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

ABSTRACT

The downregulation of the denitrosylating enzyme S-nitrosoglutathione reductase (GSNOR, EC1.1.1.284), is a feature of hepatocellular carcinoma (HCC). This condition causes mitochondrial rearrangements that sensitize these tumors to mitochondrial toxins, in particular to the mitochondrial complex II inhibitor alpha-tocopheryl succinate (αTOS). It has also been reported the GSNOR depletion impairs the selective degradation of mitochondria through mitophagy; however, if this contributes to GSNOR-deficient HCC cell sensitivity to αTOS and can be applied to anticancer therapies, is still not known. Here, we provide evidence that GSNOR-deficient HCC cells show defective mitophagy which contributes to αTOS toxicity. Mitophagy inhibition by Parkin (EC 2.3.2.31) depletion enhances αTOS anticancer effects, thus suggesting that this drug could be effective in treating mitophagy-defective tumors.