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Activation of IGF-1 and Insulin Signaling Pathways Ameliorate Mitochondrial Function and Energy Metabolism in Huntington’s Disease Human Lymphoblasts

Abstract

Huntington’s disease (HD) is an inherited neurodegenerative disease caused by a polyglutamine repeat expansion in the huntingtin protein. Mitochondrial dysfunction associated with energy failure plays an important role in this untreated pathology. In the present work, we used lymphoblasts obtained from HD patients or unaffected parentally related individuals to study the protective role of insulin-like growth factor 1 (IGF-1) versus insulin (at low nM) on signaling and metabolic and mitochondrial functions. Deregulation of intracellular signaling pathways linked to activation of insulin and IGF-1 receptors (IR,IGF-1R), Akt, and ERK was largely restored by IGF-1 and, at a less extent, by insulin in HD human lymphoblasts. Importantly, both neurotrophic factors stimulated huntingtin phosphorylation at Ser421 in HD cells. IGF-1 and insulin also rescued energy levels in HD peripheral cells, as evaluated by increased ATP and phosphocreatine, and decreased lactate levels. Moreover, IGF-1 effectively ameliorated O2 consumption and mitochondrial membrane potential (Δψm) in HD lymphoblasts, which occurred concomitantly with increased levels of cytochrome c. Indeed, constitutive phosphorylation of huntingtin was able to restore the Δψm in lymphoblasts expressing an abnormal expansion of polyglutamines. HD lymphoblasts further exhibited increased intracellular Ca2+ levels before and after exposure to hydrogen peroxide (H2O2), and decreased mitochondrial Ca2+ accumulation, being the later recovered by IGF-1 and insulin in HD lymphoblasts pre-exposed to H2O2. In summary, the data support an important role for IR/IGF-1R mediated activation of signaling pathways and improved mitochondrial and metabolic function in HD human lymphoblasts.

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References

  1. 1.

    Gil JM, Rego AC (2008) Mechanisms of neurodegeneration in Huntington’s disease. Eur J Neurosci 27:2803–2820

    PubMed  Article  Google Scholar 

  2. 2.

    Zuccato C, Valenza M, Cattaneo E (2009) Molecular mechanisms and potential therapeutical targets in Huntington's disease. Physiol Rev 90:905–981

    Article  Google Scholar 

  3. 3.

    MacDonald ME, Gines S, Gusella JF, Wheeler VC (2003) Huntington’s disease. NeuroMolecular Med 4:7–20

    CAS  PubMed  Article  Google Scholar 

  4. 4.

    Vonsattel JP, DiFiglia M (1998) Huntington disease. J Neuropathol Exp Neurol 57:369–384

    CAS  PubMed  Article  Google Scholar 

  5. 5.

    Cattaneo E, Rigamonti D, Goffredo D, Zuccato C, Squitieri F, Sipione S (2001) Loss of normal huntingtin function: new developments in Huntington's disease research. Trends Neurosci 24:182–188

    CAS  PubMed  Article  Google Scholar 

  6. 6.

    Ribeiro M, Rosenstock TR, Cunha-Oliveira T, Ferreira IL, Oliveira CR, Rego AC (2012) Glutatione redox cycle dysregulation in Huntington’s disease knock-in striatal cells. Free Radic Biol Med 53:1857–1867

    CAS  PubMed  Article  Google Scholar 

  7. 7.

    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 19:3919–3935

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  8. 8.

    Rosenstock TR, Duarte AI, Rego AC (2010) Mitochondrial-Associated Metabolic Changes and Neurodegeneration in Huntington's disease—from Clinical Features to the Bench. Curr Drug Targets 11:1–16

    Article  Google Scholar 

  9. 9.

    Almeida S, Sarmento-Ribeiro AB, Januário 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 374:599–603

    CAS  PubMed  Article  Google Scholar 

  10. 10.

    Pettegrew JW, Nichols JS, Stewart RM (1980) Membrane studies in Huntington's disease: steady-state fluorescence studies of intact erythrocytes. Ann Neurol 8:381–386

    CAS  PubMed  Article  Google Scholar 

  11. 11.

    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 5:1194–1198

    CAS  PubMed  Article  Google Scholar 

  12. 12.

    Silva AC, Almeida S, Laço M, Duarte AI, Domingues J, Oliveira CR, Januário C, Rego AC (2013) Mitochondrial respiratory chain complex activity and bioenergetics alterations in human platelets derived from pre-symptomatic and symptomatic Huntington’s disease carriers. Mitochondrion 13:801–809

    CAS  PubMed  Article  Google Scholar 

  13. 13.

    Sassone J, Colciago C, Cislaghi G, Silani V, Ciammola A (2009) Huntington's disease: the current state of research with peripheral tissues. Exp Neurol 219:385–397

    CAS  PubMed  Article  Google Scholar 

  14. 14.

    Gu M, Gash MT, Mann VM, Javoy-Agid F, Cooper JM, Schapira AH (1996) Mitochondrial defect in Huntington's disease caudate nucleus. Ann Neurol 39:385–389

    CAS  PubMed  Article  Google Scholar 

  15. 15.

    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 43:2689–2695

    CAS  PubMed  Article  Google Scholar 

  16. 16.

    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 48:72–76

    CAS  PubMed  Article  Google Scholar 

  17. 17.

    Song W, Chen J, Petrilli A et al (2011) Mutant huntingtin binds the mitochondrial fission GTPase dynamin-related protein-1 and increases its enzymatic activity. Nat Med 17:377–382

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  18. 18.

    Ferreira IL, Nascimento MV, Ribeiro M, Almeida S, Cardoso SM, Grazina M, Pratas J, Santos MJ, Januário C, Oliveira CR, Rego AC (2010) Mitochondrial-dependent apoptosis in Huntington's disease human cybrids. Exp Neurol 222:243–255

    CAS  PubMed  Article  Google Scholar 

  19. 19.

    Ferreira IL, Cunha-Oliveira T, Nascimento MV, Ribeiro M, Proença MT, Januário C, Oliveira CR, Rego AC (2011) Bioenergetics dysfunction in Huntington’s disease human cybrids. Exp Neurol 231:127–134

    CAS  PubMed  Article  Google Scholar 

  20. 20.

    Cole GM, Frautschy SA (2007) The role of insulin and neurotrophic factor signaling in brain aging and Alzheimer's disease. Exp Gerontol 42:10–21

    CAS  PubMed  Article  Google Scholar 

  21. 21.

    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 2:831–837

    CAS  PubMed  Article  Google Scholar 

  22. 22.

    Duarte AI, Santos MS, Oliveira CR, Rego AC (2005) Insulin neuroprotection against oxidative stress in cortical neurons—involvement of uric acid and glutathione antioxidant defences. Free Radic Biol Med 39:876–889

    CAS  PubMed  Article  Google Scholar 

  23. 23.

    Duarte AI, Proenca T, Oliveira CR, Santos MS, Rego AC (2006) Insulin restores metabolic function in cultured cortical neurons subjected to oxidative stress. Diabetes 55:2863–2870

    CAS  PubMed  Article  Google Scholar 

  24. 24.

    Duarte AI, Santos P, Oliveira CR, Santos MS, Rego AC (2008) Insulin neuroprotection against oxidative stress is mediated by Akt and GSK-3β signaling pathways and changes in protein expression. Biochim Biophys Acta 1783:994–1002

    CAS  PubMed  Article  Google Scholar 

  25. 25.

    Zheng WH, Kar S, Quirion R (2002) Insulin-like growth factor-1-induced phosphorylation of transcription factor FKHRL1 is mediated by phosphatidylinositol 3-kinase/Akt kinase and role of this pathway in insulin-like growth factor-1-induced survival of cultured hippocampal neurons. Mol Pharmacol 62:225–233

    CAS  PubMed  Article  Google Scholar 

  26. 26.

    Aberg MA, Aberg ND, Hedbäcker H, Oscarsson J, Eriksson PS (2000) Peripheral infusion of IGF-I selectively induces neurogenesis in the adult rat hippocampus. J Neurosci 20:2896–2903

    CAS  PubMed  Google Scholar 

  27. 27.

    Trejo JL, Carro E, Torres-Aleman I (2001) Circulating insulin-like growth factor I mediates exercise-induced increases in the number of new neurons in the adult hippocampus. J Neurosci 21:1628–1634

    CAS  PubMed  Google Scholar 

  28. 28.

    Sasone L, Reali V, Pellegrini L, Villanova L, Aventaggiato M, Marfe G, Rosa R, Nebbioso M, Tafani M, Fini M, Russo MA, Pucci B (2013) SIRT1 silencing confers neuroprotection through IGF-1 pathway activation. J Cell Physiol 228:1754–1761

    Article  Google Scholar 

  29. 29.

    Chang HC, Yang YR, Wang PS, Kuo CH, Wang RY (2013) The neuroprotective effects of intramuscular insulin-like growth factor-I treatment in brain ischemic rats. PLoS One 8:e64015

    PubMed Central  PubMed  Article  Google Scholar 

  30. 30.

    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 49:1126–1142

  31. 31.

    Pouladi MA, Xie Y, Skotte NH et al (2010) Full-length huntingtin levels modulate body weight by influencing insulin-like growth factor 1 expression. Hum Mol Genet 19:1528–1538

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  32. 32.

    Dalrymple A, Wild EJ, Joubert R et al (2007) Proteomic profiling of plasma in Huntington's disease reveals neuroinflammatory activation and biomarker candidates. J Proteome Res 6:2833–2840

    CAS  PubMed  Article  Google Scholar 

  33. 33.

    Saleh N, Moutereau S, Durr A, Krystkowiak P, Azulay JP, Tranchant C, Broussolle E, Morin F, Bachoud-Lévi AC, Maison P (2009) Neuroendocrine disturbances in Huntington’s disease. PLoS One 4:e4962

    PubMed Central  PubMed  Article  Google Scholar 

  34. 34.

    Saleh N, Moutereau S, Azulay JP, Verny C, Simonin C, Tranchant C, El Hawajri N, Bachoud-Lévi AC, Maison P (2010) High insulinlike growth factor I is associated with cognitive decline in Huntington disease. Neurology 75:57–63

    CAS  PubMed  Article  Google Scholar 

  35. 35.

    Sadagursky M, Cheng Z, Rozzo A, Palazzolo I, Kelley GR, Dong X, Krainc D, White MF (2011) IRS2 increases mitochondrial dysfunction and oxidative stress in a mouse model of Huntington disease. J Clin Invest 121:4070–4081

    Article  Google Scholar 

  36. 36.

    Almeida S, Domingues A, Rodrigues L, Oliveira CR, Rego AC (2004) FK506 prevents mitochondrial-dependent apoptotic cell death induced by 3-nitropropionic acid in rat primary cortical cultures. Neurobiol Dis 17:435–444

    CAS  PubMed  Article  Google Scholar 

  37. 37.

    Stocchi V, Cucchiarini L, Magnani M, Chiarantini L, Palma P, Crescentini G (1985) Simultaneous extraction and reverse-phase high-performance liquid chromatographic determination of adenine and pyridine nucleotides in human red blood cells. Anal Biochem 146:118–124

    CAS  PubMed  Article  Google Scholar 

  38. 38.

    Lamprecht W, Stein P, Heinz F, Weissner H (1974) Creatine phosphate. In: Bergmeyer H (ed) Methods of enzymatic analysis, vol 4. Academic Press, New York, pp 1777–1781

    Chapter  Google Scholar 

  39. 39.

    Ragan CI, Wilson MT, Darley-Usmar VM, Lowe PN (1967) Subfractionation of mitochondria and isolation of the proteins of oxidative phosphorylation. In: Darley-Usmar VM, Rickwood D, Wilson MT (eds) Mitochondria, a practical approach. IRL Press, London, pp 79–112

    Google Scholar 

  40. 40.

    Hatefi Y, Stiggall DL (1978) Preparation and properties of succinate: ubiquinone oxidoreductase (complex II). Methods Enzymol 53:21–27

    CAS  PubMed  Article  Google Scholar 

  41. 41.

    Wharton DC, Tzagotoff A (1967) Cytochrome oxidase from beef heart mitochondria. Methods Enzymol 10:245–250

    CAS  Article  Google Scholar 

  42. 42.

    Coore HG, Denton RM, Martin BR, Randle PJ (1971) Regulation of adipose tissue pyruvate dehydrogenase by insulin and others hormones. Biochem J 125:115–127

    CAS  PubMed Central  PubMed  Google Scholar 

  43. 43.

    Colin E, Régulier E, Perrin V, Dürr A, Brice A, Aebischer P, Deéglon N, Humbert S, Saudou F (2005) Akt is altered in an animal model of Huntington’s disease and in patients. Eur J Neurosci 21:1478–1488

    PubMed  Article  Google Scholar 

  44. 44.

    Stamper BD, Mecham B, Park SS, Wilkerson H, Farin FM, Bever RP, Bammler TK, Mangravite LM, Cunningham ML (2012) Transcriptome correlation analysis identifies two unique craniosynostosis subtypes associated with IRS1 activation. Physiol Genomics 44:1154–1163

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  45. 45.

    Rechler MM, Zapf J, Nissley SP, Froesch ER, Moses AC, Podskalny JM, Schilling EE, Humbel RE (1980) Interactions of insulin-like growth factors I and II and multiplication-stimulating activity with receptors and serum carrier proteins. Endocrinology 107:1451–1459

    CAS  PubMed  Article  Google Scholar 

  46. 46.

    Summers SA, Kao AW, Kohn AD, Backus GS, Roth RA, Pessin JE, BirnBaum MJ (1999) The role of glycogen synthase kinase 3beta in insulin-stimulated glucose metabolismo. J Biol Chem 274:17934–17940

    CAS  PubMed  Article  Google Scholar 

  47. 47.

    Cole A, Frame S, Cohen P (2004) Further evidence that the tyrosine phosphorylation of glycogen synthase kinase-3 (GSK3) in mammalian cells is an autophosphorylation event. Biochem J 377:249–255

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  48. 48.

    Macho A, Decaudin D, Castedo M, Hirsch T, Susin SA, Zamzami N, Kroemer G (1996) Chloromethyl-X-Rosamine is an aldehyde-fixable potential-sensitive fluorochrome for the detection of early apoptosis. Cytometry 25:333–340

    CAS  PubMed  Article  Google Scholar 

  49. 49.

    Kaufman BA, Durisic N, Mativetsky JM, Costantino S, Hancock MA, Grutter P, Shoubridge EA (2007) The mitochondrial transcription factor TFAM coordinates the assembly of multiple DNA molecules into nucleoid-like structures. Mol Biol Cell 18:3225–3236

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  50. 50.

    Wang J, Silva JP, Gustafsson CM, Rustin P, Larsson NG (2001) Increased in vivo apoptosis in cells lacking mitochondrial DNA gene expression. Proc Natl Acad Sci U S A 98:4038–4043

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  51. 51.

    Naia L, Ribeiro MJ, Rego AC (2011) Mitochondrial and metabolic-based protective strategies in Huntington’s disease: the case of creatine and coenzyme Q. Rev Neurosci 23:13–28

    PubMed  Google Scholar 

  52. 52.

    Palazzolo I, Stack C, Kong L, Musaro A, Adachi H, Katsuno M, Sobue G, Taylor JP, Sumner CJ, Fischbeck KH, Pennuto M (2009) Overexpression of IGF-1 in muscle attenuates disease in a mouse model of spinal and bulbar muscular atrophy. Neuron 63:316–328

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  53. 53.

    Apostol BL, Illes K, Pallos J, Bodai L, Wu J, Strand A, Schweitzer ES, Olson JM, Kazantsev A, Marsh JL, Thompson LM (2006) Mutant huntingtin alters MAPK signaling pathways in PC12 and striatal cells: ERK1/2 protects against mutant huntingtin-associated toxicity. Hum Mol Genet 15:273–285

    CAS  PubMed  Article  Google Scholar 

  54. 54.

    Zala D, Colin E, Rangone H, Liot G, Humbert S et al (2008) Phosphorylation of mutant huntingtin at S421 restores anterograde and retrograde transport in neurons. Hum Mol Genet 17:3837–3846

    CAS  PubMed  Article  Google Scholar 

  55. 55.

    Warby SC, Doty CN, Graham RK, Shively J, Singaraja RR et al (2009) Phosphorylation of huntingtin reduces the accumulation of its nuclear fragments. Mol Cell Neurosci 40:121–127

    CAS  PubMed  Article  Google Scholar 

  56. 56.

    Metzler M, Gan L, Mazarei G, Graham RK, Liu L, Bissada N, Lu G, Leavitt BR, Hayden MR (2010) Phosphorylation of huntingtin at Ser421 in YAC128 neurons is associated with protection of YAC128 neurons from NMDA-mediated excitotoxicity and is modulated by PP1 and PP2A. J Neurosci 30:14318–14329

    CAS  PubMed  Article  Google Scholar 

  57. 57.

    Havel LS, Wang CE, Wade B, Huang B, Li S et al (2011) Preferential accumulation of N-terminal mutant huntingtin in the nuclei of striatal neurons is regulated by phosphorylation. Hum Mol Genet 20:1424–1437

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  58. 58.

    Gu X, Greiner ER, Mishra R, Kodali R, Osmand A et al (2009) Serines 13 and 16 are critical determinants of full-length human mutant huntingtin induced disease pathogenesis in HD mice. Neuron 64:828–840

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  59. 59.

    Mishra R, Hoop CL, Kodali R, Sahoo B, van der Wel PC et al (2012) Serine phosphorylation suppresses huntingtin amyloid accumulation by altering protein aggregation properties. J Mol Biol 424:1–14

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  60. 60.

    Sarkar S, Ravikumar B, Floto RA, Rubinsztein DC (2009) Rapamycin and mTOR- independent autophagy inducers ameliorate toxicity of polyglutamine-expanded huntingtin and related proteinopathies. Cell Death Differ 16:46–56

    CAS  PubMed  Article  Google Scholar 

  61. 61.

    Gulati P, Gaspers LD, Dann SG, Joaquin M, Nobukuni T, Natt F, Kozma SC, Thomas AP, Thomas G (2008) Amino acids activate mTOR complex 1 via Ca2+/CaM signaling to hVps34. Cell Metab 7:456–465

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  62. 62.

    Chiang GG, Abraham RT (2005) Phosphorylation of mammalian target of rapamycin (mTOR) at Ser-2448 is mediated by p70S6 kinase. J Biol Chem 280:25485–25490

    CAS  PubMed  Article  Google Scholar 

  63. 63.

    Holz MK, Blenis J (2005) Identification of S6 kinase 1 as a novel mammalian target of rapamycin (mTOR)-phosphorylating kinase. J Biol Chem 280:26089–26093

    CAS  PubMed  Article  Google Scholar 

  64. 64.

    Seong IS, Ivanova E, Lee J-M, Choo YS, Fossale E, Anderson M, Gusella JF, Laramie JM, Myers RH, Lesort M, MacDonald ME (2005) HD CAG repeat implicates a dominant property of huntingtin in mitochondrial energy metabolism. Hum Mol Genet 14:2871–2880

    CAS  PubMed  Article  Google Scholar 

  65. 65.

    Wang H, Lim PJ, Karbowski M, Monteiro MJ (2009) Effects of overexpression of Huntingtin proteins on mitochondrial integrity. Hum Mol Genet 18:737–752

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  66. 66.

    Koroshetz WJ, Jenkins BG, Rosen BR, Beal MF (1997) Energy metabolism defects in Huntington’s disease and effects of coenzyme Q10. Ann Neurol 41:160–165

    CAS  PubMed  Article  Google Scholar 

  67. 67.

    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 5:731–736

    CAS  PubMed  Google Scholar 

  68. 68.

    Josefsen K, Nielsen SM, Campos A, Seifert T, Hasholt L, Nielsen JE, Nørremølle A, Skotte NH, Secher NH, Quistorff B (2010) Reduced gluconeogenesis and lactate clearance in Huntington's disease. Neurobiol Dis 40:656–662

    CAS  PubMed  Article  Google Scholar 

  69. 69.

    Martin WR, Wieler M, Hanstock CC (2007) Is brain lactate increased in Huntington's disease? J Neurol Sci 263:70–74

    CAS  PubMed  Article  Google Scholar 

  70. 70.

    van der Burg JM, Bacos K, Wood NI et al (2008) Increased metabolism in the R6/2 mouse model of Huntington’s disease. Neurobiol Dis 29:41–51

    PubMed  Article  Google Scholar 

  71. 71.

    Powers WJ, Videen TO, Markham J, McGee-Minnich L, Antenor-Dorsey JV, Hershey T, Perlmutter JS (2007) Selective defect of in vivo glycolysis in early Huntington’s disease striatum. Proc Natl Acad Sci U S A 104:2945–2949

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  72. 72.

    Milakovic T, Quintanilla RA, Johnson GV (2006) Mutant huntingtin expression induces mitochondrial calcium handling defects in clonal striatal cells: functional consequences. J Biol Chem 281:34785–34795

    CAS  PubMed  Article  Google Scholar 

  73. 73.

    Solans A, Zambrano A, Rodríguez M, Barrientos A (2006) Cytotoxicity of a mutant huntingtin fragment in yeast involves early alterations in mitochondrial OXPHOS complexes II and III. Hum Mol Genet 15:3063–3081

    CAS  PubMed  Article  Google Scholar 

  74. 74.

    Benchoua A, Trioulier Y, Zala D, Gaillard MC, Lefort N, Dufour N, Saudou F, Elalouf JM, Hirsch E, Hantraye P (2006) Involvement of mitochondrial complex II defects in neuronal death produced by N-terminus fragment of mutated huntingtin. Mol Biol Cell 17:1652–1663

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  75. 75.

    Ow YP, Green DR, Hao Z, Mak TW (2008) Cytochrome c: functions beyond respiration. Nat Rev Mol Cell Biol 9:532–542

    CAS  PubMed  Article  Google Scholar 

  76. 76.

    Vempati UD, Han X, Moraes CT (2009) Lack of cytochrome c in mouse fibroblasts disrupts assembly/stability of respiratory complexes I and IV. J Biol Chem 284:4383–4391

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  77. 77.

    Hayashi Y, Yoshida M, Yamato M et al (2008) Reverse of age-dependent memory impairment and mitochondrial DNA damage in microglia by an overexpression of human mitochondrial transcription factor a in mice. J Neurosci 28:8624–8634

    CAS  PubMed  Article  Google Scholar 

  78. 78.

    Reijonen S, Putkonen N, Nørremølle A, Lindholm D, Korhonen L (2008) Inhibition of endoplasmic reticulum stress counteracts neuronal cell death and protein aggregation caused by N-terminal mutant huntingtin proteins. Exp Cell Res 314:950–960

    CAS  PubMed  Article  Google Scholar 

  79. 79.

    Rosenstock TR, Brito OM, Lombradi 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 59:600–609

    CAS  PubMed  Article  Google Scholar 

  80. 80.

    Panov AV, Obertone T, Bennett-Desmelik J, Greenamyre JT (1999) Ca(2+)-dependent permeability transition and complex I activity in lymphoblast mitochondria from normal individuals and patients with Huntington's or Alzheimer's disease. Ann N Y Acad Sci 893:365–368

    CAS  PubMed  Article  Google Scholar 

  81. 81.

    Rockabrand E, Slepko N, Pantalone A, Nukala VN, Kazantsev A, Marsh JL, Sullivan PG, Steffan JS, Sensi SL, Thompson LM (2007) The first 17 amino acids of Huntingtin modulate its sub-cellular localization, aggregation and effects on calcium homeostasis. Hum Mol Genet 16:61–77

    CAS  PubMed  Article  Google Scholar 

  82. 82.

    Ibarra C, Estrada M, Carrasco L, Chiong M, Liberona JL, Cardenas C, Díaz-Arava G, Jaimovich E, Lavandero S (2004) Insulin-like growth factor-1 induces an inositol 1,4,5-triphosphate-dependent increase in nuclear and cytosolic calcium in cultured rat cardiac myocytes. J Biol Chem 279:7554–7565

    CAS  PubMed  Article  Google Scholar 

  83. 83.

    Valdés JA, Flores S, Fuentes EN, Osorio-Fuentealbe C, Jaimovich E, Molina A (2013) IGF-1 induces IP(3) dependent calcium signal involved in the regulation of myostatin gene expression mediated by NFAT during myoblast differentiation. J Cell Physiol 228:1452–1463

    PubMed  Article  Google Scholar 

  84. 84.

    Steelman LS, Chappell WH, Abrams SL et al (2011) Roles of the Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR pathways in controlling growth and sensitivity to therapy—implications for cancer and aging. Aging (Albany NY) 3:192–222

    CAS  Google Scholar 

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Acknowledgments

We wish to thank Doctor Luísa Cortes, head of Microscope Imaging Center of Coimbra (MICC) of CNC for the confocal image acquisition and analysis. This work was supported by “Fundação para a Ciência e Tecnologia” (FCT), Portugal, grants reference PTDC/SAU-FCF/66421/2006 and PTDC/SAU-FCF/108056/2008, and co-financed by COMPETE-“Programa Operacional Factores de Competitividade,” QREN, and the European Union (FEDER-“Fundo Europeu de Desenvolvimento Regional”). CNC is supported by project PEst-C/SAU/LA0001/2013-2014. L. Naia, M. Ribeiro, and M.J. Ribeiro are supported by Ph.D. fellowships from FCT (SFRH/BD/86655/2012, SFRH/BD/88983/2012, and SFRH/BD/41285/899/2007, respectively). T. Cunha-Oliveira, A.I. Duarte, T.R. Rosenstock, and M.N. Laço are supported by postdoctoral fellowships from FCT (SFRH/BPD/34711/2007, SFRH/BPD/26872/2006, SFRH/BPD/44246/2008, and SFRH/BPD/91811/2012, respectively).

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The authors declare that they have no conflicts of interest.

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Correspondence to A. Cristina Rego.

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L. Naia and I. L. Ferreira contributed equally for this study.

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Naia, L., Ferreira, I.L., Cunha-Oliveira, T. et al. Activation of IGF-1 and Insulin Signaling Pathways Ameliorate Mitochondrial Function and Energy Metabolism in Huntington’s Disease Human Lymphoblasts. Mol Neurobiol 51, 331–348 (2015). https://doi.org/10.1007/s12035-014-8735-4

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Keywords

  • Huntington’s disease
  • Insulin
  • IGF-1
  • Intracellular signaling
  • Mitochondria
  • Energy metabolism