Dynamin-related protein 1 regulates substrate oxidation in skeletal muscle by stabilizing cellular and mitochondrial calcium dynamics.
Por:
King WT, Axelrod CL, Zunica ERM, Noland RC, Davuluri G, Fujioka H, Tandler B, Pergola K, Hermann GE, Rogers RC, López-Domènech S, Dantas WS, Stadler K, Hoppel CL and Kirwan JP
Publicada:
1 oct 2021
Ahead of Print:
13 sep 2021
Resumen:
Mitochondria undergo continuous cycles of fission and fusion to promote inheritance, regulate quality control, and mitigate organelle stress. More recently, this process of mitochondrial dynamics has been demonstrated to be highly sensitive to nutrient supply, ultimately conferring bioenergetic plasticity to the organelle. However, whether regulators of mitochondrial dynamics play a causative role in nutrient regulation remains unclear. In this study, we generated a cellular loss-of-function model for dynamin-related protein 1 (DRP1), the primary regulator of outer membrane mitochondrial fission. Loss of DRP1 (shDRP1) resulted in extensive ultrastructural and functional remodeling of mitochondria, characterized by pleomorphic enlargement, increased electron density of the matrix, and defective NADH and succinate oxidation. Despite increased mitochondrial size and volume, shDRP1 cells exhibited reduced cellular glucose uptake and mitochondrial fatty acid oxidation. Untargeted transcriptomic profiling revealed severe downregulation of genes required for cellular and mitochondrial calcium homeostasis, which was coupled to loss of ATP-stimulated calcium flux and impaired substrate oxidation stimulated by exogenous calcium. The insights obtained herein suggest that DRP1 regulates substrate oxidation by altering whole-cell and mitochondrial calcium dynamics. These findings are relevant to the targetability of mitochondrial fission and have clinical relevance in the identification of treatments for fission-related pathologies such as hereditary neuropathies, inborn errors in metabolism, cancer, and chronic diseases.
Filiaciones:
King WT:
Department of Translational Services, Pennington Biomedical Research Center, Baton Rouge, Louisiana, USA
Integrated Physiology and Molecular Medicine Laboratory, Pennington Biomedical Research Center, Baton Rouge, Louisiana, USA
Axelrod CL:
Department of Translational Services, Pennington Biomedical Research Center, Baton Rouge, Louisiana, USA
Integrated Physiology and Molecular Medicine Laboratory, Pennington Biomedical Research Center, Baton Rouge, Louisiana, USA
Zunica ERM:
Integrated Physiology and Molecular Medicine Laboratory, Pennington Biomedical Research Center, Baton Rouge, Louisiana, USA
Department of Nutrition, School of Medicine, Case Western Reserve University, Cleveland, Ohio, USA
Noland RC:
Skeletal Muscle Metabolism Laboratory, Pennington Biomedical Research Center, Baton Rouge, Louisiana, USA
Davuluri G:
Integrated Physiology and Molecular Medicine Laboratory, Pennington Biomedical Research Center, Baton Rouge, Louisiana, USA
Fujioka H:
Center for Mitochondrial Diseases, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA
Electron Microscope Facility, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA
Tandler B:
Center for Mitochondrial Diseases, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA
Department of Biological Sciences, Case Western Reserve University School of Dental Medicine, Cleveland, Ohio, USA
Pergola K:
Department of Translational Services, Pennington Biomedical Research Center, Baton Rouge, Louisiana, USA
Integrated Physiology and Molecular Medicine Laboratory, Pennington Biomedical Research Center, Baton Rouge, Louisiana, USA
Hermann GE:
Department of Autonomic Neuroscience, Pennington Biomedical Research Center, Baton Rouge, Louisiana, USA
Rogers RC:
Department of Autonomic Neuroscience, Pennington Biomedical Research Center, Baton Rouge, Louisiana, USA
:
Integrated Physiology and Molecular Medicine Laboratory, Pennington Biomedical Research Center, Baton Rouge, Louisiana, USA
University Hospital Dr. Peset, Fisabio, Valencia, Spain
Dantas WS:
Integrated Physiology and Molecular Medicine Laboratory, Pennington Biomedical Research Center, Baton Rouge, Louisiana, USA
Stadler K:
Department of Oxidative Stress and Disease, Pennington Biomedical Research Center, Baton Rouge, Louisiana, USA
Hoppel CL:
Integrated Physiology and Molecular Medicine Laboratory, Pennington Biomedical Research Center, Baton Rouge, Louisiana, USA
Center for Mitochondrial Diseases, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA
Department of Pharmacology, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA
Kirwan JP:
Integrated Physiology and Molecular Medicine Laboratory, Pennington Biomedical Research Center, Baton Rouge, Louisiana, USA
Department of Nutrition, School of Medicine, Case Western Reserve University, Cleveland, Ohio, USA
gold, Green Published
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