Fernandez-Cardenas, Laura P. et al. (2013) International Worm Meeting "The C. elegans ATPase inhibitors MAI-1 and MAI-2 are localized in different cellular compartments."

Agredano-Moreno, L.T., Fernandez-Cardenas, Laura P., Tuena de Gomez Puyou, M., Jimenez-Garcia, L.F., Navarro, R.E., Salinas-Velazquez, L.S.

[International Worm Meeting, 2013]

In mammals, the ATPase inhibitor protein (IF1) regulates the hydrolysis activity of mitochondrial FoF1 ATPase to avoid ATP depletion. Besides mitochondria, this protein can also be found in endothelial and hepatic cell surface where its function is not well understood. In C. elegans there are two homologs for the mitochondrial IF1, MAI-1 and MAI-2. These have been studied in yeast where they both inhibit the FoF1-ATPase. MAI-1 is localized in cytoplasm while MAI-2 in mitochondria. We are studying mai-1 and mai-2 expression and function in C. elegans. To study their expression, we generated transgenic animals, that carry the constructs mai-2::gfp or mCherry::mai-1, by bombardment. We found that mai-2::gfp is expressed in all tissues during all embryonic and larval stages; where it appears to be associated to the mitochondrial network. This expression pattern correlates with its IF1 identity. Unexpectedly, mCherry::mai-1 expression is not associated to the mitochondrial network and instead appears to be diffused in the cytoplasm. While mai-2::gfp is expressed ubiquiously, mCherry::mai-1 was only observed in some cells of the nervous system, hypodermis and intestine during late embryonic, all larval stages and adult animals. mai-1(RNAi) and mai-2(RNAi) animals had normal growth, development and fertility, however have increased physiological apoptosis.

Sudevan, Surabhi et al. (2019) International Worm Meeting "Ca2+ overload due to mitochondrial dysfunction causes muscle ECM degradation."

Cooke, Michael, Kubota, Yukihiko, Etheridge, Timothy, Szewczyk, Nathaniel, Higashitani, Atsushi, Sudevan, Surabhi, Takiura, Mai, Higashitani, Nahoko, Ellwood, Rebecca

[International Worm Meeting, 2019]

Mitochondrial dysfunction impairs muscle health and causes subsequent muscle wasting. This study explores the role of mitochondrial dysfunction as an intramuscular signal for the extracellular matrix (ECM)-based proteolysis and consequentially, muscle cell dystrophy. We found that inhibition of mitochondrial electron transport chain causes paralysis as well as muscle structural damage in the nematode Caenorhabditis elegans. This was associated with a significant decline in collagen content. Both paralysis and muscle damage could be rescued with collagen IV overexpression, and calcium-dependent matrix metalloproteinase (MMP) and Furin inhibitors in Antimycin A treated animal as well as in the C. elegans Duchenne Muscular Dystrophy model. Additionally, muscle cytosolic calcium increased in the Antimycin A treated worms and its downregulation rescued the muscle damage. In our previous publication, we could see that heat stress leads to cytoplasmic calcium overload and mitochondrial fragmentation, and finally induced similar muscle structural damage (Momma K. et al 2017). These results suggest that calcium overload acts as one of the early triggers and activates Furin and MMPs for collagen degradation. In conclusion, we have established ECM degradation as an important pathway of muscle damage, and would like to propose MMP and Furin inhibitors as promising candidates for drugs against muscle wasting conditions characterized by mitochondrial dysfunction, including DMD but also heatstroke, ageing and disuse/ bedrest. Surabhi S. et al., Mitochondrial dysfunction causes Ca2+ overload and ECM degradation-mediated muscle damage in C. elegans. FASEB J 2019 in press. Monnma K. et al., Heat-Induced Calcium Leakage Causes Mitochondrial Damage in Caenorhabditis elegans Body-Wall Muscles. Genetics 2017, 206: 1985-1994.