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Robertson 2023 J Cell Sci

From Bioblast
Publications in the MiPMap
Robertson GL, Riffle S, Patel M, Bodnya C, Marshall A, Beasley HK, Garza-Lopez E, Shao J, Vue Z, Hinton A, Stoll MS, de Wet S, Theart RP, Chakrabarty RP, Loos B, Chandel NS, Mears JA, Gama V (2023) DRP1 mutations associated with EMPF1 encephalopathy alter mitochondrial membrane potential and metabolic programs.

Β» J Cell Sci 136:jcs260370. PMID: 36763487 Open Access

Robertson Gabriella L, Riffle Stellan, Patel Mira, Bodnya Caroline, Marshall Andrea, Beasley Heather K, Garza-Lopez Edgar, Shao Jianqiang, Vue Zer, Hinton Antentor, Stoll Maria S, de Wet Sholto, Theart Rensu P, Chakrabarty Ram Prosad, Loos Ben, Chandel Navdeep S, Mears Jason A, Gama Vivian (2023) J Cell Sci

Abstract: Mitochondria and peroxisomes are dynamic signaling organelles that constantly undergo fission, driven by the large GTPase dynamin-related protein 1 (DRP1; encoded by DNM1L). Patients with de novo heterozygous missense mutations in DNM1L present with encephalopathy due to defective mitochondrial and peroxisomal fission (EMPF1) - a devastating neurodevelopmental disease with no effective treatment. To interrogate the mechanisms by which DRP1 mutations cause cellular dysfunction, we used human-derived fibroblasts from patients who present with EMPF1. In addition to elongated mitochondrial morphology and lack of fission, patient cells display lower coupling efficiency, increased proton leak and upregulation of glycolysis. Mitochondrial hyperfusion also results in aberrant cristae structure and hyperpolarized mitochondrial membrane potential. Peroxisomes show a severely elongated morphology in patient cells, which is associated with reduced respiration when cells are reliant on fatty acid oxidation. Metabolomic analyses revealed impaired methionine cycle and synthesis of pyrimidine nucleotides. Our study provides insight into the role of mitochondrial dynamics in cristae maintenance and the metabolic capacity of the cell, as well as the disease mechanism underlying EMPF1. β€’ Keywords: Cristae, DRP1, Fibroblast, Glycolysis, Mitochondria, Oxidative phosphorylation, Peroxisome β€’ Bioblast editor: Plangger M

Labels: MiParea: Respiration, mt-Structure;fission;fusion, Patients  Pathology: Neurodegenerative 

Organism: Human  Tissue;cell: Fibroblast  Preparation: Permeabilized cells, Intact cells 

Coupling state: LEAK, ROUTINE, OXPHOS, ET  Pathway: F, N, S, DQ, CIV, NS, ROX  HRR: Oxygraph-2k