Loss of Mitochondrial Pyruvate Carrier 2 in the Liver Leads to Defects in Gluconeogenesis and Compensation via Pyruvate-Alanine Cycling

Abstract

SUMMARY Pyruvate transport across the inner mitochondrial membrane is believed to be a prerequisite step for gluconeogenesis in hepatocytes, which is important for maintenance of normoglycemia during prolonged food deprivation, but also contributes to hyperglycemia in diabetes. To determine the requirement for mitochondrial pyruvate import in gluconeogenesis, mice with liver-specific deletion of mitochondrial pyruvate carrier 2 (LS-Mpc2−/−) were generated. Loss of MPC2 impaired, but did not completely abolish, hepatocyte pyruvate metabolism, labelled pyruvate conversion to TCA cycle intermediates and glucose, and glucose production from pyruvate. Unbiased metabolomic analyses of livers from fasted LS-Mpc2−/− mice suggested that alterations in amino acid metabolism, including pyruvate-alanine cycling, might compensate for loss of MPC2. Indeed, inhibition of pyruvate-alanine transamination further reduced mitochondrial pyruvate metabolism and glucose production by LS-Mpc2−/− hepatocytes. These data demonstrate an important role for MPC2 in controlling hepatic gluconeogenesis and illuminate a compensatory mechanism for circumventing a block in mitochondrial pyruvate import.

MPC1-like Is a Placental Mammal-specific Mitochondrial Pyruvate Carrier Subunit Expressed in Postmeiotic Male Germ Cells

“…A decrease in MPC activity has been shown to perturb whole body glucose homeostasis through effects on glucose-stimulated insulin secretion (11,12) and gluconeogenesis (13,14). In addition, reduced MPC expression (15,16) and activity (17)(18)(19) has been observed in cancer cells, contributing to the Warburg effect.…”

Treating fatty liver disease by modulating mitochondrial pyruvate metabolism

“…This complex is required for pyruvate to enter the mitochondrial matrix, where it is metabolized, from its site of synthesis in the cytosol. Recent work has suggested the utility of targeting the MPC for treatment of a variety of metabolic and inflammatory diseases, including diabetes,1, 6, 7 Parkinson's and other neurodegenerative diseases,8, 9 and now nonalcoholic fatty liver disease (NAFLD) 10…”

“…This clinical study together with ongoing studies in preclinical models will provide a better understanding of how mTOT modulator pharmacology impacts NASH and should enable both the development and the practical use of such agents going forward. The preclinical approaches being used to further elucidate these mechanisms include newly available animal models with tissue‐specific knockout of the MPC 7, 8, 9, 10…”

“…Current drug development is trained on several specific targets directed at specific symptoms along the natural history of the disease, including lipid synthesis, inflammation, and fibrosis 32, 33. The new data suggest that modification of the usage of pyruvate could be useful at several steps along the progression of the disease from insulin resistance6, 7 to reduction of ballooning and fibrosis 10. Such a treatment modality could be useful on its own or as a component of combination therapy.…”

“…It should be noted that knockout or knockdown of the MPC results in significant compensatory changes in metabolism,7, 34 and thus compensatory metabolic pathways (increased amino acid and/or fatty acid metabolism) could reduce the efficacy of these compounds for treating NASH. However, knockout of the MPC proteins is likely to have different effects than attenuation of function by TZDs.…”