Impaired skeletal muscle mitochondrial pyruvate uptake rewires glucose metabolism to drive whole-body leanness

There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

Abstract

Metabolic cycles are a fundamental element of cellular and organismal function. Among the most critical in higher organisms is the Cori Cycle, the systemic cycling between lactate and glucose. Here, skeletal muscle-specific Mitochondrial Pyruvate Carrier (MPC) deletion in mice diverted pyruvate into circulating lactate. This switch disinhibited muscle fatty acid oxidation and drove Cori Cycling that contributed to increased energy expenditure. Loss of muscle MPC activity led to strikingly decreased adiposity with complete muscle mass and strength retention. Notably, despite decreasing muscle glucose oxidation, muscle MPC disruption increased muscle glucose uptake and whole-body insulin sensitivity. Furthermore, chronic and acute muscle MPC deletion accelerated fat mass loss on a normal diet after high fat diet-induced obesity. Our results illuminate the role of the skeletal muscle MPC as a whole-body carbon flux control point. They highlight the potential utility of modulating muscle pyruvate utilization to ameliorate obesity and type 2 diabetes.

Related collections

Most cited references 38

Record: found
Abstract: found
Article: not found

A mitochondrial pyruvate carrier required for pyruvate uptake in yeast, Drosophila, and humans.

Daniel Bricker, Eric Taylor, John Schell … (2012)

Pyruvate constitutes a critical branch point in cellular carbon metabolism. We have identified two proteins, Mpc1 and Mpc2, as essential for mitochondrial pyruvate transport in yeast, Drosophila, and humans. Mpc1 and Mpc2 associate to form an ~150-kilodalton complex in the inner mitochondrial membrane. Yeast and Drosophila mutants lacking MPC1 display impaired pyruvate metabolism, with an accumulation of upstream metabolites and a depletion of tricarboxylic acid cycle intermediates. Loss of yeast Mpc1 results in defective mitochondrial pyruvate uptake, and silencing of MPC1 or MPC2 in mammalian cells impairs pyruvate oxidation. A point mutation in MPC1 provides resistance to a known inhibitor of the mitochondrial pyruvate carrier. Human genetic studies of three families with children suffering from lactic acidosis and hyperpyruvatemia revealed a causal locus that mapped to MPC1, changing single amino acids that are conserved throughout eukaryotes. These data demonstrate that Mpc1 and Mpc2 form an essential part of the mitochondrial pyruvate carrier.

0 comments Cited 318 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Glutamine oxidation maintains the TCA cycle and cell survival during impaired mitochondrial pyruvate transport.

Chendong Yang, Bookyung Ko, Christopher Hensley … (2014)

Alternative modes of metabolism enable cells to resist metabolic stress. Inhibiting these compensatory pathways may produce synthetic lethality. We previously demonstrated that glucose deprivation stimulated a pathway in which acetyl-CoA was formed from glutamine downstream of glutamate dehydrogenase (GDH). Here we show that import of pyruvate into the mitochondria suppresses GDH and glutamine-dependent acetyl-CoA formation. Inhibiting the mitochondrial pyruvate carrier (MPC) activates GDH and reroutes glutamine metabolism to generate both oxaloacetate and acetyl-CoA, enabling persistent tricarboxylic acid (TCA) cycle function. Pharmacological blockade of GDH elicited largely cytostatic effects in culture, but these effects became cytotoxic when combined with MPC inhibition. Concomitant administration of MPC and GDH inhibitors significantly impaired tumor growth compared to either inhibitor used as a single agent. Together, the data define a mechanism to induce glutaminolysis and uncover a survival pathway engaged during compromised supply of pyruvate to the mitochondria. Copyright © 2014 Elsevier Inc. All rights reserved.

0 comments Cited 257 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: found

Is Open Access

Age-Associated Loss of OPA1 in Muscle Impacts Muscle Mass, Metabolic Homeostasis, Systemic Inflammation, and Epithelial Senescence

Caterina Tezze, Vanina Romanello, Maria Desbats … (2017)

Summary Mitochondrial dysfunction occurs during aging, but its impact on tissue senescence is unknown. Here, we find that sedentary but not active humans display an age-related decline in the mitochondrial protein, optic atrophy 1 (OPA1), that is associated with muscle loss. In adult mice, acute, muscle-specific deletion of Opa1 induces a precocious senescence phenotype and premature death. Conditional and inducible Opa1 deletion alters mitochondrial morphology and function but not DNA content. Mechanistically, the ablation of Opa1 leads to ER stress, which signals via the unfolded protein response (UPR) and FoxOs, inducing a catabolic program of muscle loss and systemic aging. Pharmacological inhibition of ER stress or muscle-specific deletion of FGF21 compensates for the loss of Opa1, restoring a normal metabolic state and preventing muscle atrophy and premature death. Thus, mitochondrial dysfunction in the muscle can trigger a cascade of signaling initiated at the ER that systemically affects general metabolism and aging.

0 comments Cited 257 times – based on 0 reviews      Review now

Bookmark

All references

Author and article information

Contributors

Eric B Taylor:

ORCID: https://orcid.org/0000-0003-4549-6567

Mark I McCarthy: Role: Senior Editor

David E James: Role: Reviewing Editor

Journal

Journal ID (nlm-ta): eLife

Journal ID (iso-abbrev): Elife

Journal ID (publisher-id): eLife

Title: eLife

Publisher: eLife Sciences Publications, Ltd

ISSN (Electronic): 2050-084X

Publication date (Electronic, pub): 18 July 2019

Publication date Collection: 2019

Volume: 8

Electronic Location Identifier: e45873

Affiliations

[1 ]deptDepartment of Biochemistry, Carver College of Medicine University of Iowa Iowa CityUnited States

[2 ]deptDepartment of Internal Medicine, Carver College of Medicine University of Iowa Iowa CityUnited States

[3 ]deptDepartment of Chemistry, School of Medicine Washington University St. LouisUnited States

[4 ]deptFraternal Order of the Eagles Diabetes Research Center (FOEDRC), Carver College of Medicine University of Iowa Iowa CityUnited States

[5 ]deptFOEDRC Metabolic Phenotyping Core Facility, Carver College of Medicine University of Iowa Iowa CityUnited States

[6 ]deptDepartment of Biochemistry, School of Medicine University of Utah Salt Lake CityUnited States

[7 ]deptMetabolomics Core Research Facility, School of Medicine University of Utah Salt Lake CityUnited States

[8 ]deptDepartment of Molecular Physiology and Biophysics, Carver College of Medicine University of Iowa Iowa CityUnited States

[9 ]deptPappajohn Biomedical Institute, Carver College of Medicine University of Iowa Iowa CityUnited States

[10 ]deptAbboud Cardiovascular Research Center, Carver College of Medicine University of Iowa Iowa CityUnited States

[11 ]deptDepartment of Physical Therapy and Rehabilitation Science, Carver College of Medicine University of Iowa Iowa CityUnited States

[12 ]deptDepartment of Pediatrics, Carver College of Medicine University of Iowa Iowa CityUnited States

[13 ]deptDepartment of Veterans Affairs, Medical Center, Carver College of Medicine University of Iowa Iowa CityUnited States

[14 ]deptFOEDRC Metabolomics Core Facility, Carver College of Medicine University of Iowa Iowa CityUnited States

University of Oxford United Kingdom

The University of Sydney Australia

East Carolina University United States

Yale University United States

Duke University United States

Author notes

[†]

These authors contributed equally to this work.

Author information

Arpit Sharma https://orcid.org/0000-0002-6132-1129

Lalita Oonthonpan https://orcid.org/0000-0001-9425-8448

Adam J Rauckhorst https://orcid.org/0000-0002-4101-0075

Emily M Cushing http://orcid.org/0000-0002-9495-802X

Gary Patti http://orcid.org/0000-0002-3748-6193

Eric B Taylor https://orcid.org/0000-0003-4549-6567

Article

Publisher ID: 45873

DOI: 10.7554/eLife.45873

PMC ID: 6684275

PubMed ID: 31305240

SO-VID: b8a11a37-6c40-40a5-b23c-300b5c3870d7

License:

This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.