Universität zu Köln

Ahola, Sofia ORCID: 0000-0001-7552-4843, Mejias, Pablo Rivera, Hermans, Steffen, Chandragiri, Srikanth, Giavalisco, Patrick, Nolte, Hendrik and Langer, Thomas (2022). OMA1-mediated integrated stress response protects against ferroptosis in mitochondrial cardiomyopathy. Cell Metab., 34 (11). S. 1875 - 1900. CAMBRIDGE: CELL PRESS. ISSN 1932-7420

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Abstract

Cardiomyopathy and heart failure are common manifestations in mitochondrial disease caused by defi-ciencies 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 mito-chondrial 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 im-pairs 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 re-sults demonstrate a protective role of the Oma1-Dele1-mediated ISR in mitochondrial cardiomyopathy and link ferroptosis to OXPHOS deficiency and mitochondrial disease.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Ahola, Sofia UNSPECIFIED orcid.org/0000-0001-7552-4843 UNSPECIFIED Mejias, Pablo Rivera UNSPECIFIED UNSPECIFIED UNSPECIFIED Hermans, Steffen UNSPECIFIED UNSPECIFIED UNSPECIFIED Chandragiri, Srikanth UNSPECIFIED UNSPECIFIED UNSPECIFIED Giavalisco, Patrick UNSPECIFIED UNSPECIFIED UNSPECIFIED Nolte, Hendrik UNSPECIFIED UNSPECIFIED UNSPECIFIED Langer, Thomas UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-665568
DOI:	10.1016/j.cmet.2022.08.017
Journal or Publication Title:	Cell Metab.
Volume:	34
Number:	11
Page Range:	S. 1875 - 1900
Date:	2022
Publisher:	CELL PRESS
Place of Publication:	CAMBRIDGE
ISSN:	1932-7420
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language MASS-SPECTROMETRY; PROTEASE OMA1; OPA1; ACTIVATION; DISEASE; FUSION; COX10; GENE; ATF4 Multiple languages Cell Biology; Endocrinology & Metabolism Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/66556