Regulation of substrate utilization by the mitochondrial pyruvate carrier

Mol Cell. 2014 Nov 6;56(3):425-35. doi: 10.1016/j.molcel.2014.09.024. Epub 2014 Oct 30.

Abstract

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 (13)C 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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*

Substances

  • Fatty Acids
  • Glutamine
  • Pyruvic Acid
  • Pcsk1 protein, mouse
  • Proprotein Convertase 1
  • Pcsk2 protein, mouse
  • Proprotein Convertase 2