Advertisement

3-Hydroxy-3-Methylglutaric Acid Impairs Redox and Energy Homeostasis, Mitochondrial Dynamics, and Endoplasmic Reticulum–Mitochondria Crosstalk in Rat Brain

  • Mateus Struecker da Rosa
  • Nevton Teixeira da Rosa-Junior
  • Belisa Parmeggiani
  • Nícolas Manzke Glänzel
  • Leonardo de Moura Alvorcem
  • Rafael Teixeira Ribeiro
  • Mateus Grings
  • Moacir Wajner
  • Guilhian LeipnitzEmail author
Original Article
  • 48 Downloads

Abstract

3-Hydroxy-3-methylglutaryl-CoA lyase (HL) deficiency is a neurometabolic disorder characterized by predominant accumulation of 3-hydroxy-3-methylglutaric acid (HMG) in tissues and biological fluids. Patients often present in the first year of life with metabolic acidosis, non-ketotic hypoglycemia, hypotonia, lethargy, and coma. Since neurological symptoms may be triggered or worsened during episodes of metabolic decompensation, which are characterized by high urinary excretion of organic acids, this study investigated the effects of HMG intracerebroventricular administration on redox homeostasis, citric acid cycle enzyme activities, dynamics (mitochondrial fusion and fission), and endoplasmic reticulum (ER)–mitochondria crosstalk in the brain of neonatal rats euthanized 1 (short term) or 20 days (long term) after injection. HMG induced lipid peroxidation and decreased the activities of glutathione peroxidase (GPx) and citric acid cycle enzymes, suggesting bioenergetic and redox disruption, 1 day after administration. Levels of VDAC1, Grp75, and mitofusin-1, proteins involved in ER-mitochondria crosstalk and mitochondrial fusion, were increased by HMG. Furthermore, HMG diminished synaptophysin levels and tau phosphorylation, and increased active caspase-3 content, indicative of cell damage. Finally, HMG decreased GPx activity and synaptophysin levels, and changed MAPK phosphorylation 20 days after injection, suggesting that long-term toxicity is further induced by this organic acid. Taken together, these data show that HMG induces oxidative stress and disrupts bioenergetics, dynamics, ER-mitochondria communication, and signaling pathways in the brain of rats soon after birth. It may be presumed that these mechanisms underlie the onset and progression of symptoms during decompensation occurring in HL-deficient patients during the neonatal period.

Keywords

3-Hydroxy-3-methyglutaric acid Redox and energy homeostasis Mitochondrial dynamics Endoplasmic reticulum-mitochondria crosstalk Cerebral cortex 

Notes

Funding Information

This work was supported by grants from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul (FAPERGS), Rede Instituto Brasileiro de Neurociência (IBN-Net), and Instituto Nacional de Ciência e Tecnologia em Excitotoxicidade e Neuroproteção (INCT-EN).

Compliance with Ethical Standards

The experiments were approved by the local Animal Ethics Commission from Universidade Federal do Rio Grande do Sul, and according to the National Animal Rights Regulations (Law 11.794/ 2008).

Conflict of Interest

The authors declare that they have no conflicts of interest.

References

  1. Aebi H (1984) Catalase in vitro. Methods Enzymol 105:121–126CrossRefGoogle Scholar
  2. Area-Gomez E, de Groof A, Bonilla E, Montesinos J, Tanji K, Boldogh I, Pon L, Schon EA (2018) A key role for MAM in mediating mitochondrial dysfunction in Alzheimer disease. Cell Death Dis 9:335.  https://doi.org/10.1038/s41419-017-0215-0 CrossRefPubMedPubMedCentralGoogle Scholar
  3. Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72:248–254CrossRefGoogle Scholar
  4. Browne RW, Armstrong D (1998) Reduced glutathione and glutathione disulfide. Methods Mol Biol 108:347–352.  https://doi.org/10.1385/0-89603-472-0:347 CrossRefPubMedGoogle Scholar
  5. Busanello EN, Moura AP, Viegas CM, Zanatta A, da Costa FG, Schuck PF, Wajner M (2010) Neurochemical evidence that glycine induces bioenergetical dysfunction. Neurochem Int 56:948–954.  https://doi.org/10.1016/j.neuint.2010.04.002 CrossRefPubMedGoogle Scholar
  6. Carlberg I, Mannervik B (1985) Glutathione reductase. Methods Enzymol 113:484–490CrossRefGoogle Scholar
  7. Correa SA, Eales KL (2012) The role of p38 MAPK and its substrates in neuronal plasticity and neurodegenerative disease. J Signal Transduct 2012:649079.  https://doi.org/10.1155/2012/649079 CrossRefPubMedPubMedCentralGoogle Scholar
  8. Csordas G, Weaver D, Hajnoczky G (2018) Endoplasmic reticulum-mitochondrial contactology: structure and signaling functions. Trends Cell Biol 28:523–540.  https://doi.org/10.1016/j.tcb.2018.02.009 CrossRefPubMedPubMedCentralGoogle Scholar
  9. da Rosa MS, Seminotti B, Amaral AU, Fernandes CG, Gasparotto J, Moreira JC, Gelain DP, Wajner M, Leipnitz G (2013) Redox homeostasis is compromised in vivo by the metabolites accumulating in 3-hydroxy-3-methylglutaryl-CoA lyase deficiency in rat cerebral cortex and liver. Free Radic Res 47:1066–1075.  https://doi.org/10.3109/10715762.2013.853876 CrossRefPubMedGoogle Scholar
  10. Dos Santos Mello M, Ribas GS, Wayhs CA, Hammerschmidt T, Guerreiro GB, Favenzani JL, Sitta A, de Moura Coelho D, Wajner M, Vargas CR (2015) Increased oxidative stress in patients with 3-hydroxy-3-methylglutaric aciduria. Mol Cell Biochem 402:149–155.  https://doi.org/10.1007/s11010-014-2322-x CrossRefPubMedGoogle Scholar
  11. Evelson P, Travacio M, Repetto M, Escobar J, Llesuy S, Lissi EA (2001) Evaluation of total reactive antioxidant potential (TRAP) of tissue homogenates and their cytosols. Arch Biochem Biophys 388:261–266.  https://doi.org/10.1006/abbi.2001.2292 CrossRefPubMedGoogle Scholar
  12. Fernandes CG, da Rosa MS, Seminotti B, Pierozan P, Martell RW, Lagranha VL, Busanello EN, Leipnitz G, Wajner M (2013) In vivo experimental evidence that the major metabolites accumulating in 3-hydroxy-3-methylglutaryl-CoA lyase deficiency induce oxidative stress in striatum of developing rats: a potential pathophysiological mechanism of striatal damage in this disorder. Mol Genet Metab 109:144–153.  https://doi.org/10.1016/j.ymgme.2013.03.017 CrossRefPubMedGoogle Scholar
  13. Fernandes CG, Pierozan P, Soares GM, Ferreira F, Zanatta A, Amaral AU, Borges CG, Wajner M, Pessoa-Pureur R (2015) NMDA receptors and oxidative stress induced by the major metabolites accumulating in HMG lyase deficiency mediate hypophosphorylation of cytoskeletal proteins in brain from adolescent rats: potential mechanisms contributing to the neuropathology of this disease. Neurotox Res 28:239–252.  https://doi.org/10.1007/s12640-015-9542-z CrossRefPubMedGoogle Scholar
  14. Fernandes CG, Rodrigues MDN, Seminotti B, Colin-Gonzalez AL, Santamaria A, Quincozes-Santos A, Wajner M (2016) Induction of a proinflammatory response in cortical astrocytes by the major metabolites accumulating in HMG-CoA lyase deficiency: the role of ERK signaling pathway in cytokine release. Mol Neurobiol 53:3586–3595.  https://doi.org/10.1007/s12035-015-9289-9 CrossRefPubMedGoogle Scholar
  15. Gardner PR, Raineri I, Epstein LB, White CW (1995) Superoxide radical and iron modulate aconitase activity in mammalian cells. J Biol Chem 270:13399–13405CrossRefGoogle Scholar
  16. Halliwell B, Gutteridge JMC (2015) Free Radicals in Biology and Medicine. 5th edition, Oxford University Press, New YorkGoogle Scholar
  17. Hoffmann GF, Seppel CK, Holmes B, Mitchell L, Christen HJ, Hanefeld F, Rating D, Nyhan WL (1993) Quantitative organic acid analysis in cerebrospinal fluid and plasma: reference values in a pediatric population. J Chromatogr 617:1–10.  https://doi.org/10.1016/0378-4347(93)80414-y CrossRefPubMedGoogle Scholar
  18. Imamura K, Izumi Y, Watanabe A, Tsukita K, Woltjen K, Yamamoto T, Hotta A, Kondo T, Kitaoka S, Ohta A, Tanaka A, Watanabe D, Morita M, Takuma H, Tamaoka A, Kunath T, Wray S, Furuya H, Era T, Makioka K, Okamoto K, Fujisawa T, Nishitoh H, Homma K, Ichijo H, Julien JP, Obata N, Hosokawa M, Akiyama H, Kaneko S, Ayaki T, Ito H, Kaji R, Takahashi R, Yamanaka S, Inoue H (2017) The Src/c-Abl pathway is a potential therapeutic target in amyotrophic lateral sclerosis. Sci Transl Med.  https://doi.org/10.1126/scitranslmed.aaf3962 CrossRefGoogle Scholar
  19. Jafari M (2007) Dose- and time-dependent effects of sulfur mustard on antioxidant system in liver and brain of rat. Toxicology 231:30–39.  https://doi.org/10.1016/j.tox.2006.11.048 CrossRefPubMedGoogle Scholar
  20. Kaushik S, Kaur J (2003) Chronic cold exposure affects the antioxidant defense system in various rat tissues. Clin Chim Acta 333:69–77CrossRefGoogle Scholar
  21. Kim SH, Markham JA, Weiler IJ, Greenough WT (2008) Aberrant early-phase ERK inactivation impedes neuronal function in fragile X syndrome. Proc Natl Acad Sci U S A 105:4429–4434.  https://doi.org/10.1073/pnas.0800257105 CrossRefPubMedPubMedCentralGoogle Scholar
  22. Krols M, van Isterdael G, Asselbergh B, Kremer A, Lippens S, Timmerman V, Janssens S (2016) Mitochondria-associated membranes as hubs for neurodegeneration. Acta Neuropathol 131:505–523.  https://doi.org/10.1007/s00401-015-1528-7 CrossRefPubMedPubMedCentralGoogle Scholar
  23. Kumar P, Jha NK, Jha SK, Ramani K, Ambasta RK (2015) Tau phosphorylation, molecular chaperones, and ubiquitin E3 ligase: clinical relevance in Alzheimer’s disease. J Alzheimers Dis 43:341–361.  https://doi.org/10.3233/JAD-140933 CrossRefPubMedGoogle Scholar
  24. Kuszczyk M, Gordon-Krajcer W, Lazarewicz JW (2009) Homocysteine-induced acute excitotoxicity in cerebellar granule cells in vitro is accompanied by PP2A-mediated dephosphorylation of tau. Neurochem Int 55:174–180.  https://doi.org/10.1016/j.neuint.2009.02.010 CrossRefPubMedGoogle Scholar
  25. Kyosseva SV, Elbein AD, Griffin WS, Mrak RE, Lyon M, Karson CN (1999) Mitogen-activated protein kinases in schizophrenia. Biol Psychiatry 46:689–696CrossRefGoogle Scholar
  26. Kyosseva SV, Elbein AD, Hutton TL, Griffin ST, Mrak RE, Sturner WQ, Karson CN (2000) Increased levels of transcription factors Elk-1, cyclic adenosine monophosphate response element-binding protein, and activating transcription factor 2 in the cerebellar vermis of schizophrenic patients. Arch Gen Psychiatry 57:685–691CrossRefGoogle Scholar
  27. Leipnitz G, Seminotti B, Haubrich J, Dalcin MB, Dalcin KB, Solano A, de Bortoli G, Rosa RB, Amaral AU, Dutra-Filho CS, Latini A, Wajner M (2008a) Evidence that 3-hydroxy-3-methylglutaric acid promotes lipid and protein oxidative damage and reduces the nonenzymatic antioxidant defenses in rat cerebral cortex. J Neurosci Res 86:683–693.  https://doi.org/10.1002/jnr.21527 CrossRefPubMedGoogle Scholar
  28. Leipnitz G, Seminotti B, Amaral AU, de Bortoli G, Solano A, Schuck PF, Wyse AT, Wannmacher CM, Latini A, Wajner M (2008b) Induction of oxidative stress by the metabolites accumulating in 3-methylglutaconic aciduria in cerebral cortex of young rats. Life Sci 82:652–662.  https://doi.org/10.1016/j.lfs.2007.12.024 CrossRefPubMedGoogle Scholar
  29. Leipnitz G, Solano AF, Seminotti B, Amaral AU, Fernandes CG, Beskow AP, Dutra Filho CS, Wajner M (2009) Glycine provokes lipid oxidative damage and reduces the antioxidant defenses in brain cortex of young rats. Cell Mol Neurobiol 29:253–261.  https://doi.org/10.1007/s10571-008-9318-6 CrossRefPubMedGoogle Scholar
  30. Liang LP, Ho YS, Patel M (2000) Mitochondrial superoxide production in kainate-induced hippocampal damage. Neuroscience 101:563–570CrossRefGoogle Scholar
  31. Lim JH, Lee HJ, Ho Jung M, Song J (2009) Coupling mitochondrial dysfunction to endoplasmic reticulum stress response: a molecular mechanism leading to hepatic insulin resistance. Cell Signal 21:169–177.  https://doi.org/10.1016/j.cellsig.2008.10.004 CrossRefPubMedGoogle Scholar
  32. Liu D, Zhang X, Hu B, Ander BP (2016) Src family kinases in brain edema after acute brain injury. Acta Neurochir Suppl 121:185–190.  https://doi.org/10.1007/978-3-319-18497-5_33 CrossRefPubMedPubMedCentralGoogle Scholar
  33. Manning BD, Toker A (2017) AKT/PKB signaling: navigating the network. Cell 169:381–405.  https://doi.org/10.1016/j.cell.2017.04.001 CrossRefPubMedPubMedCentralGoogle Scholar
  34. Marklund S (1985) Pyrogallol autoxidation. In: Greenwald RA (ed) Handbook of methods for oxygen radical research. CRC Press, Boca Raton, pp 243–247Google Scholar
  35. Mirandola SR, Melo DR, Schuck PF, Ferreira GC, Wajner M, Castilho RF (2008) Methylmalonate inhibits succinate-supported oxygen consumption by interfering with mitochondrial succinate uptake. J Inherit Metab Dis 31:44–54.  https://doi.org/10.1007/s10545-007-0798-1 CrossRefPubMedGoogle Scholar
  36. Morrison JF (1954) The activation of aconitase by ferrous ions and reducing agents. Biochem J 58:685–692PubMedPubMedCentralGoogle Scholar
  37. Moura AP, Parmeggiani B, Grings M, Alvorcem LM, Boldrini RM, Bumbel AP, Motta MM, Seminotti B, Wajner M, Leipnitz G (2016) Intracerebral glycine administration impairs energy and redox homeostasis and induces glial reactivity in cerebral cortex of newborn rats. Mol Neurobiol 53:5864–5875.  https://doi.org/10.1007/s12035-015-9493-7 CrossRefPubMedGoogle Scholar
  38. Munoz-Bonet JI, Ortega-Sanchez MD, Leon Guijarro JL (2017) Management and long-term evolution of a patient with 3-hydroxy-3-methylglutaryl-coenzyme A lyase deficiency. Ital J Pediatr 43:12.  https://doi.org/10.1186/s13052-017-0333-4 CrossRefPubMedPubMedCentralGoogle Scholar
  39. Olivera-Bravo S, Fernandez A, Sarlabos MN, Rosillo JC, Casanova G, Jimenez M, Barbeito L (2011) Neonatal astrocyte damage is sufficient to trigger progressive striatal degeneration in a rat model of glutaric acidemia-I. PLoS One 6:e20831.  https://doi.org/10.1371/journal.pone.0020831 CrossRefPubMedPubMedCentralGoogle Scholar
  40. Placido AI, Pereira CM, Correira SC, Carvalho C, Oliveira CR, Moreira PI (2017) Phosphatase 2A inhibition affects endoplasmic reticulum and mitochondria homeostasis via cytoskeletal alterations in brain endothelial cells. Mol Neurobiol 54:154–168.  https://doi.org/10.1007/s12035-015-9640-1 CrossRefPubMedGoogle Scholar
  41. Poddar R, Paul S (2009) Homocysteine-NMDA receptor-mediated activation of extracellular signal-regulated kinase leads to neuronal cell death. J Neurochem 110:1095–1106.  https://doi.org/10.1111/j.1471-4159.2009.06207.x CrossRefPubMedPubMedCentralGoogle Scholar
  42. Poddar R, Paul S (2013) Novel crosstalk between ERK MAPK and p38 MAPK leads to homocysteine-NMDA receptor-mediated neuronal cell death. J Neurochem 124:558–570.  https://doi.org/10.1111/jnc.12102 CrossRefPubMedGoogle Scholar
  43. Qi H, Prabakaran S, Cantrelle FX, Chambraud B, Gunawardena J, Lippens G, Landrieu I (2016) Characterization of neuronal tau protein as a target of extracellular signal-regulated kinase. J Biol Chem 291:7742–7753.  https://doi.org/10.1074/jbc.M115.700914 CrossRefPubMedPubMedCentralGoogle Scholar
  44. Ribeiro RT, Zanatta A, Amaral AU, Leipnitz G, de Oliveira FH, Seminotti B, Wajner M (2018) Experimental evidence that in vivo intracerebral administration of L-2-hydroxyglutaric acid to neonatal rats provokes disruption of redox status and histopathological abnormalities in the brain. Neurotox Res 33:681–692.  https://doi.org/10.1007/s12640-018-9874-6 CrossRefPubMedGoogle Scholar
  45. Roland D, Jissendi-Tchofo P, Briand G, Vamecq J, Fontaine M, Ultre V, Acquaviva-Bourdain C, Mention K, Dobbelaere D (2017) Coupled brain and urine spectroscopy - in vivo metabolomic characterization of HMG-CoA lyase deficiency in 5 patients. Mol Genet Metab 121:111–118.  https://doi.org/10.1016/j.ymgme.2017.03.006 CrossRefPubMedGoogle Scholar
  46. Rosenthal RE, Hamud F, Fiskum G, Varghese PJ, Sharpe S (1987) Cerebral ischemia and reperfusion - prevention of brain mitochondrial injury by lidoflazine. J Cereb Blood Flow Metab 7:752–758CrossRefGoogle Scholar
  47. Schmitt U, Tanimoto N, Seeliger M, Schaeffel F, Leube RE (2009) Detection of behavioral alterations and learning deficits in mice lacking synaptophysin. Neuroscience 162:234–243.  https://doi.org/10.1016/j.neuroscience.2009.04.046 CrossRefPubMedGoogle Scholar
  48. Seminotti B, Zanatta A, Ribeiro RT, da Rosa MS, Wyse ATS, Leipnitz G, Wajner M (2018) Disruption of brain redox homeostasis, microglia activation and neuronal damage induced by intracerebroventricular administration of S-adenosylmethionine to developing rats. Mol Neurobiol.  https://doi.org/10.1007/s12035-018-1275-6 CrossRefGoogle Scholar
  49. Shepherd D, Garland PB (1969) Citrate synthase from rat liver. Methods Enzymol 13:11–13CrossRefGoogle Scholar
  50. Starkov AA (2013) An update on the role of mitochondrial alpha-ketoglutarate dehydrogenase in oxidative stress. Mol Cell Neurosci 55:13–16.  https://doi.org/10.1016/j.mcn.2012.07.005 CrossRefPubMedGoogle Scholar
  51. Subramaniam S, Zirrgiebel U, von Bohlen Und Halbach O, Strelau J, Laliberte C, Kaplan DR, Unsicker K (2004) ERK activation promotes neuronal degeneration predominantly through plasma membrane damage and independently of caspase-3. J Cell Biol 165:357–369.  https://doi.org/10.1083/jcb.200403028 CrossRefPubMedPubMedCentralGoogle Scholar
  52. Sweetman L, Williams JC (2001) Branched chain organic acidurias. In: Scriver CR, Beaudet AL, Sly WS, Valle D (editors). The Metabolic and Molecular Bases of Inherited Disease. 8th edition, New York: McGraw-Hill, pp 2340-2342Google Scholar
  53. Sze CI, Troncoso JC, Kawas C, Mouton P, Price DL, Martin LJ (1997) Loss of the presynaptic vesicle protein synaptophysin in hippocampus correlates with cognitive decline in Alzheimer disease. J Neuropathol Exp Neurol 56:933–944CrossRefGoogle Scholar
  54. Terry RD (1998) The cytoskeleton in Alzheimer disease. J Neural Transm Suppl 53:141–145CrossRefGoogle Scholar
  55. Thome J, Pesold B, Baader M, Hu M, Gewirtz JC, Duman RS, Henn FA (2001) Stress differentially regulates synaptophysin and synaptotagmin expression in hippocampus. Biol Psychiatry 50:809–812CrossRefGoogle Scholar
  56. Thompson GN, Chalmers RA, Halliday D (1990) The contribution of protein catabolism to metabolic decompensation in 3-hydroxy-3-methylglutaric aciduria. Eur J Pediatr 149:346–350CrossRefGoogle Scholar
  57. Tretter L, Liktor B, Adam-Vizi V (2005) Dual effect of pyruvate in isolated nerve terminals: generation of reactive oxygen species and protection of aconitase. Neurochem Res 30:1331–1338.  https://doi.org/10.1007/s11064-005-8805-0 CrossRefPubMedGoogle Scholar
  58. van der Knaap MS, Bakker HD, Valk J (1998) MR imaging and proton spectroscopy in 3-hydroxy-3-methylglutaryl coenzyme A lyase deficiency. AJNR Am J Neuroradiol 19:378–382PubMedGoogle Scholar
  59. Wendel A (1981) Glutathione peroxidase. Methods Enzymol 77:325–333CrossRefGoogle Scholar
  60. Xu H, He J, Richardson JS, Li XM (2004) The response of synaptophysin and microtubule-associated protein 1 to restraint stress in rat hippocampus and its modulation by venlafaxine. J Neurochem 91:1380–1388.  https://doi.org/10.1111/j.1471-4159.2004.02827.x CrossRefPubMedGoogle Scholar
  61. Yagi K (1998) Simple procedure for specific assay of lipid hydroperoxides in serum or plasma. Methods Mol Biol 108:107–110.  https://doi.org/10.1385/0-89603-472-0:107 CrossRefPubMedGoogle Scholar
  62. Yilmaz O, Kitchen S, Pinto A, Daly A, Gerrard A, Hoban R, Santra S, Sreekantam S, Frost K, Pigott A, MacDonald A (2018) 3-hydroxy-3-methylglutaryl-CoA lyase deficiency: a case report and literature review. Nutr Hosp 35:237–244.  https://doi.org/10.20960/nh.1329 CrossRefPubMedGoogle Scholar
  63. Yu KN, Chang SH, Park SJ, Lim J, Lee J, Yoon TJ, Kim JS, Cho MH (2015) Titanium dioxide nanoparticles induce endoplasmic reticulum stress-mediated autophagic cell death via mitochondria-associated endoplasmic reticulum membrane disruption in normal lung cells. PLoS One 10:e0131208.  https://doi.org/10.1371/journal.pone.0131208 CrossRefPubMedPubMedCentralGoogle Scholar
  64. Yylmaz Y, Ozdemir N, Ekinci G, Baykal T, Kocaman C (2006) Corticospinal tract involvement in a patient with 3-HMG coenzyme A lyase deficiency. Pediatr Neurol 35:139–141.  https://doi.org/10.1016/j.pediatrneurol.2006.01.009 CrossRefPubMedGoogle Scholar
  65. Zafeiriou DI, Vargiami E, Mayapetek E, Augoustidou-Savvopoulou P, Mitchell GA (2007) 3-Hydroxy-3-methylglutaryl coenzyme a lyase deficiency with reversible white matter changes after treatment. Pediatr Neurol 37:47–50.  https://doi.org/10.1016/j.pediatrneurol.2007.02.007 CrossRefPubMedGoogle Scholar
  66. Zambrano CA, Egana JT, Nunez MT, Maccioni RB, Gonzalez-Billault C (2004) Oxidative stress promotes tau dephosphorylation in neuronal cells: the roles of cdk5 and PP1. Free Radic Biol Med 36:1393–1402.  https://doi.org/10.1016/j.freeradbiomed.2004.03.007 CrossRefPubMedGoogle Scholar
  67. Zhao L, Lu T, Gao L, Fu X, Zhu S, Hou Y (2017) Enriched endoplasmic reticulum-mitochondria interactions result in mitochondrial dysfunction and apoptosis in oocytes from obese mice. J Anim Sci Biotechnol 8:62.  https://doi.org/10.1186/s40104-017-0195-z CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Mateus Struecker da Rosa
    • 1
  • Nevton Teixeira da Rosa-Junior
    • 1
  • Belisa Parmeggiani
    • 1
  • Nícolas Manzke Glänzel
    • 1
  • Leonardo de Moura Alvorcem
    • 1
  • Rafael Teixeira Ribeiro
    • 1
  • Mateus Grings
    • 1
  • Moacir Wajner
    • 2
    • 3
  • Guilhian Leipnitz
    • 2
    • 4
    Email author
  1. 1.Programa de Pós-Graduação em Ciências Biológicas: BioquímicaUniversidade Federal do Rio Grande do SulPorto AlegreBrazil
  2. 2.Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Departamento de Bioquímica, Instituto de Ciências Básicas da SaúdeUniversidade Federal do Rio Grande do SulPorto AlegreBrazil
  3. 3.Serviço de Genética MédicaHospital de Clínicas de Porto AlegrePorto AlegreBrazil
  4. 4.Programa de Pós-Graduação em Fisiologia, Instituto de Ciências Básicas da SaúdeUniversidade Federal do Rio Grande do SulPorto AlegreBrazil

Personalised recommendations