Regulation of Substrate Utilization by the Mitochondrial Pyruvate Carrier

• Published in: Molecular cell 2014-11, Vol.56 (3), p.425-435
• Main Authors: Vacanti, Nathaniel M., Divakaruni, Ajit S., Green, Courtney R., Parker, Seth J., Henry, Robert R., Ciaraldi, Theodore P., Murphy, Anne N., Metallo, Christian M.
• Format: Article
• Language: English
• Subjects: Animals; Cell Line, Tumor; Cell Proliferation; Citric Acid Cycle; Fatty Acids - metabolism; Glutamine - metabolism; Humans; Lipogenesis; Metabolic Flux Analysis; Mice; Muscle Fibers, Skeletal - metabolism; Oxidation-Reduction; Proprotein Convertase 1 - metabolism; Proprotein Convertase 2 - metabolism; Pyruvic Acid - metabolism
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2014.09.024

Pyruvate lies at a central biochemical node connecting carbohydrate, amino acid, and fatty acid metabolism, and the regulation of pyruvate flux into mitochondria represents a critical step in intermediary metabolism impacting numerous diseases. To characterize changes in mitochondrial substrate utilization in the context of compromised mitochondrial pyruvate transport, we applied 13C metabolic flux analysis (MFA) to cells after transcriptional or pharmacological inhibition of the mitochondrial pyruvate carrier (MPC). Despite profound suppression of both glucose and pyruvate oxidation, cell growth, oxygen consumption, and tricarboxylic acid (TCA) metabolism were surprisingly maintained. Oxidative TCA flux was achieved through enhanced reliance on glutaminolysis through malic enzyme and pyruvate dehydrogenase (PDH) as well as fatty acid and branched-chain amino acid oxidation. Thus, in contrast to inhibition of complex I or PDH, suppression of pyruvate transport induces a form of metabolic flexibility associated with the use of lipids and amino acids as catabolic and anabolic fuels. [Display omitted] •Oxidation of fatty acids and amino acids is increased upon MPC inhibition•Respiration, proliferation, and biosynthesis are maintained when MPC is inhibited•Glutaminolytic flux supports lipogenesis in the absence of MPC•MPC inhibition is distinct from hypoxia or complex I inhibition Vacanti et al. describe the inherent metabolic flexibility of mammalian cells. In response to genetic or pharmacological inhibition of the mitochondrial pyruvate carrier (MPC), myocytes and cancer cells maintain respiration via oxidation of fatty acids and amino acids. These results highlight a potential mechanism for control of mitochondrial substrate utilization.