Mitochondrial Electron Transport Chain Complex III Is Required for Antimycin A to Inhibit Autophagy

Abstract

Autophagy is a cellular lysosome-dependent catabolic mechanism mediating the turnover of intracellular organelles and long-lived proteins. Dysfunction of autophagy has been implicated in multiple human diseases. Identification of novel autophagy factors in mammalian cells is important for understanding how this complex cellular pathway responds to a broad range of challenges. Here we report that mitochondrial electron transport chain (mETC) complex III plays a role in autophagy induction. We show that antimycin A, a known inhibitor of mETC complex III, can inhibit autophagy. A structural and functional study shows that four close analogs of antimycin A that have no effect on mitochondria inhibition also do not inhibit autophagy; while myxothiazol, another mETC complex III inhibitor with unrelated structure to antimycin A, inhibits autophagy. Additionally, antimycin A and myxothiazol cannot inhibit autophagy in mtDNA-depleted H4 and mtDNA-depleted HeLa cells. These data suggest that antimycin A inhibits autophagy through its inhibitory activity on mETC complex III. Our data suggest that mETC complex III may have a role in mediating autophagy induction.

Increased levels of reduced cytochrome b and mitophagy components are required to trigger nonspecific autophagy following induced mitochondrial dysfunction

“…All these results seem to indicate that increased levels of reduced cytochrome b could be the first signal required for this induction. These results could be related to those of Ma et al who have shown the involvement of complex III in autophagy regulation (Ma et al, 2011).…”

“…of ATP and ROS (Ma et al, 2011). Surprisingly, in these cells antimycin A did not have an obvious effect on ROS production.…”

Upregulated autophagy protects cardiomyocytes from oxidative stress-induced toxicity

“…63 Furthermore, it has been proposed that the inhibition of ETC complex III can actually have an inhibitory effect on autophagy induction, although the molecular mechanisms are as of yet, unknown. 64 We also cannot rule out the possibility that the inability to induce autophagy could be cardiomyocyte specific. Nevertheless, stimulating autophagy under oxidative stress conditions could be hypothesized to potentially remove oxidized macromolecules.…”

Inhibition of BMI1 induces autophagy-mediated necroptosis

“…To confirm that ATP depletion induced autophagy, siRNA-transfected cells (48 h) were supplemented with 2 mM ATP for the last 4 h. 10 mM FCCP, an uncoupling agent which dissipates the proton gradient across the mitochondrial inner membrane was used for 4 h as a positive control as it has been reported to induce autophagy in cells. 19 In both cell lines, a significant decrease in LC3B-II and increase in SQSTM1 levels after ATP repletion suggested that exogenous ATP supplementation in si-BMI1 treated cells could reverse the autophagic flux while si-control remained unchanged (Fig. 2B).…”