Autophagy compensates for defects in mitochondrial dynamics

by Simon Haeussler, Fabian Köhler, Michael Witting, Madeleine F. Premm, Stéphane G. Rolland, Christian Fischer, Laetitia Chauve, Olivia Casanueva, Barbara Conradt

Compromising mitochondrial fusion or fission disrupts cellular homeostasis; however, the underlying mechanism(s) are not fully understood. The loss of C. elegans fzo-1^MFN results in mitochondrial fragmentation, decreased mitochondrial membrane potential and the induction of the mitochondrial unfolded protein response (UPR^mt). We performed a genome-wide RNAi screen for genes that when knocked-down suppress fzo-1^MFN(lf)-induced UPR^mt. Of the 299 genes identified, 143 encode negative regulators of autophagy, many of which have previously not been implicated in this cellular quality control mechanism. We present evidence that increased autophagic flux suppresses fzo-1^MFN(lf)-induced UPR^mt by increasing mitochondrial membrane potential rather than restoring mitochondrial morphology. Furthermore, we demonstrate that increased autophagic flux also suppresses UPR^mt induction in response to a block in mitochondrial fission, but not in response to the loss of spg-7, which encodes a mitochondrial metalloprotease. Finally, we found that blocking mitochondrial fusion or fission leads to increased levels of certain types of triacylglycerols and that this is at least partially reverted by the induction of autophagy. We propose that the breakdown of these triacylglycerols through autophagy leads to elevated metabolic activity, thereby increasing mitochondrial membrane potential and restoring mitochondrial and cellular homeostasis.