Loss of Ptpmt1 limits mitochondrial utilization of carbohydrates and leads to muscle atrophy and heart failure in tissue-specific knockout mice

Author:

Zheng Hong12ORCID,Li Qianjin1ORCID,Li Shanhu12,Li Zhiguo1,Brotto Marco3,Weiss Daiana4,Prosdocimo Domenick5,Xu Chunhui1,Reddy Ashruth1,Puchowicz Michelle6,Zhao Xinyang7,Weitzmann M Neale4ORCID,Jain Mukesh K5,Qu Cheng-Kui12ORCID

Affiliation:

1. Department of Pediatrics, Children Healthcare of Atlanta, Emory University School of Medicine

2. Department of Medicine, Case Western Reserve University

3. College of Nursing & Health Innovation, University of Texas-Arlington

4. Department of Medicine, Emory University School of Medicine

5. Case Cardiovascular Research Institute, Department of Medicine, Case Western Reserve University

6. Case Mouse Metabolic Phenotyping Center, Case Western Reserve University

7. Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham

Abstract

While mitochondria in different tissues have distinct preferences for energy sources, they are flexible in utilizing competing substrates for metabolism according to physiological and nutritional circumstances. However, the regulatory mechanisms and significance of metabolic flexibility are not completely understood. Here, we report that the deletion of Ptpmt1, a mitochondria-based phosphatase, critically alters mitochondrial fuel selection – the utilization of pyruvate, a key mitochondrial substrate derived from glucose (the major simple carbohydrate), is inhibited, whereas the fatty acid utilization is enhanced. Ptpmt1 knockout does not impact the development of the skeletal muscle or heart. However, the metabolic inflexibility ultimately leads to muscular atrophy, heart failure, and sudden death. Mechanistic analyses reveal that the prolonged substrate shift from carbohydrates to lipids causes oxidative stress and mitochondrial destruction, which in turn results in marked accumulation of lipids and profound damage in the knockout muscle cells and cardiomyocytes. Interestingly, Ptpmt1 deletion from the liver or adipose tissue does not generate any local or systemic defects. These findings suggest that Ptpmt1 plays an important role in maintaining mitochondrial flexibility and that their balanced utilization of carbohydrates and lipids is essential for both the skeletal muscle and the heart despite the two tissues having different preferred energy sources.

Funder

National Institutes of Health

Publisher

eLife Sciences Publications, Ltd

Subject

General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience

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