Functional analyses of the mouse mitochondrial GTPase, mOPAI. -identification of binding proteins and subcellular localization -

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It has been reported that mutations of one of the dynamin family GTPases OPA1 cause autosomal dominant optic atrophy, the most frequent form of hereditary optic neuropathies. Although the involvement of OPA1 abnormality in neurodegenerative disease is apparent, little is known about the cell biological and biochemical functions of OPA1. To approach the pathophysiological mechanism of autosomal dominant optic atrophy, we have analyzed the effects of overexpressed mouse OPA1 (mOPAI) on mitochondrial morphology in transfected COS-7 cells. By the overexpression of wild type mOPA1, mitochondria of transfected cells changed their shapes to a fragmented pattern. Accordingly, the intermembrane space was distributed unevenly in the fragmented and small ring shaped mitochondria, being concentrated at one end. We observed by immunoelectron microscopy of transfected cells that the membrane structures of mitochondria changed dramatically; the inner membranes were concentrated at one end. When transfected with mOPA1 mutants with loss of function mutation in the GTP-binding domain, fragmentation of mitochondria still occurred, but the impartial distribution of intermembrane space were observed no more. These results show that GTP-dependent reaction is involved in the dramatic change of the inner membrane. We also observed that the effect of some of missense mutations with autosomal dominant optic atrophy resembled to that of the negative mutation in G1 motif.