Autophagy compensates for defects in mitochondrial dynamics

English version

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: https://doi.org/10.1371/journal.pgen.1008638

Souhrn

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^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.

Klíčová slova:

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

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