Stimulation of rat liver mitochondrial fusion by an outer membrane-derived aluminum fluoride-sensitive protein fraction

In normal livers, hepatocytes contain a large number of spheroidal mitochondria. Mitochondrial morphology changes drastically in liver disease, hut the underlying fusion-fission mechanisms are not known. We detected GTP-and aluminum fluoride-dependent membrane fusion events between rat liver mitochondria, Separation of outer mitochondrial membrane-derived proteins led to a subfraction containing a 60-kDa protein bared that is detected by specific antibodies directed to common amino acid sequences of the GTP-binding site or carboxyl-terminus of eukaryotic heterotrimeric G-protein alpha subunits. Addition of this subfraction and aluminum fluoride to permeabilized rat hepatocytes triggered a substantial morphological change in hepatic mitochondria, giving them the three-dimensional appearance of a tubulovesicular network, Comparative stereology using electron and confocal microscopy showed that these morphological changes represent true mitochondrial fusion, Addition of aluminum fluoride alone induces a more limited change in mitochondrial morphology, from spheroidal organelles to short rods, Mitochondria maintained their normal membrane potential and overall membrane ultrastructure after all these morphological changes. Our results reveal that mammalian liver mitochondria contain proteins that stimulate mitochondrial fusion and suggest that members of the GTPase superfamily control the normalcy of mitochondrial morphology, which is closely linked to physiological cellular energetics. (C) 1998 Academic Press.