Autophagy compensates for defects in mitochondrial dynamics

Abstract

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.

Mitochondrial transplantation therapy inhibit carbon tetrachloride‐induced liver injury through scavenging free radicals and protecting hepatocytes

“…The dysfunctional mitochondria caused by CCl4 would be eliminated by mitophagy, and then the healthy mitochondria would be responsible for energy supply and maintain cell function. 18,19 Mitochondria prevented cell proliferation…”

Genome-wide RNAi screen for regulators of UPRmtinCaenorhabditis elegansmutants with defects in mitochondrial fusion

“…These results raise the question whether knock-down of candidates involved in cytosolic translation specifically suppresses UPR mt or simply reduces the expression of the P hsp-6 mtHSP70 gfp reporter. We recently showed that knock-down of the cytosolic tRNA synthetase hars-1 HARS1 , which we found to suppress P hsp-6 mtHSP70 gfp expression in fzo-1(tm1133) and which presumably compromises cytosolic translation, results in reduced expression of a control reporter, P ges-1 GES2 gfp (Haeussler et al, 2020). Therefore, we cannot exclude the possibility that the knock-down of candidates related to the functional groups of transcription, RNA processing, ribosome biogenesis and translation may, at least to some extent, interfere with reporter expression per se.…”

“…The disruption of mitochondrial dynamics in C. elegans induces the mitochondrial unfolded protein response (UPR mt ) (Kim and Sieburth, 2018;Zhang et al, 2018;Rolland et al, 2019;Haeussler et al, 2020). To identify genes affecting mitochondrial homeostasis in animals with defects in mitochondrial dynamics, we used a loss-of-function mutation of fzo-1 MFN1,2 , tm1133, (National BioResource Project) to induce the UPR mt reporter P hsp-6 mtHSP70 gfp zcIs13and screened the C. elegans genome for modifiers.…”

“…Furthermore, we recently demonstrated that approximately half of the candidates in this GO-category are negative regulators of autophagy. Upon knock-down, these genes suppress fzo-1(tm1133)-induced UPR mt most probably by inducing autophagy thereby causing changes in lipid metabolism (Haeussler et al, 2020). Moreover, many cellular signaling pathways originate at the plasma membrane and, thus, are dependent on endocytosis (Sorkin and von Zastrow, 2009;Di Fiore and von Zastrow, 2014).…”

“…Furthermore, icd-1 βNAC has been described as a cytosolic stress sensor, which in the absence of stress associates with ribosomes to promote cytosolic translation, and which upon heat stress acts as a chaperone in the cytosol (Kirstein-Miles et al, 2013). We recently showed that icd-1 βNAC is also a negative regulator of autophagy and that increased autophagic flux fuels mitochondria with certain triacylglycerols, thereby suppressing UPR mt in both fzo-1(tm1133) and drp-1(tm1108) mutants (Haeussler et al, 2020). Thus, blocking mitochondrial dynamics may reduce the flux of lipids into mitochondria, which can be compensated by the induction of autophagy.…”