Mitophagy contributes to alpha-tocopheryl succinate toxicity in GSNOR-deficient hepatocellular carcinoma.

The denitrosylating enzyme S-nitrosoglutathione reductase (GSNOR), has been reported to control the selective degradation of mitochondria through mitophagy, by modulating the extent of nitric oxide-modified proteins (S-nitrosylation). The accumulation of S-nitrosylated proteins due to GSNOR downregulation is a feature of hepatocellular carcinoma, causing mitochondrial defects that sensitize these tumors to mitochondrial toxins, in particular to mitochondrial complex II inhibitor alpha-tocopheryl succinate (TOS). However, it is not known if mitophagy defects contribute to GSNOR-deficient cancer cells sensitivity to TOS, nor if mitophagy inhibition could be used as a common mechanism to sensitize liver cancers to this toxin. Here, we provide evidence that GSNOR-deficient cancer cells show defective mitophagy. Furthermore, we show that TOS is a mitophagy inducer and that mitophagy defects of GSNOR-deficient liver cancer cells contribute to its toxicity. We finally prove that the inhibition of mitophagy by depletion of Parkin, a pivotal ubiquitin ligase targeting mitochondria for degradation, enhances TOS toxicity, thus suggesting that this drug could be effective in treating mitophagy-defective tumors.