Autophagy compensates for defects in mitochondrial dynamics

Autoři: Simon Haeussler aff001;  Fabian Köhler aff001;  Michael Witting aff002;  Madeleine F. Premm aff001;  Stéphane G. Rolland aff001;  Christian Fischer aff001;  Laetitia Chauve aff005;  Olivia Casanueva aff005;  Barbara Conradt aff001
Působiště autorů: Faculty of Biology, Ludwig-Maximilians-University Munich, Munich, Germany aff001;  Research Unit Analytical BioGeoChemistry, Helmholtz Zentrum München, Neuherberg, Germany aff002;  Chair of Analytical Food Chemistry, Technische Universität München, Freising, Germany aff003;  Center for Integrated Protein Science, Ludwig-Maximilians-University Munich, Planegg-Martinsried, Germany aff004;  Epigenetics Programme, The Babraham Institute, Cambridge, United Kingdom aff005;  Department of Cell and Developmental Biology, Division of Biosciences, University College London, London, United Kingdom aff006
Vyšlo v časopise: Autophagy compensates for defects in mitochondrial dynamics. PLoS Genet 16(3): e32767. doi:10.1371/journal.pgen.1008638
Kategorie: Research Article
doi: 10.1371/journal.pgen.1008638


Compromising mitochondrial fusion or fission disrupts cellular homeostasis; however, the underlying mechanism(s) are not fully understood. The loss of C. elegans fzo-1MFN 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-1MFN(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-1MFN(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-7AFG3L2, 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.

Klíčová slova:

Autophagic cell death – Fluorescence imaging – Larvae – Lipids – Membrane potential – Mitochondria – Mitochondrial membrane – RNA interference


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