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Ahola, S.* ; Pazurek, L.A.* ; Mayer, F.* ; Lampe, P.* ; Hermans, S.* ; Becker, L. ; Amarie, O.V. ; Fuchs, H. ; Gailus-Durner, V. ; Hrabě de Angelis, M. ; Riedel, D.* ; Nolte, H.* ; Langer, T.*

Opa1 processing is dispensable in mouse development but is protective in mitochondrial cardiomyopathy.

Sci. Adv. 10:eadp0443 (2024)

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	Open Access Gold

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Mitochondrial fusion and fission accompany adaptive responses to stress and altered metabolic demands. Inner membrane fusion and cristae morphogenesis depends on optic atrophy 1 (Opa1), which is expressed in different isoforms and is cleaved from a membrane-bound, long to a soluble, short form. Here, we have analyzed the physiological role of Opa1 isoforms and Opa1 processing by generating mouse lines expressing only one cleavable Opa1 isoform or a non-cleavable variant thereof. Our results show that expression of a single cleavable or non-cleavable Opa1 isoform preserves embryonic development and the health of adult mice. Opa1 processing is dispensable under metabolic and thermal stress but prolongs life span and protects against mitochondrial cardiomyopathy in OXPHOS-deficient Cox10^-/- mice. Mechanistically, loss of Opa1 processing disturbs the balance between mitochondrial biogenesis and mitophagy, suppressing cardiac hypertrophic growth in Cox10^-/- hearts. Our results highlight the critical regulatory role of Opa1 processing, mitochondrial dynamics, and metabolism for cardiac hypertrophy.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Dynamin-related Gtpase; Fusion; Protease; Biogenesis; Extraction; Expression; Morphology; Isoforms; Mutation; Hearts

ISSN (print) / ISBN 2375-2548

e-ISSN 2375-2548

Journal Science Advances

Quellenangaben Volume: 10, Issue: 31, Article Number: eadp0443

Publisher American Association for the Advancement of Science (AAAS)

Publishing Place Washington, DC [u.a.]

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute of Experimental Genetics (IEG)

Grants German center for diabetes Research (dZd)
German Federal Ministry of education and Research
German Research Foundation)
Deutsche Forschungsgemeinschaft (DFG