King 2021 J Biol Chem
|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, Kirwan JP (2021) Dynamin-related protein 1 regulates substrate oxidation in skeletal muscle by stabilizing cellular and mitochondrial calcium dynamics. J Biol Chem [Epub ahead of print].|
King William T, Axelrod Christopher L, Zunica Elizabeth R M, Noland Robert C, Davuluri Gangarao, Fujioka Hisashi, Tandler Bernard, Pergola Kathryn, Hermann Gerlinda E, Rogers Richard C, Lopez-Domenech Sandra, Dantas Wagner S, Stadler Krisztian, Hoppel Charles L, Kirwan John P (2021) J Biol Chem
Abstract: 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, inhibition of ATP-stimulated calcium flux, and impaired substrate oxidation stimulated by calcium levels. The insights obtained herein suggest that DRP1 regulates fatty acid 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.
• Keywords: Calcium signaling, Dynamin-related protein 1, Mitochondrial dynamics, Skeletal muscle, β-oxidation • Bioblast editor: Plangger M • O2k-Network Lab: US LA Baton Rouge Noland RC, US OH Cleveland Hoppel CL
Labels: MiParea: Respiration, mt-Structure;fission;fusion, Genetic knockout;overexpression, Exercise physiology;nutrition;life style
Organism: Mouse Tissue;cell: Skeletal muscle Preparation: Permeabilized cells
Coupling state: LEAK, OXPHOS, ET Pathway: F, N, S, NS, ROX HRR: Oxygraph-2k