Mitochondrial pyruvate carrier inhibition initiates metabolic crosstalk to stimulate branched chain amino acid catabolism
Objective: 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, whic...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-04-01
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| Series: | Molecular Metabolism |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2212877823000285 |
| _version_ | 1797867647248891904 |
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| author | Daniel Ferguson Sophie J. Eichler Nicole K.H. Yiew Jerry R. Colca Kevin Cho Gary J. Patti Trevor M. Shew Andrew J. Lutkewitte Sandip Mukherjee Kyle S. McCommis Natalie M. Niemi Brian N. Finck |
| author_facet | Daniel Ferguson Sophie J. Eichler Nicole K.H. Yiew Jerry R. Colca Kevin Cho Gary J. Patti Trevor M. Shew Andrew J. Lutkewitte Sandip Mukherjee Kyle S. McCommis Natalie M. Niemi Brian N. Finck |
| author_sort | Daniel Ferguson |
| collection | DOAJ |
| description | Objective: 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. Methods: Circulating BCAA concentrations were measured in people with NASH and type 2 diabetes, who participated in a recent randomized, placebo-controlled Phase IIB clinical trial to test the efficacy and safety of the MPCi MSDC-0602K (EMMINENCE; NCT02784444). In this 52-week trial, patients were randomly assigned to placebo (n = 94) or 250 mg MSDC-0602K (n = 101). Human hepatoma cell lines and mouse primary hepatocytes were used to test the direct effects of various MPCi on BCAA catabolism in vitro. Lastly, we investigated how hepatocyte-specific deletion of MPC2 affects BCAA metabolism in the liver of obese mice and MSDC-0602K treatment of Zucker diabetic fatty (ZDF) rats. Results: In patients with NASH, MSDC-0602K treatment, which led to marked improvements in insulin sensitivity and diabetes, had 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. In multiple human hepatoma cell lines, MPCi markedly reduced BCKDH phosphorylation and stimulated branched chain keto acid catabolism; an effect that required the BCKDH phosphatase PPM1K. Mechanistically, the effects of MPCi were linked to activation of the energy sensing AMP-dependent protein kinase (AMPK) and mechanistic target of rapamycin (mTOR) kinase signaling cascades in vitro. BCKDH phosphorylation was reduced in liver of obese, hepatocyte-specific MPC2 knockout (LS-Mpc2−/−) mice compared to wild-type controls concomitant with activation of mTOR signaling in vivo. Finally, while MSDC-0602K treatment improved glucose homeostasis and increased the concentrations of some BCAA metabolites in ZDF rats, it did not lower plasma BCAA concentrations. Conclusions: 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 by activating the mTOR axis. However, the effects of MPCi on glucose homeostasis may be separable from its effects on BCAA concentrations. |
| first_indexed | 2024-04-09T23:43:30Z |
| format | Article |
| id | doaj.art-3898d186981f4a0e95dd6457eab4e374 |
| institution | Directory Open Access Journal |
| issn | 2212-8778 |
| language | English |
| last_indexed | 2024-04-09T23:43:30Z |
| publishDate | 2023-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Metabolism |
| spelling | doaj.art-3898d186981f4a0e95dd6457eab4e3742023-03-18T04:40:58ZengElsevierMolecular Metabolism2212-87782023-04-0170101694Mitochondrial pyruvate carrier inhibition initiates metabolic crosstalk to stimulate branched chain amino acid catabolismDaniel Ferguson0Sophie J. Eichler1Nicole K.H. Yiew2Jerry R. Colca3Kevin Cho4Gary J. Patti5Trevor M. Shew6Andrew J. Lutkewitte7Sandip Mukherjee8Kyle S. McCommis9Natalie M. Niemi10Brian N. Finck11Department of Medicine, Center for Human Nutrition, Washington University in St. Louis, United StatesDepartment of Medicine, Center for Human Nutrition, Washington University in St. Louis, United StatesDepartment of Medicine, Center for Human Nutrition, Washington University in St. Louis, United StatesDepartment of Biomedical Sciences, Western Michigan University School of Medicine, Kalamazoo, MI, Cirius Therapeutics, Kalamazoo, MI, United StatesDepartment of Chemistry, Washington University in St. Louis, United States; Center for Metabolomics and Isotope Tracing, Washington University in St. Louis, United StatesDepartment of Medicine, Center for Human Nutrition, Washington University in St. Louis, United States; Department of Chemistry, Washington University in St. Louis, United States; Siteman Cancer Center, Washington University in St. Louis, United States; Center for Metabolomics and Isotope Tracing, Washington University in St. Louis, United StatesDepartment of Medicine, Center for Human Nutrition, Washington University in St. Louis, United StatesDepartment of Medicine, Center for Human Nutrition, Washington University in St. Louis, United StatesDepartment of Medicine, Center for Human Nutrition, Washington University in St. Louis, United StatesDepartment of Biochemistry & Molecular Biology, Saint Louis University School of Medicine, United StatesDepartment of Biochemistry and Molecular Biophysics, Washington University in St. Louis, United StatesDepartment of Medicine, Center for Human Nutrition, Washington University in St. Louis, United States; Corresponding author. MSC 8031-0014-01, 660 S. Euclid Avenue, St. Louis, MO 63110, United States.Objective: 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. Methods: Circulating BCAA concentrations were measured in people with NASH and type 2 diabetes, who participated in a recent randomized, placebo-controlled Phase IIB clinical trial to test the efficacy and safety of the MPCi MSDC-0602K (EMMINENCE; NCT02784444). In this 52-week trial, patients were randomly assigned to placebo (n = 94) or 250 mg MSDC-0602K (n = 101). Human hepatoma cell lines and mouse primary hepatocytes were used to test the direct effects of various MPCi on BCAA catabolism in vitro. Lastly, we investigated how hepatocyte-specific deletion of MPC2 affects BCAA metabolism in the liver of obese mice and MSDC-0602K treatment of Zucker diabetic fatty (ZDF) rats. Results: In patients with NASH, MSDC-0602K treatment, which led to marked improvements in insulin sensitivity and diabetes, had 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. In multiple human hepatoma cell lines, MPCi markedly reduced BCKDH phosphorylation and stimulated branched chain keto acid catabolism; an effect that required the BCKDH phosphatase PPM1K. Mechanistically, the effects of MPCi were linked to activation of the energy sensing AMP-dependent protein kinase (AMPK) and mechanistic target of rapamycin (mTOR) kinase signaling cascades in vitro. BCKDH phosphorylation was reduced in liver of obese, hepatocyte-specific MPC2 knockout (LS-Mpc2−/−) mice compared to wild-type controls concomitant with activation of mTOR signaling in vivo. Finally, while MSDC-0602K treatment improved glucose homeostasis and increased the concentrations of some BCAA metabolites in ZDF rats, it did not lower plasma BCAA concentrations. Conclusions: 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 by activating the mTOR axis. However, the effects of MPCi on glucose homeostasis may be separable from its effects on BCAA concentrations.http://www.sciencedirect.com/science/article/pii/S2212877823000285PyruvateLiverBranched chain amino acidsMitochondriaDiabetes |
| spellingShingle | Daniel Ferguson Sophie J. Eichler Nicole K.H. Yiew Jerry R. Colca Kevin Cho Gary J. Patti Trevor M. Shew Andrew J. Lutkewitte Sandip Mukherjee Kyle S. McCommis Natalie M. Niemi Brian N. Finck Mitochondrial pyruvate carrier inhibition initiates metabolic crosstalk to stimulate branched chain amino acid catabolism Molecular Metabolism Pyruvate Liver Branched chain amino acids Mitochondria Diabetes |
| title | Mitochondrial pyruvate carrier inhibition initiates metabolic crosstalk to stimulate branched chain amino acid catabolism |
| title_full | Mitochondrial pyruvate carrier inhibition initiates metabolic crosstalk to stimulate branched chain amino acid catabolism |
| title_fullStr | Mitochondrial pyruvate carrier inhibition initiates metabolic crosstalk to stimulate branched chain amino acid catabolism |
| title_full_unstemmed | Mitochondrial pyruvate carrier inhibition initiates metabolic crosstalk to stimulate branched chain amino acid catabolism |
| title_short | Mitochondrial pyruvate carrier inhibition initiates metabolic crosstalk to stimulate branched chain amino acid catabolism |
| title_sort | mitochondrial pyruvate carrier inhibition initiates metabolic crosstalk to stimulate branched chain amino acid catabolism |
| topic | Pyruvate Liver Branched chain amino acids Mitochondria Diabetes |
| url | http://www.sciencedirect.com/science/article/pii/S2212877823000285 |
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