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

Author(s)

Kakimoto, Pamela A. ^[1] ; Serna, Julian David C. ^[1] ; Ramos, Vitor de Miranda ^[1] ; Zorzano, Antonio ^[2] ; Kowaltowski, Alicia J. ^[1]

Affiliation

^[1] Univ Sao Paulo, Dept Bioquim, Inst Quim, Sao Paulo - Brazil

^[2] Univ Barcelona, CIBER Diabet & Enfermedades Metab Asociadas CIBER, Inst Res Biomed IRB Barcelona, Fac Biol, Inst Salud Carlos III, Dept Bioquim & Biomed Mol, Barcelona - Spain

• Document type: Journal article
• Source: REDOX BIOLOGY; v. 45, SEP 2021.
• Web of Science Citations: 0

Abstract

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. (AU)

• FAPESP's process: 19/18402-4 - Effects of mitochondrial calcium transport regulation in autophagic process of hepatocytes
• Grantee: Vitor de Miranda Ramos
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 13/07937-8 - Redoxome - Redox Processes in Biomedicine
• Grantee: Ohara Augusto
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC
• FAPESP's process: 15/25862-0 - Hepatic bioenergetics and redox signaling in obesity murine model: integrative analysis of nutritional, hormonal, and inflammatory stimuli
• Grantee: Pâmela Aiako Hypólito Brito Kakimoto
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• FAPESP's process: 19/05226-3 - Effects of caloric restriction on mitochondrial Ca2+ transport in cardiac and skeletal muscles
• Grantee: Julian David Cualcialpud Serna
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)