Abstract
Mitochondrial dynamics plays an important role in mitochondrial quality control and the adaptation of metabolic activity in response to environmental changes. The disruption of mitochondrial dynamics has detrimental consequences for mitochondrial and cellular homeostasis and leads to the activation of the mitochondrial unfolded protein response (UPRmt), a quality control mechanism that adjusts cellular metabolism and restores homeostasis. To identify genes involved in the induction of UPRmt in response to a block in mitochondrial fusion, we performed a genome-wide RNAi screen in Caenorhabditis elegans mutants lacking the gene fzo-1, which encodes the ortholog of mammalian Mitofusin, and identified 299 suppressors and 86 enhancers. Approximately 90% of these 385 genes are conserved in humans, and one-third of the conserved genes have been implicated in human disease. Furthermore, many have roles in developmental processes, which suggests that mitochondrial function and their response to stress are defined during development and maintained throughout life. Our dataset primarily contains mitochondrial enhancers and non-mitochondrial suppressors of UPRmt, indicating that the maintenance of mitochondrial homeostasis has evolved as a critical cellular function, which, when disrupted, can be compensated for by many different cellular processes. Analysis of the subsets “non-mitochondrial enhancers” and “mitochondrial suppressors” suggests that organellar contact sites, especially between the ER and mitochondria, are of importance for mitochondrial homeostasis. In addition, we identified several genes involved in IP3 signaling that modulate UPRmt in fzo-1 mutants and found a potential link between pre-mRNA splicing and UPRmt activation.
Highlights
Mitochondria are important for cellular adenosine triphosphate (ATP) production, iron-sulfurcluster biogenesis, lipid metabolism and apoptosis, and mitochondrial homeostasis is tightly regulated by several quality control mechanisms (Tatsuta and Langer, 2008; Kornmann, 2014)
Dynamics of mitochondrial membranes is controlled by large guanosine triphosphate-binding proteins (GTPases) of the dynamin-like family, which are conserved from yeast to humans (Hales and Fuller, 1997; Otsuga et al, 1998; Smirnova et al, 1998; Bleazard et al, 1999; Labrousse et al, 1999; Shepard and Yaffe, 1999; Chen et al, 2003; Santel et al, 2003; Ichishita et al, 2008; Kanazawa et al, 2008)
All except three genes induce Phsp-6 mtHSP70gfp expression when knocked-down in wild-type animals, suggesting that the induction of UPRmt by depletion of these candidates is independent of the loss of fzo-1. (Candidates that encode mitochondrial proteins and that induce UPRmt in a wild-type background upon knock-down were included in a recent publication, which reported the systematic identification of mitochondrial inducers of UPRmt (Rolland et al, 2019))
Summary
© The Author(s) (2021) . Published by Oxford University Press on behalf of the Genetics Society of America. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
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