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

被引:7
作者
Ahola, Sofia [1 ]
Pazurek, Lilli A. [1 ]
Mayer, Fiona [1 ]
Lampe, Philipp [1 ]
Hermans, Steffen [1 ]
Becker, Lore [2 ]
Amarie, Oana, V [2 ]
Fuchs, Helmut [2 ]
Gailus-Durner, Valerie [2 ]
de Angelis, Martin Hrabe [2 ,3 ,4 ]
Riedel, Dietmar [5 ]
Nolte, Hendrik [1 ]
Langer, Thomas [1 ,6 ]
机构
[1] Max Planck Inst Biol Ageing, Cologne, Germany
[2] German Res Ctr Environm Hlth GmbH, Helmholtz Zentrum Munchen, Inst Expt Genet, German Mouse Clin, Neuherberg, Germany
[3] Tech Univ Munich, TUM Sch Life Sci, Expt Genet, Freising Weihenstephan, Germany
[4] German Ctr Diabetes Res DZD, D-85764 Neuherberg, Germany
[5] Max Planck Inst Multidisciplinary Sci, Gottingen, Germany
[6] Univ Cologne, Cologne Excellence Cluster Cellular Stress Respons, Fac Med,Univ Hosp Cologne, Cologne, Germany
关键词
DYNAMIN-RELATED GTPASE; FUSION; PROTEASE; BIOGENESIS; EXTRACTION; EXPRESSION; MORPHOLOGY; ISOFORMS; MUTATION; HEARTS;
D O I
10.1126/sciadv.adp0443
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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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页数:17
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