Mitochondrial fragmentation causes cellular acidification in the nematode C. elegans

Abstract

Mitochondrial structural dynamics (MSD) occur through the opposing processes of membrane fission and fusion. Diseases such as autosomal dominant optic atrophy and Charcot‐Marie‐Tooth syndrome Type 2A result from haploinsufficiency at genetic loci whose gene products regulate MSD and null mutations in these genes are lethal in mice. However, the nematode C. elegans tolerates a complete loss of fission and fusion proteins, and the physiologic consequences of MSD loss‐of‐function (lf) can be studied in a whole animal genetic model. Dynamic fluorescent imaging of genetically‐encoded biosensors in live transgenic worms indicates that mitochondrial fragmentation caused by mutation of the profusion gene eat‐3 (Opa1 in man) induces cellular acidification in multiple tissues. Epistasis analysis further suggests that fragmentation itself rather than an unrelated protein function is causative. The results of dichloroacetate supplementation experiments demonstrate that it is unlikely that the acidosis is caused by lactate accumulation, while AMP/ATP ratios suggest that basal energy balance is conserved in MSD mutants. However, using a redox‐sensitive fluorescent probe we have found that the mitochondrial matrix in eat‐3lf mutants is significantly oxidized compared to that of wildtype worms. We are currently exploring the hypothesis that reactive oxygen species play a role in the acidification. Support: USPHS F31GM084506 (DWJ).