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Haeussler, Simon; Köhler, Fabian; Witting, Michael; Premm, Madeleine F.; Rolland, Stephane G.; Fischer, Christian; Chauve, Laetitia; Casanueva, Olivia; Conradt, Barbara (2020): Autophagy compensates for defects in mitochondrial dynamics.
In: PLOS Genetics 16(3), e1008638
Creative Commons Attribution 4MB


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 (UPRmt). We performed a genome-wide RNAi screen for genes that when knocked-down suppress fzo-1(MFN)(lf)-induced UPRmt. 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 UPRmt by increasing mitochondrial membrane potential rather than restoring mitochondrial morphology. Furthermore, we demonstrate that increased autophagic flux also suppresses UPRmt induction in response to a block in mitochondrial fission, but not in response to the loss of spg-7(AFG3L2), 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. Author summary Various quality control mechanisms within the cell ensure mitochondrial homeostasis. Specifically, mitochondrial fission and fusion, the mitochondrial unfolded protein response (UPRmt) and/or mitophagy are induced upon mitochondrial stress to maintain or restore mitochondrial homeostasis. How these different quality control mechanisms are coordinated and how they influence each other is currently not well understood. Interestingly, the disruption of mitochondrial dynamics has recently been shown to induce UPRmt. We performed a genome-wide RNAi screen for suppressors of UPRmt induced by a block in mitochondrial fusion and found approximately half of the candidate genes identified to negatively regulate autophagy, a central quality control mechanism that adjusts cellular metabolism under conditions of stress. Furthermore, we found that induction of autophagy also suppresses UPRmt induced by a block in mitochondrial fission. In addition, we demonstrate that defects in mitochondrial dynamics lead to changes in lipid metabolism, which can partially be reverted by the induction of autophagy. Taken together, our results suggest a so far unknown functional connection between UPRmt and autophagy in animals with defects in mitochondrial dynamics.