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Nat Cell Biol. 2017 Jul;19(7):856-863. doi: 10.1038/ncb3560. Epub 2017 Jun 19.

Molecular basis of selective mitochondrial fusion by heterotypic action between OPA1 and cardiolipin.

Author information

1
Department of Protein Biochemistry, Institute of Life Science, Kurume University, Kurume 839-0864, Japan.
2
Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, Cologne 50931, Germany.
3
Laboratory of Biomolecular Science, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan.
4
Department of Life Science, Rikkyo University, Tokyo 171-8501, Japan.
5
Graduate School of Medical Science, Kyushu University, Fukuoka 812-8582, Japan.

Abstract

Mitochondria are highly dynamic organelles that undergo frequent fusion and fission. Optic atrophy 1 (OPA1) is an essential GTPase protein for both mitochondrial inner membrane (IM) fusion and cristae morphology. Under mitochondria-stress conditions, membrane-anchored L-OPA1 is proteolytically cleaved to form peripheral S-OPA1, leading to the selection of damaged mitochondria for mitophagy. However, molecular details of the selective mitochondrial fusion are less well understood. Here, we showed that L-OPA1 and cardiolipin (CL) cooperate in heterotypic mitochondrial IM fusion. We reconstituted an in vitro membrane fusion reaction using purified human L-OPA1 protein expressed in silkworm, and found that L-OPA1 on one side of the membrane and CL on the other side are sufficient for fusion. GTP-independent membrane tethering through L-OPA1 and CL primes the subsequent GTP-hydrolysis-dependent fusion, which can be modulated by the presence of S-OPA1. These results unveil the most minimal intracellular membrane fusion machinery. In contrast, independent of CL, a homotypic trans-OPA1 interaction mediates membrane tethering, thereby supporting the cristae structure. Thus, multiple OPA1 functions are modulated by local CL conditions for regulation of mitochondrial morphology and quality control.

PMID:
28628083
DOI:
10.1038/ncb3560
[Indexed for MEDLINE]

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