Journal Article

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

Qu, Cheng-Kui, Li, Shanhu, Li, Qianjin, Weiss, Daiana, Reddy, Ashruth, Jain, Mukesh K, Li, Zhiguo, Prosdocimo, Domenick, Weitzmann, M Neale, Puchowicz, Michelle, Zhao, Xinyang, Brotto, Marco, Xu, Chunhui, Zheng, Hong

2023

Overview

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. Cells are powered by mitochondria, a group of organelles that produce chemical energy in the form of molecules called ATP. This energy is derived from the breakdown of carbohydrates, fats, and proteins. The number of mitochondria in a cell and the energy source they use to produce ATP varies depending on the type of cell. Mitochondria can also switch the molecules they use to produce energy when the cell is responding to stress or disease. The heart and the skeletal muscles – which allow movement – are two tissues that require large amounts of energy, but it remained unknown whether disrupting mitochondrial fuel selection affects how these tissues work. To answer these questions, Zheng, Li, Li et al. investigated the role of an enzyme found in mitochondria called Ptpmt1. Genetically deleting Ptpmt1 in the heart and skeletal muscle of mice showed that while the development of these organs was not affected, mitochondria in these cells switched from using carbohydrates to using fats as an energy source. Over time, this shift damaged both the mitochondria and the tissues, leading to muscle wasting, heart failure, and sudden death in the mice. This suggests that balanced use of carbohydrates and fats is essential for the muscles and heart. These findings imply that long-term use of medications that alter the fuel that mitochondria use may be detrimental to patients’ health and could cause heart dysfunction. This may be important for future drug development, as well as informing decisions about medication taken in the clinic.

• Publisher: eLife Sciences Publications Ltd,eLife Sciences Publications, Ltd
• Subject: Adipose tissue / Atrophy / bioenergetics / Carbohydrates / Cardiac muscle / Cardiomyocytes / Congestive heart failure / Energy resources / Fatty acids / Fitness equipment / Gene deletion / Genotype & phenotype / Glucose / heart / Heart failure / Kinases / Lipids / Males / Medicine / Metabolism / Metabolites / Mitochondria / Musculoskeletal system / Oxidative stress / Ptpmt1 / Pyruvic acid / Skeletal muscle