RT Journal Article
SR Electronic
T1 Mitochondrial Pyruvate Carrier Inhibition Initiates Metabolic Crosstalk to Stimulate Branched Chain Amino Acid Catabolism
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.05.11.491550
DO 10.1101/2022.05.11.491550
A1 Daniel Ferguson
A1 Sophie J. Eichler
A1 Nicole K.H. Yiew
A1 Jerry R. Colca
A1 Kevin Cho
A1 Gary J. Patti
A1 Kyle S. McCommis
A1 Natalie M. Niemi
A1 Brian N. Finck
YR 2022
UL http://biorxiv.org/content/early/2022/05/11/2022.05.11.491550.abstract
AB The mitochondrial pyruvate carrier (MPC) has emerged as a therapeutic target for treating insulin resistance, type 2 diabetes, and nonalcoholic steatohepatitis (NASH). We evaluated whether MPC inhibitors (MPCi) might correct impairments in branched chain amino acid (BCAA) catabolism, which are predictive of developing diabetes and NASH. In a randomized, placebo-controlled trial of an MPCi (MSDC-0602K) in people with NASH (EMMINENCE; NCT02784444), MSDC-0602K treatment, which led to marked improvements in insulin sensitivity and diabetes, decreased plasma concentrations of BCAAs compared to baseline while placebo had no effect. The rate-limiting enzyme in BCAA catabolism is the mitochondrial branched chain ketoacid dehydrogenase (BCKDH), which is deactivated by phosphorylation. BCKDH phosphorylation was reduced in liver of obese, hepatocyte-specific MPC2 knockout (LS-Mpc2-/-) mice compared to wild-type controls. In multiple human hepatoma cell lines, MPCi markedly reduced BCKDH phosphorylation and stimulated branched chain keto acid catabolism. Mechanistically, the effects of MPCi could be mimicked by activating mitochondrial pyruvate oxidation and reversed by addition of mitochondrial-permeable methyl-pyruvate, suggesting that intramitochondrial pyruvate accumulation suppresses BCKDH activity. The effects of MPCi on BCKDH phosphorylation were mediated by the BCKDH phosphatase PPM1K, and MPCi treatment also reduced phosphorylation of PPM1K likely at a key serine residue near the substrate binding cleft. These data demonstrate novel cross talk between mitochondrial pyruvate and BCAA metabolism and suggest that MPC inhibition leads to lower plasma BCAA concentrations and BCKDH phosphorylation via the phosphatase PPM1K.Competing Interest StatementBNF is a shareholder and a member of the Scientific Advisory Board for Cirius Therapeutics, which is developing an MPC modulator for treating nonalcoholic steatohepatitis. JRC is the co-founder and part owner of Metabolic Solutions Development and Cirius Therapeutics which are developing clinical candidates including this class of potential therapeutics.