Increased glycolysis is an early consequence of palmitate lipotoxicity mediated by redox signaling

Redox Biology

Julian David C. Serna¹  Pamela A. Kakimoto²  Vitor de Miranda Ramos²  Antonio Zorzano²  Alicia J. Kowaltowski³ 

[1] Corresponding author. Av. Prof. Lineu Prestes, 748, Cidade Universitária, 05508-000, São Paulo, SP, Brazil.;Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, Brazil;Institute for Research in Biomedicine (IRB Barcelona), Departament de Bioquímica I Biomedicina Molecular, Facultat de Biologia, Universitat de Barcelona, CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Barcelona, Spain;

关键词: Palmitic acid;    Mitochondria;    Glycolysis;    Oxidative stress;    Reactive oxygen species;   

DOI  :  

来源: DOAJ

【 摘 要 】

Exposure to toxic levels of fatty acids (lipotoxicity) leads to cell damage and death and is involved in the pathogenesis of the metabolic syndrome. Since the metabolic consequences of lipotoxicity are still poorly understood, we studied the bioenergetic effects of the saturated fatty acid palmitate, quantifying changes in mitochondrial morphology, real-time oxygen consumption, ATP production sources, and extracellular acidification in hepatoma cells. Surprisingly, glycolysis was enhanced by the presence of palmitate as soon as 1 h after stimulus, while oxygen consumption and oxidative phosphorylation were unchanged, despite overt mitochondrial fragmentation. Palmitate only induced mitochondrial fragmentation if glucose and glutamine were available, while glycolytic enhancement did not require glutamine, showing it is independent of mitochondrial morphological changes. Redox state was altered by palmitate, as indicated by NAD(P)H quantification. Furthermore, the mitochondrial antioxidant mitoquinone, or a selective inhibitor of complex I electron leakage (S1QEL) further enhanced palmitate-induced glycolysis. Our results demonstrate that palmitate overload and lipotoxicity involves an unexpected and early increase in glycolytic flux, while, surprisingly, no changes in oxidative phosphorylation are observed. Interestingly, enhanced glycolysis involves signaling by mitochondrially-generated oxidants, uncovering a novel regulatory mechanism for this pathway.

【 授权许可】

Unknown