OMA1-mediated integrated stress response protects against ferroptosis in mitochondrial cardiomyopathy

• Published in: Cell metabolism 2022-11, Vol.34 (11), p.1875-1891.e7
• Main Authors: Ahola, Sofia, Rivera Mejías, Pablo, Hermans, Steffen, Chandragiri, Srikanth, Giavalisco, Patrick, Nolte, Hendrik, Langer, Thomas
• Format: Article
• Language: English
• Subjects: Alkyl and Aryl Transferases; Animals; Atf4; Cardiomyopathies - metabolism; cardiomyopathy; Dele1; Electron Transport Complex IV - metabolism; Ferroptosis; glutathione; Gpx4; integrated stress response; Membrane Proteins - metabolism; Metalloproteases - metabolism; Mice; mitochondria; Mitochondria - metabolism; Mitochondrial Proteins - genetics; Mitochondrial Proteins - metabolism; Oma1; selenium
• ISSN: 1550-4131; 1932-7420
• DOI: 10.1016/j.cmet.2022.08.017

Cardiomyopathy and heart failure are common manifestations in mitochondrial disease caused by deficiencies in the oxidative phosphorylation (OXPHOS) system of mitochondria. Here, we demonstrate that the cardiac-specific loss of the assembly factor Cox10 of the cytochrome c oxidase causes mitochondrial cardiomyopathy in mice, which is associated with OXPHOS deficiency, lysosomal defects, and an aberrant mitochondrial morphology. Activation of the mitochondrial peptidase Oma1 in Cox10−/− mice results in mitochondrial fragmentation and induction of the integrated stress response (ISR) along the Oma1-Dele1-Atf4 signaling axis. Ablation of Oma1 or Dele1 in Cox10−/− mice aggravates cardiomyopathy. ISR inhibition impairs the cardiac glutathione metabolism, limits the selenium-dependent accumulation of the glutathione peroxidase Gpx4, and increases lipid peroxidation in the heart, ultimately culminating in ferroptosis. Our results demonstrate a protective role of the Oma1-Dele1-mediated ISR in mitochondrial cardiomyopathy and link ferroptosis to OXPHOS deficiency and mitochondrial disease. [Display omitted] •Oma1-Dele1-Atf4 signaling elicits the ISR in OXPHOS-deficient hearts•Loss of Oma1 or Dele1 aggravates mitochondrial cardiomyopathy•Oma1-Dele1-Atf4 signaling protects against ferroptosis in OXPHOS deficiency•Oma1-dependent ISR promotes selenium-dependent accumulation of Gpx4 Ahola et al. demonstrate that OXPHOS deficiency in the heart of Cox10−/− mice causes cardiomyopathy and elicits an integrated stress response along the Oma1-Dele1-Atf4 axis. Oma1-dependent stress signaling preserves the glutathione metabolism and Gpx4 accumulation to limit lipid peroxidation, suppress ferroptosis, and delay cardiomyopathy.