Selective mitochondrial fusion by heterotypic action between OPA1 and cardiolipin

Identification: Ishihara, Naotada


Selective mitochondrial fusion by heterotypic action between OPA1 and cardiolipin
Tadato Ban1, and Naotada Ishihara1
1Institute of Life Science, Kurume University, Kurume, Japan
Optic atrophy 1 (OPA1) is an essential GTPase protein for both mitochondrial inner membrane 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 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 cardiolipin (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. 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. Now we are further analyzing detailed molecular mechanism of membrane tethering and fusion mediated by mitochondrial GTPase proteins.
T. Ban, T. Ishihara, H. Kohno, S. Saita, A. Ichimura, K. Maenaka, T. Oka, K. Mihara, and N. Ishihara.  Molecular basis of selective mitochondrial fusion by heterotypic action between OPA1 and cardiolipin. Nature Cell Biol. 19: 856-863 (2017)
N. Ishihara, Y. Fujita, T. Oka, and K. Mihara.  Regulation of mitochondrial morphology through proteolytic cleavage of OPA1. EMBO J. 25: 2966-2977 (2006)


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