CMT2A-linked mitochondrial hyperfusion-driving mutant MFN2 perturbs ER-mitochondrial associations and Ca homeostasis.

BACKGROUND INFORMATION

Mitofusin2 (MFN2), an important molecular player that regulates mitochondrial fusion, also helps maintain the inter-organellar contact sites, referred as mitochondria associated membranes (MAMs) that exist between the ER and mitochondria. The study deals with a mutant of MFN2, R364W-MFN2, linked with the neuropathy, Charcot Marie Tooth (CMT) disease. Previous studies show that this mutant promotes mitochondrial hyperfusion. Here, we try to decipher the role of R364W-MFN2 in affecting the ER mitochondrial associations at the MAM junctions and inter-organellar calcium signalling between the ER and the mitochondria.

RESULTS

Our results show that R364W-MFN2 altered ER-mitochondria association at the MAM junctions, predisposed mitochondria towards cellular stress with the mitochondria undergoing rapid fission upon induction of mild stress and perturbs inter-organellar calcium homeostasis.

CONCLUSION

The results indicate that R364W-MFN2 not only affects mitochondrial morphology and dynamics but also modulate its interaction with the ER and Ca signalling between the two organelles.

SIGNIFICANCE

This study provides significant insight that presence of the R364W-MFN2 mutation makes cells susceptible towards stress, thus negatively affecting cellular health which altogether might culminate in the form of the CMT neuropathy.