Relationship between OPA1 and cardiolipin in mitochondrial inner-membrane fusion

Mitochondria are highly dynamic organelles that undergo frequent fusion and fission. The large GTPase optic atrophy 1 (OPAL) is identified as a core component of inner membrane (IM) fusion. OPAL exists as the membrane-anchored L-OPAL and the proteolytically cleavage soluble S-OPAL. Recently, we showed that OPAL and mitochondria-localized lipid cardiolipin (CL) cooperate in heterotypic IM fusion [Ban et al., Nat. Cell Biol. 19 (2017) 856-863]. We reconstituted an in vitro membrane fusion reaction using purified human L-OPAL and S-OPA1 expressed in silkworm and found that L-OPAL on one side of the membrane and CL on the other side were sufficient for mitochondrial fusion. L-OPAL is the major fusion-prone factor in heterotypic fusion. However, the role of S-OPAL remains unknown as S-OPAL promoted L-OPAL-dependent heterotypic membrane fusion and homotypic CL-containing membrane fusion, but S-OPA1 alone was not sufficient for heterotypic membrane fusion. L-OPAL- and CL-mediated heterotypic mitochondrial fusion was confirmed in living cells, but tafazzin (Taz1), the causal gene product of Barth syndrome, was not essential for mitochondrial fusion. Taz1-dependent CL maturation might have other roles in the remodeling of mitochondrial DNA nucleoids.