Advertisement

Mitochondrial Etiology of Neuropsychiatric Disorders

Published:November 20, 2017DOI:https://doi.org/10.1016/j.biopsych.2017.11.018

      Abstract

      The brain has the highest mitochondrial energy demand of any organ. Therefore, subtle changes in mitochondrial energy production will preferentially affect the brain. Considerable biochemical evidence has accumulated revealing mitochondrial defects associated with neuropsychiatric diseases. Moreover, the mitochondrial genome encompasses over a thousand nuclear DNA genes plus hundreds to thousands of copies of the maternally inherited mitochondrial DNA (mtDNA). Therefore, partial defects in either the nuclear DNA or mtDNA genes or combinations of the two can be sufficient to cause neuropsychiatric disorders. Inherited and acquired mtDNA mutations have recently been associated with autism spectrum disorder, which parallels previous evidence of mtDNA variation in other neurological diseases. Therefore, mitochondrial dysfunction may be central to the etiology of a wide spectrum of neurological diseases. The mitochondria and the nucleus communicate to coordinate energy production and utilization, providing the potential for therapeutics by manipulating nuclear regulation of mitochondrial gene expression.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Biological Psychiatry
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Magistretti P.J.
        Brain energy metabolism.
        in: Squire L.R. Fundamental Neuroscience, 2nd ed. Academic Press, New York2003: 339-360
        • Wallace D.C.
        A mitochondrial paradigm of metabolic and degenerative diseases, aging, and cancer: A dawn for evolutionary medicine.
        Annu Rev Genet. 2005; 39: 359-407
        • Wallace D.C.
        Mitochondrial bioenergetic etiology of disease.
        J Clin Invest. 2013; 123: 1405-1412
        • Wallace D.C.
        • Lott M.T.
        • Procaccio V.
        Mitochondrial medicine: The mitochondrial biology and genetics of metabolic and degenerative diseases, cancer, and aging.
        in: Rimoin D.L. Pyeritz R.E. Korf B.R. Emery and Rimoin's Principles and Practice of Medical Genetics, 6th ed. Churchill Livingstone Elsevier, Philadelphia2013: 35-37
        • Wallace D.C.
        • Fan W.
        Energetics, epigenetics, mitochondrial genetics.
        Mitochondrion. 2010; 10: 12-31
        • Wallace D.C.
        • Fan W.
        • Procaccio V.
        Mitochondrial energetics and therapeutics.
        Annu Rev Path. 2010; 5: 297-348
        • Pancrazi L.
        • Di Benedetto G.
        • Colombaioni L.
        • Della Sala G.
        • Testa G.
        • Olimpico F.
        • et al.
        Foxg1 localizes to mitochondria and coordinates cell differentiation and bioenergetics.
        Proc Natl Acad Sci U S A. 2015; 112: 13910-13915
        • Saleem A.
        • Adhihetty P.J.
        • Hood D.A.
        Role of p53 in mitochondrial biogenesis and apoptosis in skeletal muscle.
        Physiol Genomics. 2009; 37: 58-66
        • Saleem A.
        • Hood D.A.
        Acute exercise induces tumour suppressor protein p53 translocation to the mitochondria and promotes a p53-Tfam-mitochondrial DNA complex in skeletal muscle.
        J Physiol. 2013; 591: 3625-3636
        • Shock L.S.
        • Thakkar P.V.
        • Peterson E.J.
        • Moran R.G.
        • Taylor S.M.
        DNA methyltransferase 1, cytosine methylation, and cytosine hydroxymethylation in mammalian mitochondria.
        Proc Natl Acad Sci U S A. 2011; 108: 3630-3635
        • Chestnut B.A.
        • Chang Q.
        • Price A.
        • Lesuisse C.
        • Wong M.
        • Martin L.J.
        Epigenetic regulation of motor neuron cell death through DNA methylation.
        J Neurosci. 2011; 31: 16619-16636
        • Martin L.J.
        • Wong M.
        Aberrant regulation of DNA methylation in amyotrophic lateral sclerosis: A new target of disease mechanisms.
        Neurotherapeutics. 2013; 10: 722-733
        • Pedram A.
        • Razandi M.
        • Wallace D.C.
        • Levin E.R.
        Functional estrogen receptors in the mitochondria of breast cancer cells.
        Mol Biol Cell. 2006; 17: 2125-2137
        • Pisano A.
        • Preziuso C.
        • Iommarini L.
        • Perli E.
        • Grazioli P.
        • Campese A.F.
        • et al.
        Targeting estrogen receptor beta as preventive therapeutic strategy for Leber's hereditary optic neuropathy.
        Hum Mol Genet. 2015; 24: 6921-6931
        • Picard M.
        • Zhang J.
        • Hancock S.
        • Derbeneva O.
        • Golhar R.
        • Golik P.
        • et al.
        Progressive increase in mtDNA 3243A>G heteroplasmy causes abrupt transcriptional reprogramming.
        Proc Natl Acad Sci U S A. 2014; 111: E4033-E4042
        • Guha M.
        • Tang W.
        • Sondheimer N.
        • Avadhani N.G.
        Role of calcineurin, hnRNPA2 and Akt in mitochondrial respiratory stress-mediated transcription activation of nuclear gene targets.
        Biochim Biophys Acta. 2010; 1797: 1055-1065
        • Wallace D.C.
        Mitochondrial DNA variation in human radiation and disease.
        Cell. 2015; 163: 33-38
        • Mishmar D.
        • Ruiz-Pesini E.E.
        • Golik P.
        • Macaulay V.
        • Clark A.G.
        • Hosseini S.
        • et al.
        Natural selection shaped regional mtDNA variation in humans.
        Proc Natl Acad Sci U S A. 2003; 100: 171-176
        • Ruiz-Pesini E.
        • Mishmar D.
        • Brandon M.
        • Procaccio V.
        • Wallace D.C.
        Effects of purifying and adaptive selection on regional variation in human mtDNA.
        Science. 2004; 303: 223-226
        • Wallace D.C.
        A mitochondrial etiology of neuropsychiatric disorders.
        JAMA Psychiatry. 2017; 74: 863-864
        • Kujoth G.C.
        • Hiona A.
        • Pugh T.D.
        • Someya S.
        • Panzer K.
        • Wohlgemuth S.E.
        • et al.
        Mitochondrial DNA mutations, oxidative stress, and apoptosis in mammalian aging.
        Science. 2005; 309: 481-484
        • Trifunovic A.
        • Wredenberg A.
        • Falkenberg M.
        • Spelbrink J.N.
        • Rovio A.T.
        • Bruder C.E.
        • et al.
        Premature ageing in mice expressing defective mitochondrial DNA polymerase.
        Nature. 2004; 429: 417-423
        • Vermulst M.
        • Wanagat J.
        • Kujoth G.C.
        • Bielas J.H.
        • Rabinovitch P.S.
        • Prolla T.A.
        • et al.
        DNA deletions and clonal mutations drive premature aging in mitochondrial mutator mice.
        Nat Genet. 2008; 40: 392-394
        • Schriner S.E.
        • Linford N.J.
        • Martin G.M.
        • Treuting P.
        • Ogburn C.E.
        • Emond M.
        • et al.
        Extension of murine life span by overexpression of catalase targeted to mitochondria.
        Science. 2005; 308: 1909-1911
        • Coskun P.
        • Wyrembak J.
        • Schriner S.E.
        • Chen H.W.
        • Marciniack C.
        • LaFerla F.
        • et al.
        A mitochondrial etiology of Alzheimer and Parkinson disease.
        Biochim Biophys Acta. 2012; 1820: 553-564
        • Lin M.T.
        • Beal M.F.
        Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases.
        Nature. 2006; 443: 787-795
        • Lin M.T.
        • Beal M.F.
        Alzheimer's APP mangles mitochondria.
        Nat Med. 2006; 12: 1241-1243
        • Reddy P.H.
        • McWeeney S.
        • Park B.S.
        • Manczak M.
        • Gutala R.V.
        • Partovi D.
        • et al.
        Gene expression profiles of transcripts in amyloid precursor protein transgenic mice: Up-regulation of mitochondrial metabolism and apoptotic genes is an early cellular change in Alzheimer's disease.
        Hum Mol Genet. 2004; 13: 1225-1240
        • Reddy P.H.
        • Tripathi R.
        • Troung Q.
        • Tirumala
        • Reddy T.P.
        • Anekonda V.
        • et al.
        Abnormal mitochondrial dynamics and synaptic degeneration as early events in Alzheimer's disease: Implications to mitochondria-targeted antioxidant therapeutics.
        Biochim Biophys Acta. 2012; 1822: 639-649
        • Orr A.L.
        • Li S.
        • Wang C.E.
        • Li H.
        • Wang J.
        • Rong J.
        • et al.
        N-terminal mutant huntingtin associates with mitochondria and impairs mitochondrial trafficking.
        J Neurosci. 2008; 28: 2783-2792
        • Shirendeb U.
        • Reddy A.P.
        • Manczak M.
        • Calkins M.J.
        • Mao P.
        • Tagle D.A.
        • et al.
        Abnormal mitochondrial dynamics, mitochondrial loss and mutant huntingtin oligomers in Huntington's disease: Implications for selective neuronal damage.
        Hum Mol Genet. 2011; 20: 1438-1455
        • Reddy P.H.
        • Reddy T.P.
        • Manczak M.
        • Calkins M.J.
        • Shirendeb U.
        • Mao P.
        Dynamin-related protein 1 and mitochondrial fragmentation in neurodegenerative diseases.
        Brain Res Rev. 2011; 67: 103-118
        • Shoffner J.M.
        • Brown M.D.
        • Torroni A.
        • Lott M.T.
        • Cabell M.R.
        • Mirra S.S.
        • et al.
        Mitochondrial DNA variants observed in Alzheimer disease and Parkinson disease patients.
        Genomics. 1993; 17: 171-184
        • van der Walt J.M.
        • Dementieva Y.A.
        • Martin E.R.
        • Scott W.K.
        • Nicodemus K.K.
        • Kroner C.C.
        • et al.
        Analysis of European mitochondrial haplogroups with Alzheimer disease risk.
        Neurosci Lett. 2004; 365: 28-32
        • van der Walt J.M.
        • Nicodemus K.K.
        • Martin E.R.
        • Scott W.K.
        • Nance M.A.
        • Watts R.L.
        • et al.
        Mitochondrial polymorphisms significantly reduce the risk of Parkinson disease.
        Am J Hum Genet. 2003; 72: 804-811
        • Khusnutdinova E.
        • Gilyazova I.
        • Ruiz-Pesini E.
        • Derbeneva O.
        • Khusainova R.
        • Khidiyatova I.
        • et al.
        A mitochondrial etiology of neurodegenerative diseases: Evidence from Parkinson's disease.
        Ann N Y Acad Sci. 2008; 1147: 1-20
        • Corral-Debrinski M.
        • Horton T.
        • Lott M.T.
        • Shoffner J.M.
        • McKee A.C.
        • Beal M.F.
        • et al.
        Marked changes in mitochondrial DNA deletion levels in Alzheimer brains.
        Genomics. 1994; 23: 471-476
        • Bender A.
        • Krishnan K.J.
        • Morris C.M.
        • Taylor G.A.
        • Reeve A.K.
        • Perry R.H.
        • et al.
        High levels of mitochondrial DNA deletions in substantia nigra neurons in aging and Parkinson disease.
        Nat Genet. 2006; 38: 515-517
        • Kraytsberg Y.
        • Kudryavtseva E.
        • McKee A.C.
        • Geula C.
        • Kowall N.W.
        • Khrapko K.
        Mitochondrial DNA deletions are abundant and cause functional impairment in aged human substantia nigra neurons.
        Nat Genet. 2006; 38: 518-520
        • Horton T.M.
        • Graham B.H.
        • Corral-Debrinski M.
        • Shoffner J.M.
        • Kaufman A.E.
        • Beal B.F.
        • et al.
        Marked increase in mitochondrial DNA deletion levels in the cerebral cortex of Huntington's disease patients.
        Neurology. 1995; 45: 1879-1883
        • Coskun P.E.
        • Beal M.F.
        • Wallace D.C.
        Alzheimer's brains harbor somatic mtDNA control-region mutations that suppress mitochondrial transcription and replication.
        Proc Natl Acad Sci U S A. 2004; 101: 10726-10731
        • Coskun P.E.
        • Wyrembak J.
        • Derbereva O.
        • Melkonian G.
        • Doran E.
        • Lott I.T.
        • et al.
        Systemic mitochondrial dysfunction and the etiology of Alzheimer's disease and down syndrome dementia.
        J Alzheimers Dis. 2010; 20: S293-S310
        • Cataldo A.M.
        • McPhie D.L.
        • Lange N.T.
        • Punzell S.
        • Elmiligy S.
        • Ye N.Z.
        • et al.
        Abnormalities in mitochondrial structure in cells from patients with bipolar disorder.
        Am J Pathol. 2010; 177: 575-585
        • McMahon F.J.
        • Stine O.C.
        • Meyers D.A.
        • Simpson S.G.
        • DePaulo J.R.
        Patterns of maternal transmission in bipolar affective disorder.
        Am J Hum Genet. 1995; 56: 1277-1286
        • McMahon F.J.
        • Chen Y.S.
        • Patel S.
        • Kokoszka J.
        • Brown M.D.
        • Torroni A.
        • et al.
        Mitochondrial DNA sequence diversity in bipolar affective disorder.
        Am J Psychiatry. 2000; 157: 1058-1064
        • Sequeira A.
        • Martin M.V.
        • Rollins B.
        • Moon E.A.
        • Bunney W.E.
        • Macciardi F.
        • et al.
        Mitochondrial mutations and polymorphisms in psychiatric disorders.
        Front Genet. 2012; 3: 103
        • Rollins B.
        • Martin M.V.
        • Sequeira P.A.
        • Moon E.A.
        • Morgan L.Z.
        • Watson S.J.
        • et al.
        Mitochondrial variants in schizophrenia, bipolar disorder, and major depressive disorder.
        PLoS One. 2009; 4: e4913
      1. Filipek PA (2005): Medical aspects of autism. In: Volkmar FR, Klin A, Paul R, Cohen DJ, editors. Handbook of Autism and Pervasive Developmental Disorders. New York: Wiley, 534-578 (Chapter 520).

        • Rossignol D.A.
        • Frye R.E.
        Mitochondrial dysfunction in autism spectrum disorders: A systematic review and meta-analysis.
        Mol Psychiatry. 2012; 17: 290-314
        • Giulivi C.
        • Zhang Y.F.
        • Omanska-Klusek A.
        • Ross-Inta C.
        • Wong S.
        • Hertz-Picciotto I.
        • et al.
        Mitochondrial dysfunction in autism.
        JAMA. 2010; 304: 2389-2396
        • Guevara-Campos J.
        • Gonzalez-Guevara L.
        • Cauli O.
        Autism and intellectual disability associated with mitochondrial disease and hyperlactacidemia.
        Int J Mol Sci. 2015; 16: 3870-3884
        • Tang G.
        • Gutierrez Rios P.
        • Kuo S.H.
        • Akman H.O.
        • Rosoklija G.
        • Tanji K.
        • et al.
        Mitochondrial abnormalities in temporal lobe of autistic brain.
        Neurobiol Dis. 2013; 54: 349-361
        • Goh S.
        • Dong Z.
        • Zhang Y.
        • Dimauro S.
        • Peterson B.S.
        Mitochondrial dysfunction as a neurobiological subtype of autism spectrum disorder: Evidence from brain imaging.
        JAMA Psychiatry. 2014; 71: 665-671
        • Zhao X.
        • Leotta A.
        • Kustanovich V.
        • Lajonchere C.
        • Geschwind D.H.
        • Law K.
        • et al.
        A unified genetic theory for sporadic and inherited autism.
        Proc Natl Acad Sci U S A. 2007; 104: 12831-12836
        • Leppa V.M.
        • Kravitz S.N.
        • Martin C.L.
        • Andrieux J.
        • Le Caignec C.
        • Martin-Coignard D.
        • et al.
        Rare inherited and de novo CNVs reveal complex contributions to ASD risk in multiplex families.
        Am J Hum Genet. 2016; 99: 540-554
        • Krumm N.
        • O'Roak B.J.
        • Shendure J.
        • Eichler E.E.
        A de novo convergence of autism genetics and molecular neuroscience.
        Trends Neurosci. 2014; 37: 95-105
        • De Rubeis S.
        • He X.
        • Goldberg A.P.
        • Poultney C.S.
        • Samocha K.
        • Cicek A.E.
        • et al.
        Synaptic, transcriptional and chromatin genes disrupted in autism.
        Nature. 2014; 515: 209-215
        • Kosmicki J.A.
        • Samocha K.E.
        • Howrigan D.P.
        • Sanders S.J.
        • Slowikowski K.
        • Lek M.
        • et al.
        Refining the role of de novo protein-truncating variants in neurodevelopmental disorders by using population reference samples.
        Nat Genet. 2017; 49: 504-510
        • Bishop S.L.
        • Farmer C.
        • Bal V.
        • Robinson E.B.
        • Willsey A.J.
        • Werling D.M.
        • et al.
        Identification of developmental and behavioral markers associated with genetic abnormalities in autism spectrum disorder.
        Am J Psychiatry. 2017; 174: 576-585
        • Brandler W.M.
        • Antaki D.
        • Gujral M.
        • Noor A.
        • Rosanio G.
        • Chapman T.R.
        • et al.
        Frequency and complexity of de novo structural mutation in autism.
        Am J Hum Genet. 2016; 98: 667-679
        • Robinson E.B.
        • St Pourcain B.
        • Anttila V.
        • Kosmicki J.A.
        • Bulik-Sullivan B.
        • Grove J.
        • et al.
        Genetic risk for autism spectrum disorders and neuropsychiatric variation in the general population.
        Nat Genet. 2016; 48: 552-555
        • Gaugler T.
        • Klei L.
        • Sanders S.J.
        • Bodea C.A.
        • Goldberg A.P.
        • Lee A.B.
        • et al.
        Most genetic risk for autism resides with common variation.
        Nat Genet. 2014; 46: 881-885
        • Weiner D.J.
        • Wigdor E.M.
        • Ripke S.
        • Walters R.K.
        • Kosmicki J.A.
        • Grove J.
        • et al.
        Polygenic transmission disequilibrium confirms that common and rare variation act additively to create risk for autism spectrum disorders.
        Nat Genet. 2017; 49: 978-985
        • Autism Spectrum Disorders Working Group of The Psychiatric Genomics Consortium
        Meta-analysis of GWAS of over 16,000 individuals with autism spectrum disorder highlights a novel locus at 10q24.32 and a significant overlap with schizophrenia.
        Mol Autism. 2017; 8: 21
        • Smith M.
        • Flodman P.L.
        • Gargus J.J.
        • Simon M.T.
        • Verrell K.
        • Haas R.
        • et al.
        Mitochondrial and ion channel gene alterations in autism.
        Biochim Biophys Acta. 2012; 1817: 1796-1802
        • Yoon J.C.
        • Ng A.
        • Kim B.H.
        • Bianco A.
        • Xavier R.J.
        • Elledge S.J.
        Wnt signaling regulates mitochondrial physiology and insulin sensitivity.
        Genes Dev. 2010; 24: 1507-1518
        • Sanders S.J.
        • He X.
        • Willsey A.J.
        • Ercan-Sencicek A.G.
        • Samocha K.E.
        • Cicek A.E.
        • et al.
        Insights into autism spectrum disorder genomic architecture and biology from 71 risk loci.
        Neuron. 2015; 87: 1215-1233
        • Chalkia D.
        • Singh L.N.
        • Leipzig J.
        • Lvova M.
        • Derbeneva O.
        • Lakatos A.
        • et al.
        Association between mitochondrial DNA haplogroup variation and autism spectrum disorders.
        JAMA Psychiatry. 2017; 74: 1161-1168
        • Wang Y.
        • Picard M.
        • Gu Z.
        Genetic evidence for elevated pathogenicity of mitochondrial DNA heteroplasmy in Autism spectrum disorder.
        PLoS Genet. 2016; 12: e1006391
        • Wallace D.C.
        • Singh G.
        • Lott M.T.
        • Hodge J.A.
        • Schurr T.G.
        • Lezza A.M.
        • et al.
        Mitochondrial DNA mutation associated with Leber's hereditary optic neuropathy.
        Science. 1988; 242: 1427-1430
        • Sadun A.A.
        • La Morgia C.
        • Carelli V.
        Leber's hereditary optic neuropathy.
        Curr Treat Options Neurol. 2011; 13: 109-117
        • Sharpley M.S.
        • Marciniak C.
        • Eckel-Mahan K.
        • McManus M.J.
        • Crimi M.
        • Waymire K.
        • et al.
        Heteroplasmy of mouse mtDNA Is genetically unstable and results in altered behavior and cognition.
        Cell. 2012; 151: 333-343
        • Lin-Hendel E.G.
        • McManus M.J.
        • Wallace D.C.
        • Anderson S.A.
        • Golden J.A.
        Differential mitochondrial requirements for radially and non-radially migrating cortical neurons: implications for mitochondrial disorders.
        Cell Rep. 2016; 15: 229-237
        • Pons R.
        • Andreu A.L.
        • Checcarelli N.
        • Vila M.R.
        • Engelstad K.
        • Sue C.M.
        • et al.
        Mitochondrial DNA abnormalities and autistic spectrum disorders.
        J Pediatr. 2004; 144: 81-85
        • van den Ouweland J.M.
        • Lemkes H.H.
        • Trembath R.C.
        • Ross R.
        • Velho G.
        • Cohen D.
        • et al.
        Maternally inherited diabetes and deafness is a distinct subtype of diabetes and associates with a single point mutation in the mitochondrial tRNALeu(UUR) gene.
        Diabetes. 1994; 43: 746-751
        • Goto Y.
        • Nonaka I.
        • Horai S.
        A mutation in the tRNALeu(UUR) gene associated with the MELAS subgroup of mitochondrial encephalomyopathies.
        Nature. 1990; 348: 651-653
        • Picard M.
        • McManus M.J.
        • Gray J.D.
        • Nasca C.
        • Moffat C.
        • Kopinski P.K.
        • et al.
        Mitochondrial functions modulate neuroendocrine, metabolic, inflammatory, and transcriptional responses to acute psychological stress.
        Proc Natl Acad Sci U S A. 2015; 112: E6614-E6623
        • Derosa G.
        • Sahebkar A.
        • Maffioli P.
        The role of various peroxisome proliferator-activated receptors and their ligands in clinical practice.
        J Cell Physiol. 2018; 233: 153-161
        • Bridges H.R.
        • Sirvio V.A.
        • Agip A.N.
        • Hirst J.
        Molecular features of biguanides required for targeting of mitochondrial respiratory complex I and activation of AMP-kinase.
        BMC Biol. 2016; 14: 65
        • Jager S.
        • Handschin C.
        • St-Pierre J.
        • Spiegelman B.M.
        AMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1alpha.
        Proc Natl Acad Sci U S A. 2007; 104: 12017-12022
        • Subramanian S.
        • Gottschalk W.K.
        • Kim S.Y.
        • Roses A.D.
        • Chiba-Falek O.
        The effects of PPARgamma on the regulation of the TOMM40-APOE-C1 genes cluster.
        Biochim Biophys Acta. 2017; 1863: 810-816
        • Strum J.C.
        • Shehee R.
        • Virley D.
        • Richardson J.
        • Mattie M.
        • Selley P.
        • et al.
        Rosiglitazone induces mitochondrial biogenesis in mouse brain.
        J Alzheimers Dis. 2007; 11: 45-51
        • Risner M.E.
        • Saunders A.M.
        • Altman J.F.
        • Ormandy G.C.
        • Craft S.
        • Foley I.M.
        • et al.
        Efficacy of rosiglitazone in a genetically defined population with mild-to-moderate Alzheimer's disease.
        Pharmacogenomics J. 2006; 6: 246-254
        • Lakatos A.
        • Derbeneva O.
        • Younes D.
        • Keator D.
        • Bakken T.
        • Lvova M.
        • et al.
        Association between mitochondrial DNA variations and Alzheimer's disease in the ADNI cohort.
        Neurobiol Aging. 2010; 31: 1355-1363
        • Coskun P.
        • Helguera P.
        • Nemati Z.
        • Bohannan R.C.
        • Thomas J.
        • Samuel S.E.
        • et al.
        Metabolic and growth rate alterations in lymphoblastic cell lines discriminate between Down syndrome and Alzheimer's disease.
        J Alzheimers Dis. 2016; 55: 737-748
        • Pei L.
        • Mu Y.
        • Leblanc M.
        • Alaynick W.
        • Barish G.D.
        • Pankratz M.
        • et al.
        Dependence of hippocampal function on ERRgamma-regulated mitochondrial metabolism.
        Cell Metab. 2015; 21: 628-636
        • Howarth C.
        • Gleeson P.
        • Attwell D.
        Updated energy budgets for neural computation in the neocortex and cerebellum.
        J Cereb Blood Flow Metab. 2012; 32: 1222-1232
        • Patel A.B.
        • de Graaf R.A.
        • Mason G.F.
        • Kanamatsu T.
        • Rothman D.L.
        • Shulman R.G.
        • et al.
        Glutamatergic neurotransmission and neuronal glucose oxidation are coupled during intense neuronal activation.
        J Cereb Blood Flow Metab. 2004; 24: 972-985
        • McNay E.C.
        • Gold P.E.
        Food for thought: Fluctuations in brain extracellular glucose provide insight into the mechanisms of memory modulation.
        Behav Cogn Neurosci Rev. 2002; 1: 264-280
        • Shulman R.G.
        • Rothman D.L.
        • Behar K.L.
        • Hyder F.
        Energetic basis of brain activity: Implications for neuroimaging.
        Trends Neurosci. 2004; 27: 489-495
        • Fox P.T.
        • Raichle M.E.
        • Mintun M.A.
        • Dence C.
        Nonoxidative glucose consumption during focal physiologic neural activity.
        Science. 1988; 241: 462-464
        • Alberini C.M.
        Transcription factors in long-term memory and synaptic plasticity.
        Physiol Rev. 2009; 89: 121-145
        • Mattson M.P.
        • Gleichmann M.
        • Cheng A.
        Mitochondria in neuroplasticity and neurological disorders.
        Neuron. 2008; 60: 748-766
        • Zheng X.
        • Boyer L.
        • Jin M.
        • Mertens J.
        • Kim Y.
        • Ma L.
        • et al.
        Metabolic reprogramming during neuronal differentiation from aerobic glycolysis to neuronal oxidative phosphorylation.
        eLife. 2016; 5e13374
        • Bliss T.V.
        • Collingridge G.L.
        A synaptic model of memory: Long-term potentiation in the hippocampus.
        Nature. 1993; 361: 31-39
        • Kelleher 3rd, R.J.
        • Govindarajan A.
        • Tonegawa S.
        Translational regulatory mechanisms in persistent forms of synaptic plasticity.
        Neuron. 2004; 44: 59-73
        • Wang T.
        • McDonald C.
        • Petrenko N.B.
        • Leblanc M.
        • Giguere V.
        • Evans R.M.
        • et al.
        Estrogen-related receptor alpha (ERRalpha) and ERRgamma are essential coordinators of cardiac metabolism and function.
        Mol Cell Biol. 2015; 35: 1281-1298
        • Alaynick W.A.
        • Kondo R.P.
        • Xie W.
        • He W.
        • Dufour C.R.
        • Downes M.
        • et al.
        ERRgamma directs and maintains the transition to oxidative metabolism in the postnatal heart.
        Cell Metab. 2007; 6: 13-24
        • Dufour C.R.
        • Wilson B.J.
        • Huss J.M.
        • Kelly D.P.
        • Alaynick W.A.
        • Downes M.
        • et al.
        Genome-wide orchestration of cardiac functions by the orphan nuclear receptors ERRalpha and gamma.
        Cell Metab. 2007; 5: 345-356
        • Alaynick W.A.
        • Way J.M.
        • Wilson S.A.
        • Benson W.G.
        • Pei L.
        • Downes M.
        • et al.
        ERRgamma regulates cardiac, gastric, and renal potassium homeostasis.
        Mol Endocrinol. 2010; 24: 299-309
        • Misra J.
        • Kim D.K.
        • Choi H.S.
        ERRgamma: A junior orphan with a senior role in metabolism.
        Trends Endocrinol Metab. 2017; 28: 261-272
        • Lorke D.E.
        • Susens U.
        • Borgmeyer U.
        • Hermans-Borgmeyer I.
        Differential expression of the estrogen receptor-related receptor gamma in the mouse brain.
        Brain Res Mol Brain Res. 2000; 77: 277-280
        • Gofflot F.
        • Chartoire N.
        • Vasseur L.
        • Heikkinen S.
        • Dembele D.
        • Le Merrer J.
        • et al.
        Systematic gene expression mapping clusters nuclear receptors according to their function in the brain.
        Cell. 2007; 131: 405-418
        • Real M.A.
        • Heredia R.
        • Davila J.C.
        • Guirado S.
        Efferent retinal projections visualized by immunohistochemical detection of the estrogen-related receptor beta in the postnatal and adult mouse brain.
        Neurosci Lett. 2008; 438: 48-53
        • Luo J.
        • Sladek R.
        • Bader J.A.
        • Matthyssen A.
        • Rossant J.
        • Giguere V.
        Placental abnormalities in mouse embryos lacking the orphan nuclear receptor ERR-beta.
        Nature. 1997; 388: 778-782
        • Luo J.
        • Sladek R.
        • Carrier J.
        • Bader J.A.
        • Richard D.
        • Giguere V.
        Reduced fat mass in mice lacking orphan nuclear receptor estrogen-related receptor alpha.
        Mol Cell Biol. 2003; 23: 7947-7956
        • Cui H.
        • Lu Y.
        • Khan M.Z.
        • Anderson R.M.
        • McDaniel L.
        • Wilson H.E.
        • et al.
        Behavioral disturbances in estrogen-related receptor alpha-null mice.
        Cell Rep. 2015; 11: 344-350
        • Lin J.
        • Handschin C.
        • Spiegelman B.M.
        Metabolic control through the PGC-1 family of transcription coactivators.
        Cell Metab. 2005; 1: 361-370
        • Wu Z.
        • Puigserver P.
        • Andersson U.
        • Zhang C.
        • Adelmant G.
        • Mootha V.
        • et al.
        Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1.
        Cell. 1999; 98: 115-124
        • Mootha V.K.
        • Lindgren C.M.
        • Eriksson K.F.
        • Subramanian A.
        • Sihag S.
        • Lehar J.
        • et al.
        PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes.
        Nat Genet. 2003; 34: 267-273
        • Huss J.M.
        • Kopp R.P.
        • Kelly D.P.
        Peroxisome proliferator-activated receptor coactivator-1alpha (PGC-1alpha) coactivates the cardiac-enriched nuclear receptors estrogen-related receptor-alpha and -gamma. Identification of novel leucine-rich interaction motif within PGC-1alpha.
        J Biol Chem. 2002; 277: 40265-40274
        • Lai L.
        • Leone T.C.
        • Zechner C.
        • Schaeffer P.J.
        • Kelly S.M.
        • Flanagan D.P.
        • et al.
        Transcriptional coactivators PGC-1alpha and PGC-lbeta control overlapping programs required for perinatal maturation of the heart.
        Genes Dev. 2008; 22: 1948-1961
        • Lin J.
        • Wu P.H.
        • Tarr P.T.
        • Lindenberg K.S.
        • St-Pierre J.
        • Zhang C.Y.
        • et al.
        Defects in adaptive energy metabolism with CNS-linked hyperactivity in PGC-1alpha null mice.
        Cell. 2004; 119: 121-135
        • Leone T.C.
        • Lehman J.J.
        • Finck B.N.
        • Schaeffer P.J.
        • Wende A.R.
        • Boudina S.
        • et al.
        PGC-1alpha deficiency causes multi-system energy metabolic derangements: muscle dysfunction, abnormal weight control and hepatic steatosis.
        PLoS Biol. 2005; 3: e101
        • Ma D.
        • Li S.
        • Lucas E.K.
        • Cowell R.M.
        • Lin J.D.
        Neuronal inactivation of peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC-1alpha) protects mice from diet-induced obesity and leads to degenerative lesions.
        J Biol Chem. 2010; 285: 39087-39095
        • Tsunemi T.
        • La Spada A.R.
        PGC-1α at the intersection of bioenergetics regulation and neuron function: From Huntington's disease to Parkinson's disease and beyond.
        Prog Neurobiology. 2012; 97: 142-151
        • St-Pierre J.
        • Drori S.
        • Uldry M.
        • Silvaggi J.M.
        • Rhee J.
        • Jager S.
        • et al.
        Suppression of reactive oxygen species and neurodegeneration by the PGC-1 transcriptional coactivators.
        Cell. 2006; 127: 397-408
        • Cui L.
        • Jeong H.
        • Borovecki F.
        • Parkhurst C.N.
        • Tanese N.
        • Krainc D.
        Transcriptional repression of PGC-1alpha by mutant huntingtin leads to mitochondrial dysfunction and neurodegeneration.
        Cell. 2006; 127: 59-69
        • Weydt P.
        • Soyal S.M.
        • Gellera C.
        • Didonato S.
        • Weidinger C.
        • Oberkofler H.
        • et al.
        The gene coding for PGC-1alpha modifies age at onset in Huntington's disease.
        Mol Neurodegener. 2009; 4: 3
        • Zheng B.
        • Liao Z.
        • Locascio J.J.
        • Lesniak K.A.
        • Roderick S.S.
        • Watt M.L.
        • et al.
        PGC-1alpha, a potential therapeutic target for early intervention in Parkinson's disease.
        Sci Transl Med. 2010; 2: 52ra73
        • Shin J.H.
        • Ko H.S.
        • Kang H.
        • Lee Y.
        • Lee Y.I.
        • Pletinkova O.
        • et al.
        PARIS (ZNF746) repression of PGC-1alpha contributes to neurodegeneration in Parkinson's disease.
        Cell. 2011; 144: 689-702

      Linked Article

      • So Happy Together: The Storied Marriage Between Mitochondria and the Mind
        Biological PsychiatryVol. 83Issue 9
        • Preview
          More than a billion years ago—or so the thinking goes—one of our single-celled ancestors happened to engulf a unicellular prokaryote. Like many couples that would follow them, the cells realized that life together—while not uncomplicated—was easier than life apart. As it turns out, the prokaryote was useful; it had figured out how to perform aerobic respiration to generate large amounts of energy in the form of adenosine triphosphate (ATP).
        • Full-Text
        • PDF