Mitochondrial structural dynamics occur through the opposing processes of membrane fission and fusion. Although the physiologic role(s) of changes in morphology are incompletely understood, mitochondrial synthesis, transport and perhaps function are all thought to be regulated by morphology. In fact, genetic mutations that reduce the function of protein components of the fission or fusion machinery have been associated with mammalian disease, and a complete loss of these proteins causes embryonic lethality in mice. However, loss-of-function mutations in genes coding for fission and fusion orthologs is tolerated in worms, making C. elegans one of the only models for studying the physiologic effects of mitochondrial morphology. We have found that fragmentation of the mitochondrial network through mutation of either
eat-3 or
fzo-1, required for inner and outer membrane fusion, respectively, causes cellular acidification in all of the tissues tested. These genes are epistatic to one another, and mutations in the profission gene
drp-1 alleviate acidosis in an
eat-3(
ad426) mutant with reduced function (rf). Neither the rf nor complete deletion of
drp-1 on its own has significant effects on intracellular pH, suggesting that the changes in morphology that cause acidification are specific to fragmentation. We further show that mutations in the electron transport chain cause lactic acidosis and also reduce the ATP content of the worms, but in contrast morphologic acidosis is not caused by lactate accumulation, although the ATP content is reduced in
eat-3 mutants. We are currently testing if the extent of acidification correlates with energy demand in worms. We have extended these observations to include cultured mammalian cells. Clone 9 cells were transfected with either a construct overexpressing the profission Fis1, or with dsRNA targeting Opa1, the mammalian ortholog of EAT-3. These treatments resulted in mitochondrial fragmentations and caused cellular acidification, suggesting an evolutionarily-conserved link between morphology and pH homeostasis. We have also found that quiescence induced by serum starvation causes acidification on its own, likely resulting from the loss of Na+/H+ exchange activity; however, fragmentation of the mitochondria in quiescent cells does not cause further acidification. This suggests that either fragmentation can regulate Na+/H+ exchange activity or that, as we predict occurs in worms, energy demand correlates with acidification. Finally, we present a model where fragmentation-induced acidification plays a physiologic role under high energy demand, in addition to contributing to the patho-physiology of morphology diseases.