Mitochondrial Dysfunction in Huntington’s Disease

  • Catarina Carmo
  • Luana Naia
  • Carla Lopes
  • A. Cristina Rego
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1049)


Mitochondrial dysfunction has been described as an early pathological mechanism delineating the selective neurodegeneration that occurs in Huntington’s disease (HD), a polyglutamine-expansion disorder that largely affects the striatum and the cerebral cortex. Over the years, mitochondria roles in eukaryotic cells (e.g. in neurons) have largely diverged from the classically attributed cell power source; indeed, mitochondria not only contribute for synthesis of several metabolites, but are also dynamic organelles that fragment and fuse to achieve a maximal bioenergetic performance, are transported along microtubules, regulate intracellular calcium homeostasis through the interaction with the endoplasmic reticulum, produce free radicals and participate in cell death processes. Indeed, most of these activities have been demonstrated to be affected in HD, potentially contributing for the neuronal dysfunction in pre-symptomatic stages. This chapter resumes some of the evidences that pose mitochondria as a main regulatory organelle in HD-affected neurons, uncovering some potentially therapeutic mitochondrial-based relevant targets.


Calcium dyshomeostasis Oxidative stress Metabolic deficits Mitochondrial dynamics Cell death 



Mitochondrial membrane potential


α-ketoglutarate dehydrogenase


3-nitropropionic acid


Apoptosis inducing factor


Apoptotic protease-activating factor 1


Adenosine triphosphate


B-cell lymphoma 2


Brain derived neurotrophic factor


Bcl-2 homology 3


BH3 interacting-domain death agonist


Bcl-2 interacting mediator of cell death


BCL2/adenovirus E1B 19 kDa protein-interacting protein 3


CREB-binding protein


Creatine kinase


Coenzyme Q


cAMP response element-binding protein


Dynamin-related protein 1


Electron transport chain


Mitochondrial fission 1


Flavin mononucleotide


γ-aminobutyric acid


Glyceraldehyde-3-phosphate dehydrogenase


Glutathione peroxidases


Guanosine triphosphate


Hydrogen peroxide


Huntington’s disease


Human embryonic stem cells


Human huntingtin protein/gene


Rodent huntingtin protein


Inhibitor of Apoptosis Protein-1


Induced pluripotent stem cells




Light chain 3


Mitochondrial calcium uniporter


Mitochondrial fission factor




Human mutant HTT


Rodent mutant Htt


Mitochondrial inner membrane


Mitochondrial intermembrane space


Mitochondrial outer membrane


Mitochondrial DNA


β-nicotinamide adenine dinucleotide


NADH dehydrogenase subunit 5


Nuclear respiratory factor


Nuclear factor-erythroid 2-related factor-2


Optic atrophy 1


Oxidative phosphorylation




Pyruvate dehydrogenase




PTEN-induced putative kinase 1




Peroxisome proliferator-activated receptor




Phosphatase and tensin homolog


Permeability transition pore


p53 upregulated modulator of apoptosis


Reactive oxygen species


Succinate dehydrogenase


Second mitochondria derived activator of caspase/direct inhibitor of apoptosis-binding protein with low pI


Superoxide dismutase


TBP-associated factor 4


TATA-binding protein


Tricarboxylic acid


Mitochondrial transcription factor A


Translocase of the inner membrane


Trafficking kinesin protein


X-linked inhibitor of apoptosis


Yeast artificial chromosome



The authors acknowledge financial support from ‘Fundação para a Ciência e a Tecnologia’ (FCT), Portugal (projects ref. EXPL/BIM-MEC/2220/2013 and Pest-C/SAU/LA0001/2013–2014), co-financed by ‘Programa Operacional Temático Factores de Competividade’ (COMPETE) and supported by the European community fund (FEDER). ACR also acknowledges financial support from ‘Santa Casa da Misericórdia de Lisboa’ (SCML)—Mantero Belard Neuroscience Prize 2013, and ‘Fundação Luso-Americana para o Desenvolvimento’ (FLAD)—Life Science 2020, Portugal. LN holds a Ph.D. fellowship from ‘Fundação para a Ciência e a Tecnologia’ (FCT), Portugal (Reference SFRH/BD/86655/2012). CL was supported by ‘Fundação Luso-Americana para o Desenvolvimento’ (FLAD) Life Science 2020 Postdoctoral Fellowship.


  1. 1.
    Chaturvedi RK, Flint Beal M (2013) Mitochondrial diseases of the brain. Free Radic Biol Med 63:1–29PubMedCrossRefGoogle Scholar
  2. 2.
    Collaborative THsD (1993) A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes. The Huntington’s Disease Collaborative Research Group. In Cell 971–983Google Scholar
  3. 3.
    Kim J, Moody JP, Edgerly CK, Bordiuk OL, Cormier K, Smith K, Beal MF, Ferrante RJ (2010) Mitochondrial loss, dysfunction and altered dynamics in Huntington’s disease. Hum Mol Genet 19:3919–3935PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    Kodsi MH, Swerdlow NR (1997) Mitochondrial toxin 3-nitropropionic acid produces startle reflex abnormalities and striatal damage in rats that model some features of Huntington’s disease. Neurosci Lett 231:103–107PubMedCrossRefGoogle Scholar
  5. 5.
    Saft C, Zange J, Andrich J, Muller K, Lindenberg K, Landwehrmeyer B, Vorgerd M, Kraus PH, Przuntek H, Schols L (2005) Mitochondrial impairment in patients and asymptomatic mutation carriers of Huntington’s disease. Mov Disord Off J Mov Disord Soc 20:674–679CrossRefGoogle Scholar
  6. 6.
    Goebel HH, Heipertz R, Scholz W, Iqbal K, Tellez-Nagel I (1978) Juvenile Huntington chorea: clinical, ultrastructural, and biochemical studies. Neurology 28:23–31PubMedCrossRefGoogle Scholar
  7. 7.
    Beal MF, Brouillet E, Jenkins BG, Ferrante RJ, Kowall NW, Miller JM, Storey E, Srivastava R, Rosen BR, Hyman BT (1993) Neurochemical and histologic characterization of striatal excitotoxic lesions produced by the mitochondrial toxin 3-nitropropionic acid. J Neurosci Off J Soc Neurosci 13:4181–4192CrossRefGoogle Scholar
  8. 8.
    Brouillet E, Hantraye P, Ferrante RJ, Dolan R, Leroy-Willig A, Kowall NW, Beal MF (1995) Chronic mitochondrial energy impairment produces selective striatal degeneration and abnormal choreiform movements in primates. Proc Natl Acad Sci USA 92:7105–7109PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Gu M, Gash MT, Mann VM, Javoy-Agid F, Cooper JM, Schapira AH (1996) Mitochondrial defect in Huntington’s disease caudate nucleus. Ann Neurol 39:385–389PubMedCrossRefGoogle Scholar
  10. 10.
    Choo YS, Johnson GV, MacDonald M, Detloff PJ, Lesort M (2004) Mutant huntingtin directly increases susceptibility of mitochondria to the calcium-induced permeability transition and cytochrome c release. Hum Mol Genet 13:1407–1420PubMedCrossRefGoogle Scholar
  11. 11.
    Panov AV, Gutekunst CA, Leavitt BR, Hayden MR, Burke JR, Strittmatter WJ, Greenamyre JT (2002) Early mitochondrial calcium defects in Huntington’s disease are a direct effect of polyglutamines. Nat Neurosci 5:731–736PubMedCrossRefGoogle Scholar
  12. 12.
    Song W, Chen J, Petrilli A, Liot G, Klinglmayr E, Zhou Y, Poquiz P, Tjong J, Pouladi MA, Hayden MR et al (2011) Mutant huntingtin binds the mitochondrial fission GTPase dynamin-related protein-1 and increases its enzymatic activity. Nat Med 17:377–382PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Napoli E, Wong S, Hung C, Ross-Inta C, Bomdica P, Giulivi C (2013) Defective mitochondrial disulfide relay system, altered mitochondrial morphology and function in Huntington’s disease. Hum Mol Genet 22:989–1004PubMedCrossRefGoogle Scholar
  14. 14.
    Squitieri F, Cannella M, Sgarbi G, Maglione V, Falleni A, Lenzi P, Baracca A, Cislaghi G, Saft C, Ragona G et al (2006) Severe ultrastructural mitochondrial changes in lymphoblasts homozygous for Huntington disease mutation. Mech Ageing Dev 127:217–220PubMedCrossRefGoogle Scholar
  15. 15.
    Yano H, Baranov SV, Baranova OV, Kim J, Pan Y, Yablonska S, Carlisle DL, Ferrante RJ, Kim AH, Friedlander RM (2014) Inhibition of mitochondrial protein import by mutant huntingtin. Nat Neurosci 17:822–831PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Nicholls DG, Ward MW (2000) Mitochondrial membrane potential and neuronal glutamate excitotoxicity: mortality and millivolts. Trends Neurosci 23(4):166–174PubMedCrossRefGoogle Scholar
  17. 17.
    Milakovic T, Quintanilla RA, Johnson GV (2006) Mutant huntingtin expression induces mitochondrial calcium handling defects in clonal striatal cells: functional consequences. J Biol Chem 281:34785–34795PubMedCrossRefGoogle Scholar
  18. 18.
    Naia L, Ferreira IL, Cunha-Oliveira T, Duarte AI, Ribeiro M, Rosenstock TR, Laco MN, Ribeiro MJ, Oliveira CR, Saudou F et al (2015) Activation of IGF-1 and insulin signaling pathways ameliorate mitochondrial function and energy metabolism in Huntington’s Disease human lymphoblasts. Mol Neurobiol 51:331–348PubMedCrossRefGoogle Scholar
  19. 19.
    Sawa A, Wiegand GW, Cooper J, Margolis RL, Sharp AH, Lawler JF Jr, Greenamyre JT, Snyder SH, Ross CA (1999) Increased apoptosis of Huntington disease lymphoblasts associated with repeat length-dependent mitochondrial depolarization. Nat Med 5:1194–1198PubMedCrossRefGoogle Scholar
  20. 20.
    Almeida S, Sarmento-Ribeiro AB, Januario C, Rego AC, Oliveira CR (2008) Evidence of apoptosis and mitochondrial abnormalities in peripheral blood cells of Huntington’s disease patients. Biochem Biophys Res Commun 374:599–603PubMedCrossRefGoogle Scholar
  21. 21.
    Ferreira IL, Nascimento MV, Ribeiro M, Almeida S, Cardoso SM, Grazina M, Pratas J, Santos MJ, Januario C, Oliveira CR et al (2010) Mitochondrial-dependent apoptosis in Huntington’s disease human cybrids. Exp Neurol 222:243–255PubMedCrossRefGoogle Scholar
  22. 22.
    Humbert S, Bryson EA, Cordelieres FP, Connors NC, Datta SR, Finkbeiner S, Greenberg ME, Saudou F (2002) The IGF-1/Akt pathway is neuroprotective in Huntington’s disease and involves Huntingtin phosphorylation by Akt. Dev Cell 2:831–837PubMedCrossRefGoogle Scholar
  23. 23.
    Benchoua A, Trioulier Y, Zala D, Gaillard MC, Lefort N, Dufour N, Saudou F, Elalouf JM, Hirsch E, Hantraye P et al (2006) Involvement of mitochondrial complex II defects in neuronal death produced by N-terminus fragment of mutated huntingtin. Mol Biol Cell 17:1652–1663PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Browne SE (2008) Mitochondria and Huntington’s disease pathogenesis: insight from genetic and chemical models. Ann N Y Acad Sci 1147:358–382PubMedCrossRefGoogle Scholar
  25. 25.
    Maksimovic ID, Jovanovic MD, Colic M, Mihajlovic R, Micic D, Selakovic V, Ninkovic M, Malicevic Z, Rusic-Stojiljkovic M, Jovicic A (2001) Oxidative damage and metabolic dysfunction in experimental Huntington’s disease: selective vulnerability of the striatum and hippocampus. Vojnosanit Pregl 58:237–242PubMedGoogle Scholar
  26. 26.
    Pandey M, Varghese M, Sindhu KM, Sreetama S, Navneet AK, Mohanakumar KP, Usha R (2008) Mitochondrial NAD + -linked State 3 respiration and complex-I activity are compromised in the cerebral cortex of 3-nitropropionic acid-induced rat model of Huntington’s disease. J Neurochem 104:420–434PubMedGoogle Scholar
  27. 27.
    Silva AC, Almeida S, Laco M, Duarte AI, Domingues J, Oliveira CR, Januario C, Rego AC (2013) Mitochondrial respiratory chain complex activity and bioenergetic alterations in human platelets derived from pre-symptomatic and symptomatic Huntington’s disease carriers. Mitochondrion 13:801–809PubMedCrossRefGoogle Scholar
  28. 28.
    Chakraborty J, Rajamma U, Mohanakumar KP (2014) A mitochondrial basis for Huntington’s disease: therapeutic prospects. Mol Cell Biochem 389:277–291PubMedCrossRefGoogle Scholar
  29. 29.
    Oliveira JM, Jekabsons MB, Chen S, Lin A, Rego AC, Goncalves J, Ellerby LM, Nicholls DG (2007) Mitochondrial dysfunction in Huntington’s disease: the bioenergetics of isolated and in situ mitochondria from transgenic mice. J Neurochem 101:241–249PubMedCrossRefGoogle Scholar
  30. 30.
    Brustovetsky N, LaFrance R, Purl KJ, Brustovetsky T, Keene CD, Low WC, Dubinsky JM (2005) Age-dependent changes in the calcium sensitivity of striatal mitochondria in mouse models of Huntington’s Disease. J Neurochem 93:1361–1370PubMedCrossRefGoogle Scholar
  31. 31.
    Pellman JJ, Hamilton J, Brustovetsky T, Brustovetsky N (2015) Ca(2+) handling in isolated brain mitochondria and cultured neurons derived from the YAC128 mouse model of Huntington’s disease. J Neurochem 134:652–667PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    HD iPSC Consortium (2012) Induced pluripotent stem cells from patients with Huntington’s disease show CAG-repeat-expansion-associated phenotypes. Cell stem cell 11:264–278CrossRefGoogle Scholar
  33. 33.
    Mochel F, N’Guyen TM, Deelchand D, Rinaldi D, Valabregue R, Wary C, Carlier PG, Durr A, Henry PG (2012) Abnormal response to cortical activation in early stages of Huntington disease. Movement disorders: official journal of the Movement Disorder Society 27:907–910CrossRefGoogle Scholar
  34. 34.
    Lopes C, Ribeiro M, Duarte AI, Humbert S, Saudou F, Pereira de Almeida L, Hayden M, Rego AC (2014) IGF-1 intranasal administration rescues Huntington’s disease phenotypes in YAC128 mice. Mol Neurobiol 49:1126–1142PubMedCrossRefGoogle Scholar
  35. 35.
    Mochel F, Durant B, Meng X, O’Callaghan J, Yu H, Brouillet E, Wheeler VC, Humbert S, Schiffmann R, Durr A (2012) Early alterations of brain cellular energy homeostasis in Huntington disease models. J Biol Chem 287:1361–1370PubMedCrossRefGoogle Scholar
  36. 36.
    Seong IS, Ivanova E, Lee JM, Choo YS, Fossale E, Anderson M, Gusella JF, Laramie JM, Myers RH, Lesort M et al (2005) HD CAG repeat implicates a dominant property of huntingtin in mitochondrial energy metabolism. Hum Mol Genet 14:2871–2880PubMedCrossRefGoogle Scholar
  37. 37.
    Zhang SF, Hennessey T, Yang L, Starkova NN, Beal MF, Starkov AA (2011) Impaired brain creatine kinase activity in Huntington’s disease. Neurodegener Dis 8:194–201PubMedCrossRefGoogle Scholar
  38. 38.
    Lodi R, Schapira AH, Manners D, Styles P, Wood NW, Taylor DJ, Warner TT (2000) Abnormal in vivo skeletal muscle energy metabolism in Huntington’s disease and dentatorubropallidoluysian atrophy. Ann Neurol 48:72–76PubMedCrossRefGoogle Scholar
  39. 39.
    Naia L, Ribeiro M, Rodrigues J, Duarte AI, Lopes C, Rosenstock TR, Hayden MR, Rego AC (2016) Insulin and IGF-1 regularize energy metabolites in neural cells expressing full-length mutant huntingtin. NeuropeptidesGoogle Scholar
  40. 40.
    Antonini A, Leenders KL, Spiegel R, Meier D, Vontobel P, Weigell-Weber M, Sanchez-Pernaute R, de Yebenez JG, Boesiger P, Weindl A et al (1996) Striatal glucose metabolism and dopamine D2 receptor binding in asymptomatic gene carriers and patients with Huntington’s disease. Brain A J Neurol 119(Pt 6):2085–2095CrossRefGoogle Scholar
  41. 41.
    Mazziotta JC, Phelps ME, Pahl JJ, Huang SC, Baxter LR, Riege WH, Hoffman JM, Kuhl DE, Lanto AB, Wapenski JA et al (1987) Reduced cerebral glucose metabolism in asymptomatic subjects at risk for Huntington’s disease. The New England journal of medicine 316:357–362PubMedCrossRefGoogle Scholar
  42. 42.
    Powers WJ, Haas RH, Le T, Videen TO, Hershey T, McGee-Minnich L, Perlmutter JS (2007) Normal platelet mitochondrial complex I activity in Huntington’s disease. Neurobiology of disease 27:99–101PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Burke JR, Enghild JJ, Martin ME, Jou YS, Myers RM, Roses AD, Vance JM, Strittmatter WJ (1996) Huntingtin and DRPLA proteins selectively interact with the enzyme GAPDH. Nat Med 2:347–350PubMedCrossRefGoogle Scholar
  44. 44.
    Jacobsen JC, Gregory GC, Woda JM, Thompson MN, Coser KR, Murthy V, Kohane IS, Gusella JF, Seong IS, MacDonald ME et al (2011) HD CAG-correlated gene expression changes support a simple dominant gain of function. Hum Mol Genet 20:2846–2860PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Jenkins BG, Koroshetz WJ, Beal MF, Rosen BR (1993) Evidence for impairment of energy metabolism in vivo in Huntington’s disease using localized 1H NMR spectroscopy. Neurology 43:2689–2695PubMedCrossRefGoogle Scholar
  46. 46.
    Koroshetz WJ, Jenkins BG, Rosen BR, Beal MF (1997) Energy metabolism defects in Huntington’s disease and effects of coenzyme Q10. Ann Neurol 41:160–165PubMedCrossRefGoogle Scholar
  47. 47.
    Martin WR, Wieler M, Hanstock CC (2007) Is brain lactate increased in Huntington’s disease? J Neurol Sci 263:70–74PubMedCrossRefGoogle Scholar
  48. 48.
    Tsang TM, Woodman B, McLoughlin GA, Griffin JL, Tabrizi SJ, Bates GP, Holmes E (2006) Metabolic characterization of the R6/2 transgenic mouse model of Huntington’s disease by high-resolution MAS 1H NMR spectroscopy. J Proteome Res 5:483–492PubMedCrossRefGoogle Scholar
  49. 49.
    Ferreira IL, Cunha-Oliveira T, Nascimento MV, Ribeiro M, Proenca MT, Januario C, Oliveira CR, Rego AC (2011) Bioenergetic dysfunction in Huntington’s disease human cybrids. Exp Neurol 231:127–134PubMedCrossRefGoogle Scholar
  50. 50.
    Butterworth J, Yates CM, Reynolds GP (1985) Distribution of phosphate-activated glutaminase, succinic dehydrogenase, pyruvate dehydrogenase and gamma-glutamyl transpeptidase in post-mortem brain from Huntington’s disease and agonal cases. J Neurol Sci 67:161–171PubMedCrossRefGoogle Scholar
  51. 51.
    Sorbi S, Bird ED, Blass JP (1983) Decreased pyruvate dehydrogenase complex activity in Huntington and Alzheimer brain. Ann Neurol 13:72–78PubMedCrossRefGoogle Scholar
  52. 52.
    Andreassen OA, Ferrante RJ, Huang HM, Dedeoglu A, Park L, Ferrante KL, Kwon J, Borchelt DR, Ross CA, Gibson GE et al (2001) Dichloroacetate exerts therapeutic effects in transgenic mouse models of Huntington’s disease. Ann Neurol 50:112–117PubMedCrossRefGoogle Scholar
  53. 53.
    Klivenyi P, Starkov AA, Calingasan NY, Gardian G, Browne SE, Yang L, Bubber P, Gibson GE, Patel MS, Beal MF (2004) Mice deficient in dihydrolipoamide dehydrogenase show increased vulnerability to MPTP, malonate and 3-nitropropionic acid neurotoxicity. J Neurochem 88:1352–1360PubMedCrossRefGoogle Scholar
  54. 54.
    Tabrizi SJ, Cleeter MW, Xuereb J, Taanman JW, Cooper JM, Schapira AH (1999) Biochemical abnormalities and excitotoxicity in Huntington’s disease brain. Ann Neurol 45:25–32PubMedCrossRefGoogle Scholar
  55. 55.
    Naseri NN, Xu H, Bonica J, Vonsattel JP, Cortes EP, Park LC, Arjomand J, Gibson GE (2015) Abnormalities in the tricarboxylic Acid cycle in Huntington disease and in a Huntington disease mouse model. J Neuropathol Exp Neurol 74:527–537PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Sorolla MA, Rodriguez-Colman MJ, Tamarit J, Ortega Z, Lucas JJ, Ferrer I, Ros J, Cabiscol E (2010) Protein oxidation in Huntington disease affects energy production and vitamin B6 metabolism. Free Radic Biol Med 49:612–621PubMedCrossRefGoogle Scholar
  57. 57.
    Vinogradov AD, Grivennikova VG (2015) Oxidation of NADH and ROS production by respiratory complex I. Biochim Biophys ActaGoogle Scholar
  58. 58.
    Bleier L, Drose S (2013) Superoxide generation by complex III: from mechanistic rationales to functional consequences. Biochim Biophys Acta 1827:1320–1331PubMedCrossRefGoogle Scholar
  59. 59.
    Murphy MP (2009) How mitochondria produce reactive oxygen species. Biochem J 417:1–13PubMedCrossRefGoogle Scholar
  60. 60.
    Flynn JM, Melov S (2013) SOD2 in mitochondrial dysfunction and neurodegeneration. Free Radic Biol Med 62:4–12PubMedCrossRefGoogle Scholar
  61. 61.
    Rabilloud T, Heller M, Rigobello MP, Bindoli A, Aebersold R, Lunardi J (2001) The mitochondrial antioxidant defence system and its response to oxidative stress. Proteomics 1:1105–1110PubMedCrossRefGoogle Scholar
  62. 62.
    Hands S, Sajjad MU, Newton MJ, Wyttenbach A (2011) In vitro and in vivo aggregation of a fragment of huntingtin protein directly causes free radical production. J Biol Chem 286:44512–44520PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Sorolla MA, Reverter-Branchat G, Tamarit J, Ferrer I, Ros J, Cabiscol E (2008) Proteomic and oxidative stress analysis in human brain samples of Huntington disease. Free Radic Biol Med 45:667–678PubMedCrossRefGoogle Scholar
  64. 64.
    Tabrizi SJ, Schapira AH (1999) Secondary abnormalities of mitochondrial DNA associated with neurodegeneration. Biochem Soc Symp 66:99–110PubMedCrossRefGoogle Scholar
  65. 65.
    Tabrizi SJ, Workman J, Hart PE, Mangiarini L, Mahal A, Bates G, Cooper JM, Schapira AH (2000) Mitochondrial dysfunction and free radical damage in the Huntington R6/2 transgenic mouse. Ann Neurol 47:80–86PubMedCrossRefGoogle Scholar
  66. 66.
    Ribeiro M, Rosenstock TR, Oliveira AM, Oliveira CR, Rego AC (2014) Insulin and IGF-1 improve mitochondrial function in a PI-3 K/Akt-dependent manner and reduce mitochondrial generation of reactive oxygen species in Huntington’s disease knock-in striatal cells. Free Radic Biol Med 74:129–144PubMedCrossRefGoogle Scholar
  67. 67.
    Ribeiro M, Rosenstock TR, Cunha-Oliveira T, Ferreira IL, Oliveira CR, Rego AC (2012) Glutathione redox cycle dysregulation in Huntington’s disease knock-in striatal cells. Free Radic Biol Med 53:1857–1867PubMedCrossRefGoogle Scholar
  68. 68.
    Chae JI, Kim DW, Lee N, Jeon YJ, Jeon I, Kwon J, Kim J, Soh Y, Lee DS, Seo KS et al (2012) Quantitative proteomic analysis of induced pluripotent stem cells derived from a human Huntington’s disease patient. Biochem J 446:359–371PubMedCrossRefGoogle Scholar
  69. 69.
    Stotland A, Gottlieb RA (2015) Mitochondrial quality control: easy come, easy go. Biochim Biophys Acta 1853:2802–2811PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Zhu J, Wang KZ, Chu CT (2013) After the banquet: mitochondrial biogenesis, mitophagy, and cell survival. Autophagy 9:1663–1676PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    Jin YN, Johnson GV (2010) The interrelationship between mitochondrial dysfunction and transcriptional dysregulation in Huntington disease. J Bioenerg Biomembr 42:199–205PubMedPubMedCentralCrossRefGoogle Scholar
  72. 72.
    Steffan JS, Kazantsev A, Spasic-Boskovic O, Greenwald M, Zhu YZ, Gohler H, Wanker EE, Bates GP, Housman DE, Thompson LM (2000) The Huntington’s disease protein interacts with p53 and CREB-binding protein and represses transcription. Proc Natl Acad Sci USA 97:6763–6768PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Cui L, Jeong H, Borovecki F, Parkhurst CN, Tanese N, Krainc D (2006) Transcriptional repression of PGC-1alpha by mutant huntingtin leads to mitochondrial dysfunction and neurodegeneration. Cell 127:59–69PubMedCrossRefGoogle Scholar
  74. 74.
    Johri A, Chandra A, Beal MF (2013) PGC-1alpha, mitochondrial dysfunction, and Huntington’s disease. Free Radic Biol Med 62:37–46PubMedPubMedCentralCrossRefGoogle Scholar
  75. 75.
    Palikaras K, Tavernarakis N (2014) Mitochondrial homeostasis: the interplay between mitophagy and mitochondrial biogenesis. Exp Gerontol 56:182–188PubMedCrossRefGoogle Scholar
  76. 76.
    Shirendeb UP, Calkins MJ, Manczak M, Anekonda V, Dufour B, McBride JL, Mao P, Reddy PH (2012) Mutant huntingtin’s interaction with mitochondrial protein Drp1 impairs mitochondrial biogenesis and causes defective axonal transport and synaptic degeneration in Huntington’s disease. Hum Mol Genet 21:406–420PubMedCrossRefGoogle Scholar
  77. 77.
    Weydt P, Pineda VV, Torrence AE, Libby RT, Satterfield TF, Lazarowski ER, Gilbert ML, Morton GJ, Bammler TK, Strand AD et al (2006) Thermoregulatory and metabolic defects in Huntington’s disease transgenic mice implicate PGC-1alpha in Huntington’s disease neurodegeneration. Cell Metab 4:349–362PubMedCrossRefGoogle Scholar
  78. 78.
    Detmer SA, Chan DC (2007) Functions and dysfunctions of mitochondrial dynamics. Nat Rev Mol Cell Biol 8:870–879PubMedCrossRefGoogle Scholar
  79. 79.
    Rosenstock TR, Brett AC, Rego AC (2012) Modified mitochondrial dynamics, turnover and function in neurodegeneration: a focus on Huntington’s Disease. Cell Bioenerg Health Dis New Perspect Mitochondrial Biol, 149–194Google Scholar
  80. 80.
    Shirendeb U, Reddy AP, Manczak M, Calkins MJ, Mao P, Tagle DA, Reddy PH (2011) Abnormal mitochondrial dynamics, mitochondrial loss and mutant huntingtin oligomers in Huntington’s disease: implications for selective neuronal damage. Hum Mol Genet 20:1438–1455PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Reddy PH, Shirendeb UP (2012) Mutant huntingtin, abnormal mitochondrial dynamics, defective axonal transport of mitochondria, and selective synaptic degeneration in Huntington’s disease. Biochim Biophys Acta 1822:101–110PubMedCrossRefGoogle Scholar
  82. 82.
    Knott AB, Perkins G, Schwarzenbacher R, Bossy-Wetzel E (2008) Mitochondrial fragmentation in neurodegeneration. Nat Rev Neurosci 9:505–518PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Loson OC, Song Z, Chen H, Chan DC (2013) Fis1, Mff, MiD49, and MiD51 mediate Drp1 recruitment in mitochondrial fission. Mol Biol Cell 24(5):659–667PubMedPubMedCentralCrossRefGoogle Scholar
  84. 84.
    Griffin EE, Detmer SA, Chan DC (2006) Molecular mechanism of mitochondrial membrane fusion. Biochim Biophys Acta 1763:482–489PubMedCrossRefGoogle Scholar
  85. 85.
    Costa V, Giacomello M, Hudec R, Lopreiato R, Ermak G, Lim D, Malorni W, Davies KJ, Carafoli E, Scorrano L (2010) Mitochondrial fission and cristae disruption increase the response of cell models of Huntington’s disease to apoptotic stimuli. EMBO Mol Med 2:490–503PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Zinsmaier KE, Babic M, Russo GJ (2009) Mitochondrial transport dynamics in axons and dendrites. Results Probl Cell Differ 48:107–139PubMedGoogle Scholar
  87. 87.
    Lin MY, Sheng ZH (2015) Regulation of mitochondrial transport in neurons. Exp Cell Res 334:35–44PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Orr AL, Li S, Wang CE, Li H, Wang J, Rong J, Xu X, Mastroberardino PG, Greenamyre JT, Li XJ (2008) N-terminal mutant huntingtin associates with mitochondria and impairs mitochondrial trafficking. J Neurosci Off J Soc Neurosci 28:2783–2792CrossRefGoogle Scholar
  89. 89.
    Trushina E, Dyer RB, Badger JD 2nd, Ure D, Eide L, Tran DD, Vrieze BT, Legendre-Guillemin V, McPherson PS, Mandavilli BS et al (2004) Mutant huntingtin impairs axonal trafficking in mammalian neurons in vivo and in vitro. Mol Cell Biol 24:8195–8209PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Chang TWD, Rintoul GL, Pandipati S, Reynolds IJ (2006) Mutant huntingtin aggregates impair mitochondrial movement and trafficking in cortical neurons. Neurobiol Dis 22(2):388–400PubMedCrossRefGoogle Scholar
  91. 91.
    Twig G, Shirihai OS (2011) The interplay between mitochondrial dynamics and mitophagy. Antioxid Redox Signal 14:1939–1951PubMedPubMedCentralCrossRefGoogle Scholar
  92. 92.
    Allen GF, Toth R, James J, Ganley IG (2013) Loss of iron triggers PINK1/Parkin-independent mitophagy. EMBO Rep 14:1127–1135PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Strappazzon F, Nazio F, Corrado M, Cianfanelli V, Romagnoli A, Fimia GM, Campello S, Nardacci R, Piacentini M, Campanella M et al (2015) AMBRA1 is able to induce mitophagy via LC3 binding, regardless of PARKIN and p62/SQSTM1. Cell Death Differ 22:517PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    Chu CT, Ji J, Dagda RK, Jiang JF, Tyurina YY, Kapralov AA, Tyurin VA, Yanamala N, Shrivastava IH, Mohammadyani D et al (2013) Cardiolipin externalization to the outer mitochondrial membrane acts as an elimination signal for mitophagy in neuronal cells. Nat Cell Biol 15:1197–1205PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Deas E, Plun-Favreau H, Gandhi S, Desmond H, Kjaer S, Loh SH, Renton AE, Harvey RJ, Whitworth AJ, Martins LM et al (2011) PINK1 cleavage at position A103 by the mitochondrial protease PARL. Hum Mol Genet 20:867–879PubMedCrossRefGoogle Scholar
  96. 96.
    Greene AW, Grenier K, Aguileta MA, Muise S, Farazifard R, Haque ME, McBride HM, Park DS, Fon EA (2012) Mitochondrial processing peptidase regulates PINK1 processing, import and Parkin recruitment. EMBO Rep 13:378–385PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Okatsu K, Kimura M, Oka T, Tanaka K, Matsuda N (2015) Unconventional PINK1 localization to the outer membrane of depolarized mitochondria drives Parkin recruitment. J Cell Sci 128:964–978PubMedPubMedCentralCrossRefGoogle Scholar
  98. 98.
    Kazlauskaite A, Martinez-Torres RJ, Wilkie S, Kumar A, Peltier J, Gonzalez A, Johnson C, Zhang J, Hope AG, Peggie M et al (2015) Binding to serine 65-phosphorylated ubiquitin primes Parkin for optimal PINK1-dependent phosphorylation and activation. EMBO Rep 16:939–954PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Narendra D, Tanaka A, Suen DF, Youle RJ (2008) Parkin is recruited selectively to impaired mitochondria and promotes their autophagy. J Cell Biol 183:795–803PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Khalil B, El Fissi N, Aouane A, Cabirol-Pol MJ, Rival T, Lievens JC (2015) PINK1-induced mitophagy promotes neuroprotection in Huntington’s disease. Cell Death Dis 6:e1617PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Wong YC, Holzbaur EL (2014) The regulation of autophagosome dynamics by huntingtin and HAP1 is disrupted by expression of mutant huntingtin, leading to defective cargo degradation. J Neurosci Off J Soc Neurosci 34:1293–1305CrossRefGoogle Scholar
  102. 102.
    Rui YN, Xu Z, Patel B, Chen Z, Chen D, Tito A, David G, Sun Y, Stimming EF, Bellen HJ et al (2015) Huntingtin functions as a scaffold for selective macroautophagy. Nat Cell Biol 17:262–275PubMedPubMedCentralCrossRefGoogle Scholar
  103. 103.
    Sun N, Yun J, Liu J, Malide D, Liu C, Rovira II, Holmstrom KM, Fergusson MM, Yoo YH, Combs CA et al (2015) Measuring In Vivo Mitophagy. Mol Cell 60:685–696PubMedPubMedCentralCrossRefGoogle Scholar
  104. 104.
    Kuwana T, Newmeyer DD (2003) Bcl-2-family proteins and the role of mitochondria in apoptosis. Curr Opin Cell Biol 15:691–699PubMedCrossRefGoogle Scholar
  105. 105.
    Parsons MJ, Green DR (2010) Mitochondria in cell death. Essays Biochem 47:99–114PubMedCrossRefGoogle Scholar
  106. 106.
    Tait SW, Green DR (2012) Mitochondria and cell signalling. J Cell Sci 125:807–815PubMedPubMedCentralCrossRefGoogle Scholar
  107. 107.
    Culmsee C, Mattson MP (2005) p53 in neuronal apoptosis. Biochem Biophys Res Commun 331:761–777PubMedCrossRefGoogle Scholar
  108. 108.
    Duan W, Peng Q, Masuda N, Ford E, Tryggestad E, Ladenheim B, Zhao M, Cadet JL, Wong J, Ross CA (2008) Sertraline slows disease progression and increases neurogenesis in N171-82Q mouse model of Huntington’s disease. Neurobiol Dis 30:312–322PubMedPubMedCentralCrossRefGoogle Scholar
  109. 109.
    Ju TC, Chen HM, Lin JT, Chang CP, Chang WC, Kang JJ, Sun CP, Tao MH, Tu PH, Chang C et al (2011) Nuclear translocation of AMPK-alpha1 potentiates striatal neurodegeneration in Huntington’s disease. J Cell Biol 194:209–227PubMedPubMedCentralCrossRefGoogle Scholar
  110. 110.
    Kong PJ, Kil MO, Lee H, Kim SS, Johnson GV, Chun W (2009) Increased expression of Bim contributes to the potentiation of serum deprivation-induced apoptotic cell death in Huntington’s disease knock-in striatal cell line. Neurol Res 31:77–83PubMedCrossRefGoogle Scholar
  111. 111.
    Leon R, Bhagavatula N, Ulukpo O, McCollum M, Wei J (2010) BimEL as a possible molecular link between proteasome dysfunction and cell death induced by mutant huntingtin. Eur J Neurosci 31:1915–1925PubMedPubMedCentralCrossRefGoogle Scholar
  112. 112.
    Sassone J, Colciago C, Marchi P, Ascardi C, Alberti L, Di Pardo A, Zippel R, Sipione S, Silani V, Ciammola A (2010) Mutant Huntingtin induces activation of the Bcl-2/adenovirus E1B 19-kDa interacting protein (BNip3). Cell Death Dis 1:e7PubMedPubMedCentralCrossRefGoogle Scholar
  113. 113.
    Garcia-Martinez JM, Perez-Navarro E, Xifro X, Canals JM, Diaz-Hernandez M, Trioulier Y, Brouillet E, Lucas JJ, Alberch J (2007) BH3-only proteins Bid and Bim(EL) are differentially involved in neuronal dysfunction in mouse models of Huntington’s disease. J Neurosci Res 85:2756–2769PubMedCrossRefGoogle Scholar
  114. 114.
    Hansson O, Castilho RF, Korhonen L, Lindholm D, Bates GP, Brundin P (2001) Partial resistance to malonate-induced striatal cell death in transgenic mouse models of Huntington’s disease is dependent on age and CAG repeat length. J Neurochem 78:694–703PubMedCrossRefGoogle Scholar
  115. 115.
    Teles AV, Rosenstock TR, Okuno CS, Lopes GS, Bertoncini CR, Smaili SS (2008) Increase in bax expression and apoptosis are associated in Huntington’s disease progression. Neurosci Lett 438:59–63PubMedCrossRefGoogle Scholar
  116. 116.
    Chiang MC, Chen CM, Lee MR, Chen HW, Chen HM, Wu YS, Hung CH, Kang JJ, Chang CP, Chang C et al (2010) Modulation of energy deficiency in Huntington’s disease via activation of the peroxisome proliferator-activated receptor gamma. Hum Mol Genet 19:4043–4058PubMedCrossRefGoogle Scholar
  117. 117.
    Zhang Y, Ona VO, Li M, Drozda M, Dubois-Dauphin M, Przedborski S, Ferrante RJ, Friedlander RM (2003) Sequential activation of individual caspases, and of alterations in Bcl-2 proapoptotic signals in a mouse model of Huntington’s disease. J Neurochem 87:1184–1192PubMedCrossRefGoogle Scholar
  118. 118.
    Goffredo D, Rigamonti D, Zuccato C, Tartari M, Valenza M, Cattaneo E (2005) Prevention of cytosolic IAPs degradation: a potential pharmacological target in Huntington’s Disease. Pharmacol Res 52:140–150PubMedCrossRefGoogle Scholar
  119. 119.
    Rosenstock TR, de Brito OM, Lombardi V, Louros S, Ribeiro M, Almeida S, Ferreira IL, Oliveira CR, Rego AC (2011) FK506 ameliorates cell death features in Huntington’s disease striatal cell models. Neurochem Int 59:600–609PubMedCrossRefGoogle Scholar
  120. 120.
    Vis JC, Schipper E, de Boer-van Huizen RT, Verbeek MM, de Waal RM, Wesseling P, ten Donkelaar HJ, Kremer B (2005) Expression pattern of apoptosis-related markers in Huntington’s disease. Acta Neuropathol 109:321–328PubMedCrossRefGoogle Scholar
  121. 121.
    Ciammola A, Sassone J, Alberti L, Meola G, Mancinelli E, Russo MA, Squitieri F, Silani V (2006) Increased apoptosis, Huntingtin inclusions and altered differentiation in muscle cell cultures from Huntington’s disease subjects. Cell Death Differ 13:2068–2078PubMedCrossRefGoogle Scholar
  122. 122.
    Graham RK, Deng Y, Carroll J, Vaid K, Cowan C, Pouladi MA, Metzler M, Bissada N, Wang L, Faull RL et al (2010) Cleavage at the 586 amino acid caspase-6 site in mutant huntingtin influences caspase-6 activation in vivo. J Neurosci 30:15019–15029PubMedPubMedCentralCrossRefGoogle Scholar
  123. 123.
    Graham RK, Deng Y, Slow EJ, Haigh B, Bissada N, Lu G, Pearson J, Shehadeh J, Bertram L, Murphy Z et al (2006) Cleavage at the caspase-6 site is required for neuronal dysfunction and degeneration due to mutant huntingtin. Cell 125:1179–1191PubMedCrossRefGoogle Scholar
  124. 124.
    Hermel E, Gafni J, Propp SS, Leavitt BR, Wellington CL, Young JE, Hackam AS, Logvinova AV, Peel AL, Chen SF et al (2004) Specific caspase interactions and amplification are involved in selective neuronal vulnerability in Huntington’s disease. Cell Death Differ 11:424–438PubMedCrossRefGoogle Scholar
  125. 125.
    Warby SC, Doty CN, Graham RK, Carroll JB, Yang YZ, Singaraja RR, Overall CM, Hayden MR (2008) Activated caspase-6 and caspase-6-cleaved fragments of huntingtin specifically colocalize in the nucleus. Hum Mol Genet 17:2390–2404PubMedCrossRefGoogle Scholar
  126. 126.
    Tebbenkamp AT, Green C, Xu G, Denovan-Wright EM, Rising AC, Fromholt SE, Brown HH, Swing D, Mandel RJ, Tessarollo L et al (2011) Transgenic mice expressing caspase-6-derived N-terminal fragments of mutant huntingtin develop neurologic abnormalities with predominant cytoplasmic inclusion pathology composed largely of a smaller proteolytic derivative. Hum Mol Genet 20:2770–2782PubMedPubMedCentralCrossRefGoogle Scholar
  127. 127.
    Waldron-Roby E, Ratovitski T, Wang X, Jiang M, Watkin E, Arbez N, Graham RK, Hayden MR, Hou Z, Mori S et al (2012) Transgenic mouse model expressing the caspase 6 fragment of mutant huntingtin. J Neurosci 32:183–193PubMedCrossRefGoogle Scholar
  128. 128.
    Gafni J, Papanikolaou T, Degiacomo F, Holcomb J, Chen S, Menalled L, Kudwa A, Fitzpatrick J, Miller S, Ramboz S et al (2012) Caspase-6 activity in a BACHD mouse modulates steady-state levels of mutant huntingtin protein but is not necessary for production of a 586 amino acid proteolytic fragment. J Neurosci 32:7454–7465PubMedPubMedCentralCrossRefGoogle Scholar
  129. 129.
    Landles C, Weiss A, Franklin S, Howland D, Bates G (2012) Caspase-6 does not contribute to the proteolysis of mutant huntingtin in the HdhQ150 knock-in mouse model of Huntington’s disease. PLoS Curr 4, e4fd085bfc9973PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • Catarina Carmo
    • 1
  • Luana Naia
    • 1
    • 2
  • Carla Lopes
    • 1
    • 2
  • A. Cristina Rego
    • 1
    • 3
  1. 1.CNC-Center for Neuroscience and Cell BiologyUniversity of CoimbraCoimbraPortugal
  2. 2.IIIUC-Institute for Interdisciplinary ResearchUniversity of CoimbraCoimbraPortugal
  3. 3.FMUC-Faculty of MedicineUniversity of CoimbraCoimbraPortugal

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