , 2010, Neurobiology of Aging.

[36]  P. Rothwell,et al.  Mitochondrial DNA haplogroups and risk of transient ischaemic attack and ischaemic stroke: a genetic association study , 2010, The Lancet Neurology.

[37]  Robert W. Taylor,et al.  Mitochondrial DNA mutations and human disease. , 2010, Biochimica et biophysica acta.

[38]  N. Lax,et al.  The mitochondrial brain: From mitochondrial genome to neurodegeneration , 2010, Biochimica et biophysica acta.

[39]  M. Rossi,et al.  Mitochondrial Localization of PARP-1 Requires Interaction with Mitofilin and Is Involved in the Maintenance of Mitochondrial DNA Integrity* , 2009, The Journal of Biological Chemistry.

[40]  D. Turnbull,et al.  Do organellar genomes function as long-term redox damage sensors? , 2009, Trends in genetics : TIG.

[41]  P. Pinton,et al.  Mitochondria, calcium and cell death: a deadly triad in neurodegeneration. , 2009, Biochimica et biophysica acta.

[42]  Manfred Kayser,et al.  Updated comprehensive phylogenetic tree of global human mitochondrial DNA variation , 2009, Human mutation.

[43]  Jie-Jin Wang,et al.  Mitochondrial DNA haplogroups J and K are not protective for Parkinson's disease in the Australian community , 2009, Movement disorders : official journal of the Movement Disorder Society.

[44]  S. Mitra,et al.  Long Patch Base Excision Repair in Mammalian Mitochondrial Genomes* , 2008, Journal of Biological Chemistry.

[45]  R. Maletta,et al.  No evidence of association between frontotemporal dementia and major European mtDNA haplogroups , 2008, European journal of neurology.

[46]  Keith W. Caldecott,et al.  Single-strand break repair and genetic disease , 2008, Nature Reviews Genetics.

[47]  C. Meissner,et al.  The 4977bp deletion of mitochondrial DNA in human skeletal muscle, heart and different areas of the brain: A useful biomarker or more? , 2008, Experimental Gerontology.

[48]  R. Scarpulla Transcriptional paradigms in mammalian mitochondrial biogenesis and function. , 2008, Physiological reviews.

[49]  David C Samuels,et al.  What causes mitochondrial DNA deletions in human cells? , 2008, Nature Genetics.

[50]  A. Plaitakis,et al.  Mitochondrial DNA polymorphisms and haplogroups in Parkinson's disease and control individuals with a similar genetic background , 2008, Journal of Human Genetics.

[51]  Robert W. Taylor,et al.  Mutation of OPA1 causes dominant optic atrophy with external ophthalmoplegia, ataxia, deafness and multiple mitochondrial DNA deletions: a novel disorder of mtDNA maintenance. , 2008, Brain : a journal of neurology.

[52]  J. Elson,et al.  Strong Purifying Selection in Transmission of Mammalian Mitochondrial DNA , 2008, PLoS biology.

[53]  Z. Chrzanowska-Lightowlers,et al.  How do mammalian mitochondria synthesize proteins? , 2007, Biochemical Society transactions.

[54]  W. Tate,et al.  mtRF1a Is a Human Mitochondrial Translation Release Factor Decoding the Major Termination Codons UAA and UAG , 2007, Molecular cell.

[55]  A. Bacci,et al.  Lack of association between mtDNA haplogroups and Alzheimer’s disease in Tuscany , 2007, Neurological Sciences.

[56]  J. Jankovic,et al.  A randomized clinical trial of coenzyme Q10 and GPI-1485 in early Parkinson disease , 2007, Neurology.

[57]  Pierre Baldi,et al.  An enhanced MITOMAP with a global mtDNA mutational phylogeny , 2006, Nucleic Acids Res..

[58]  M. Beal,et al.  Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases , 2006, Nature.

[59]  Robert W. Taylor,et al.  High levels of mitochondrial DNA deletions in substantia nigra neurons in aging and Parkinson disease , 2006, Nature Genetics.

[60]  Laura C. Greaves,et al.  Mitochondrial DNA mutations in human disease , 2006, IUBMB life.

[61]  D. Turnbull,et al.  mtDNA mutations and common neurodegenerative disorders. , 2005, Trends in genetics : TIG.

[62]  M. Beal,et al.  Mitochondria take center stage in aging and neurodegeneration , 2005, Annals of neurology.

[63]  M. van der Giezen,et al.  Degenerate mitochondria , 2005, EMBO reports.

[64]  M. T. Pellecchia,et al.  Mitochondrial DNA haplogroup K is associated with a lower risk of Parkinson's disease in Italians , 2005, European Journal of Human Genetics.

[65]  Shamkant B. Navathe,et al.  MITOMAP: a human mitochondrial genome database—2004 update , 2004, Nucleic Acids Res..

[66]  M. Beal,et al.  Alzheimer's brains harbor somatic mtDNA control-region mutations that suppress mitochondrial transcription and replication. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[67]  Howard T. Jacobs,et al.  Premature ageing in mice expressing defective mitochondrial DNA polymerase , 2004, Nature.

[68]  I. Santana,et al.  Frontotemporal dementia and mitochondrial DNA transitions , 2004, Neurobiology of Disease.

[69]  A. Godzik,et al.  Mitochondrial fission in apoptosis, neurodegeneration and aging. , 2003, Current opinion in cell biology.

[70]  W. Kuhn,et al.  Coenzyme Q10 supplementation provides mild symptomatic benefit in patients with Parkinson's disease , 2003, Neuroscience Letters.

[71]  Jean-Pierre Mazat,et al.  Mitochondrial threshold effects. , 2003, The Biochemical journal.

[72]  M. Fardeau,et al.  Ageing muscle: clonal expansions of mitochondrial DNA point mutations and deletions cause focal impairment of mitochondrial function , 2002, Neuromuscular Disorders.

[73]  M. Beal,et al.  High aggregate burden of somatic mtDNA point mutations in aging and Alzheimer's disease brain. , 2002, Human molecular genetics.

[74]  M. Beal,et al.  In Vivo Regulation of Oxidative Phosphorylation in Cells Harboring a Stop-codon Mutation in Mitochondrial DNA-encoded Cytochrome c Oxidase Subunit I* , 2001, The Journal of Biological Chemistry.

[75]  P. Ince,et al.  Mitochondrial enzyme-deficient hippocampal neurons and choroidal cells in AD , 2001, Neurology.

[76]  D. Turnbull,et al.  Random intracellular drift explains the clonal expansion of mitochondrial DNA mutations with age. , 2001, American journal of human genetics.

[77]  T. Parsons,et al.  Point mutations of the mtDNA control region in normal and neurodegenerative human brains. , 2001, American Journal of Human Genetics.

[78]  J. Mazziotta,et al.  Cerebral metabolic and cognitive decline in persons at genetic risk for Alzheimer's disease. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[79]  P. Donnelly,et al.  The mutation rate in the human mtDNA control region. , 2000, American journal of human genetics.

[80]  H. Jacobs,et al.  Coupled Leading- and Lagging-Strand Synthesis of Mammalian Mitochondrial DNA , 2000, Cell.

[81]  G. Attardi,et al.  Tight Control of Respiration by NADH Dehydrogenase ND5 Subunit Gene Expression in Mouse Mitochondria , 2000, Molecular and Cellular Biology.

[82]  D. Turnbull,et al.  Reanalysis and revision of the Cambridge reference sequence for human mitochondrial DNA , 1999, Nature Genetics.

[83]  B. Sykes,et al.  Phylogeography of mitochondrial DNA in western Europe , 1998, Annals of human genetics.

[84]  Massimo Zeviani,et al.  Cytochrome c Oxidase subunit I microdeletion in a patient with motor neuron disease , 1998, Annals of neurology.

[85]  F. Castora,et al.  Elevated levels of the Kearns-Sayre syndrome mitochondrial DNA deletion in temporal cortex of Alzheimer's patients. , 1997, Mutation research.

[86]  S. Weis,et al.  Cytochrome c oxidase defects of the human substantia nigra in normal aging , 1996, Neurobiology of Aging.

[87]  M. Murphy,et al.  Altered mitochondrial function in fibroblasts containing MELAS or MERRF mitochondrial DNA mutations. , 1996, The Biochemical journal.

[88]  John X. Morris,et al.  Increased risk of dementia in mothers of Alzheimer's disease cases , 1996, Neurology.

[89]  J. Enríquez,et al.  MtDNA mutation in MERRF syndrome causes defective aminoacylation of tRNALys and premature translation termination , 1995, Nature Genetics.

[90]  B. V. van Oost,et al.  The relationship between mitochondrial genotype and mitochondrial phenotype in lymphoblasts with a heteroplasmic mtDNA deletion. , 1994, Human molecular genetics.

[91]  H. Reichmann,et al.  Electron transport chain defects in Alzheimer's disease. , 1994, Neurology.

[92]  C. Filley,et al.  Electron transport chain defects in Alzheimer's disease brain , 1994, Neurology.

[93]  J V Neel,et al.  Asian affinities and continental radiation of the four founding Native American mtDNAs. , 1993, American journal of human genetics.

[94]  J. Haines,et al.  Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis , 1993, Nature.

[95]  E. Shoubridge,et al.  Distribution and threshold expression of the tRNA(Lys) mutation in skeletal muscle of patients with myoclonic epilepsy and ragged-red fibers (MERRF). , 1992, American journal of human genetics.

[96]  M. Beal,et al.  Mitochondrial DNA deletions in human brain: regional variability and increase with advanced age , 1992, Nature Genetics.

[97]  N. Arnheim,et al.  Mosaicism for a specific somatic mitochondrial DNA mutation in adult human brain , 1992, Nature Genetics.

[98]  J. Cooper,et al.  Analyses of mitochondrial respiratory chain function and mitochondrial DNA deletion in human skeletal muscle: Effect of ageing , 1992, Journal of the Neurological Sciences.

[99]  D. Wallace,et al.  Association of mitochondrial DNA damage with aging and coronary atherosclerotic heart disease. , 1992, Mutation research.

[100]  D. Shibata,et al.  A pattern of accumulation of a somatic deletion of mitochondrial DNA in aging human tissues. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[101]  J. Nobrega,et al.  Brain Cytochrome Oxidase in Alzheimer's Disease , 1992, Journal of neurochemistry.

[102]  R. Wiesner,et al.  Counting target molecules by exponential polymerase chain reaction: copy number of mitochondrial DNA in rat tissues. , 1992, Biochemical and biophysical research communications.

[103]  R. Sternglanz,et al.  Identification and characterization of yeast mutants and the gene for a cruciform cutting endonuclease. , 1992, The EMBO journal.

[104]  J. Hayashi,et al.  Introduction of disease-related mitochondrial DNA deletions into HeLa cells lacking mitochondrial DNA results in mitochondrial dysfunction. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[105]  L. Spremulli,et al.  Initiation of protein synthesis in animal mitochondria. Purification and characterization of translational initiation factor 2. , 1991, The Journal of biological chemistry.

[106]  J. Müller‐Höcker Cytochrome c oxidase deficient fibres in the limb muscle and diaphragm of man without muscular disease: An age-related alteration , 1990, Journal of the Neurological Sciences.

[107]  C. Filley,et al.  Cytochrome oxidase deficiency in Alzheimer's disease , 1990, Neurology.

[108]  L. Spremulli,et al.  Bovine mitochondrial protein synthesis elongation factors. Identification and initial characterization of an elongation factor Tu-elongation factor Ts complex. , 1989, The Journal of biological chemistry.

[109]  J. Müller‐Höcker,et al.  Cytochrome-c-oxidase deficient cardiomyocytes in the human heart--an age-related phenomenon. A histochemical ultracytochemical study. , 1989, The American journal of pathology.

[110]  Edward Byrne,et al.  DECLINE IN SKELETAL MUSCLE MITOCHONDRIAL RESPIRATORY CHAIN FUNCTION: POSSIBLE FACTOR IN AGEING , 1989, The Lancet.

[111]  B. Reisberg,et al.  Positron emission tomographic studies of aging and Alzheimer disease. , 1983, AJNR. American journal of neuroradiology.

[112]  D. A. Clayton,et al.  Replication of animal mitochondrial DNA , 1982, Cell.

[113]  F. Sanger,et al.  Sequence and organization of the human mitochondrial genome , 1981, Nature.

[114]  A. Alexiou,et al.  Prediction of Alzheimer's disease , 2020 .

[115]  A. Alexiou,et al.  Recent developments in the etiology, treatment, and potential therapeutic targets for Parkinson's disease: a focus on biochemistry , 2020 .

[116]  E. Hwang Pharmacological Nicotinamide: Mechanisms Centered Around SIRT1 Activity , 2019, Pharmacoepigenetics.

[117]  F. Coppedè,et al.  Decreased Methylation of the Mitochondrial D-Loop Region in Late-Onset Alzheimer's Disease. , 2017, Journal of Alzheimer's disease : JAD.

[118]  L. Polito,et al.  Sirtuin Modulation as Novel Neuroprotective Strategy for Alzheimer’s Disease , 2017 .

[119]  A. Reeve,et al.  An Introduction to Mitochondria, Their Structure and Functions , 2016 .

[120]  Yidong Bai,et al.  Physiology and pathophysiology of mitochondrial DNA. , 2012, Advances in experimental medicine and biology.

[121]  I. McKeith,et al.  The relationship between mitochondria and α-synuclein-A study of single substantia nigra neurons , 2011 .