Mitochondrial fusion is primarily catalyzed by the large GTPases mitofusin 1 (MFN1) and mitofusin 2 (MFN2) at the outer mitochondrial membrane ( Chen et al., 2003). The underlying morphology of the mitochondria is an important determinant for the ability of this organelle to regulate a variety of cellular processes, such as apoptosis, cell fate, lipid biosynthesis and epigenetic modifications ( Bayraktar et al., 2019 Iwata et al., 2020 Khacho et al., 2016 King et al., 2021 Prigione and Adjaye, 2011 Rasmussen et al., 2020 Vantaggiato et al., 2019). Mitochondrial dynamics are controlled and executed by a vast group of proteins and other organelles. 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. Metabolomic analyses revealed impaired methionine cycle and synthesis of pyrimidine nucleotides. Peroxisomes show a severely elongated morphology in patient cells, which is associated with reduced respiration when cells are reliant on fatty acid oxidation. Mitochondrial hyperfusion also results in aberrant cristae structure and hyperpolarized mitochondrial membrane potential. ![]() In addition to elongated mitochondrial morphology and lack of fission, patient cells display lower coupling efficiency, increased proton leak and upregulation of glycolysis. To interrogate the mechanisms by which DRP1 mutations cause cellular dysfunction, we used human-derived fibroblasts from patients who present with EMPF1. 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. ![]() Mitochondria and peroxisomes are dynamic signaling organelles that constantly undergo fission, driven by the large GTPase dynamin-related protein 1 (DRP1 encoded by DNM1L).
0 Comments
Leave a Reply. |
AuthorWrite something about yourself. No need to be fancy, just an overview. ArchivesCategories |