In a genetic screen for Caenorhabditis elegans mutants with abnormal mitochondrial morphology, we identified
mma-1 (mitochondrial morphology abnormal-1), a C. elegans homolog of the French Canadian Leigh Syndrome gene LRPPRC (leucine-rich pentatricopeptide repeat containing). Inactivation of
mma-1 in C. elegans or LRPPRC in mammalian cells results in a decrease in the production of mitochondria-encoded subunits of cytochrome c oxidase (COX) and consequently a reduction in COX activity. We have previously shown that in this context, mitochondria form a hyperfused network that transiently maintains cellular ATP levels (Rolland et al, 2013). We now demonstrate that the inactivation of
mma-1 LRPPRC also leads to an imbalance between mitochondria- and nuclear-encoded COX subunits, which triggers a conserved mitochondrial unfolded protein response (UPRmt). We also show that the activation of UPRmt leads to the restoration of mitochondrial proteostasis. Finally, we present evidence that UPRmt and the mitochondrial hyperfusion response are coordinated but mediated by genetically distinct pathways. We propose that in the context of
mma-1 LRPPRC knock-down, mitochondrial hyperfusion helps to transiently maintain cellular ATP levels enabling UPRmt to restore mitochondrial proteostasis.Rolland, S.G., Motori, E., Memar, N., Hench, J., Frank, S., Winklhofer, K.F. , and Conradt, B. (2013). Impaired complex IV activity in response to loss of LRPPRC function can be compensated by mitochondrial hyperfusion. PNAS 110, E2967-2976.Barbara Conradt and Stephane Rolland are co-corresponding authors.