Mitochondrial fission process 1 (MTFP1) controls bioenergetic efficiency and prevents inflammatory cardiomyopathy and heart failure in mice
| Autor: | Timothy Wai, Erminia Donnarumma, Christoph Maack, Thibault Chaze, Quentin Giai Gianetto, Mariette Matondo, Elodie Vimont, Etienne Kornobis, Michael Kohlhaas, Maryse Moya-Nilges |
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| Přispěvatelé: | Biologie mitochondriale – Mitochondrial biology, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), University Clinic Würzburg, Biomics (plateforme technologique), Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics HUB, Plateforme de Spectrométrie de Masse Protéomique - Mass Spectrometry Proteomics Platform (MSPP), Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université de Montpellier (UM) |
| Rok vydání: | 2021 |
| Předmět: |
uncoupling
Programmed cell death permeability transition pore Cardiac fibrosis Chemistry oxidative phosphorylation Cardiomyopathy Oxidative phosphorylation Mitochondrion medicine.disease Cell biology mitochondria Mitochondrial permeability transition pore Knockout mouse medicine [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie Mitochondrial fission cardiomyopathy |
| DOI: | 10.1101/2021.10.21.465262 |
| Popis: | Mitochondria are paramount to the metabolism and survival of cardiomyocytes. Here we show that Mitochondrial Fission Process 1 (MTFP1) is essential for cardiac structure and function. Constitutive knockout of cardiomyocyte MTFP1 in mice resulted in adult-onset dilated cardiomyopathy (DCM) characterized by sterile inflammation and cardiac fibrosis that progressed to heart failure and middle-aged death. Failing hearts from cardiomyocyte-restricted knockout mice displayed a general decline in mitochondrial gene expression and oxidative phosphorylation (OXPHOS) activity. Pre-DCM, we observed no defects in mitochondrial morphology, content, gene expression, OXPHOS assembly nor phosphorylation dependent respiration. However, knockout cardiac mitochondria displayed reduced membrane potential and increased non-phosphorylation dependent respiration, which could be rescued by pharmacological inhibition of the adenine nucleotide translocase ANT. Primary cardiomyocytes from pre-symptomatic knockout mice exhibited normal excitation-contraction coupling but increased sensitivity to programmed cell death (PCD), which was accompanied by an opening of the mitochondrial permeability transition pore (mPTP). Intriguingly, mouse embryonic fibroblasts deleted for Mtfp1 recapitulated PCD sensitivity and mPTP opening, both of which could be rescued by pharmacological or genetic inhibition of the mPTP regulator Cyclophilin D. Collectively, our data demonstrate that contrary to previous in vitro studies, the loss of the MTFP1 promotes mitochondrial uncoupling and increases cell death sensitivity, causally mediating pathogenic cardiac remodeling. |
| Databáze: | OpenAIRE |
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