De Moura Alvorcem 2021 J Neurochem

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de Moura Alvorcem, L, Britto R, Cecatto C, Roginski AC, Rohden F, Scholl JN, Guma FCR, Figueiro F, Amaral AU, Zanatta G, Seminotti B, Wajner M, Leipnitz G. (2021) Ethylmalonic acid impairs bioenergetics by disturbing succinate and glutamate oxidation and induces mitochondrial permeability transition pore opening in rat cerebellum.. J Neurochem 158(2): 262–81.

» PMID: 33837559

de Moura Alvorcem Leonardo, Britto Renata, Cecatto Cristiane, Roginski Ana C, Rohden Francieli, Scholl Juliete N, Guma Fatima CR, Figueiro Fabricio, Amaral Alexandre U, Zanatta Geancarlo, Seminotti Bianca, Wajner Moacir, Leipnitz Guilhian (2021) J Neurochem

Abstract: Tissue accumulation and high urinary excretion of ethylmalonic acid (EMA) are found in ethylmalonic encephalopathy (EE), an inherited disorder associated with cerebral and cerebellar atrophy whose pathogenesis is poorly established. The in vitro and in vivo effects of EMA on bioenergetics and redox homeostasis were investigated in rat cerebellum. For the in vitro studies, cerebellum preparations were exposed to EMA, whereas intracerebellar injection of EMA was used for the in vivo evaluation. EMA reduced state 3 and uncoupled respiration in vitro in succinate-, glutamate-, and malate-supported mitochondria, whereas decreased state 4 respiration was observed using glutamate and malate. Furthermore, mitochondria permeabilization and succinate supplementation diminished the decrease in state 3 with succinate. EMA also inhibited the activity of KGDH, an enzyme necessary for glutamate oxidation, in a mixed manner and augmented mitochondrial efflux of α-ketoglutarate. ATP levels were markedly reduced by EMA, reflecting a severe bioenergetic disruption. Docking simulations also indicated interactions between EMA and KGDH and a competition with glutamate and succinate for their mitochondrial transporters. In vitro findings also showed that EMA decreased mitochondrial membrane potential and Ca2+ retention capacity, and induced swelling in the presence of Ca2+, which were prevented by cyclosporine A and ADP and ruthenium red, indicating mitochondrial permeability transition (MPT). Moreover, EMA, at high concentrations, mildly increased ROS levels and altered antioxidant defenses in vitro and in vivo. Our data indicate that EMA-induced impairment of glutamate and succinate oxidation and MPT may contribute to the pathogenesis of the cerebellum abnormalities in EE. Keywords: bioenergetics; cerebellum; ethylmalonic acid; mitochondrial permeability transition; redox homeostasis. Bioblast editor: Cecatto C O2k-Network Lab: BR Porto Alegre Souza DOG

Labels: MiParea: Respiration  Pathology: Inherited  Stress:Permeability transition, Oxidative stress;RONS  Organism: Rat  Tissue;cell: Nervous system  Preparation: Homogenate, Isolated mitochondria  Enzyme: TCA cycle and matrix dehydrogenases  Regulation: ATP production, Calcium  Coupling state: LEAK, OXPHOS  Pathway: N, S  HRR: Oxygraph-2k