ATG12 Deficiency Leads to Tumor Cell Oncosis Owing to Diminished Mitochondrial Biogenesis and Reduced Cellular Bioenergetics

Liu et al. find a non-canonical role for an autophagy-related protein, ATG12, in regulating mitochondrial biogenesis and cellular bioenergetics. Cells deficient in ATG12 show distinct global metabolic features, decreasing β-oxidation (FAO), glycolysis, Krebs cycle (TCA cycle) activity, mitochondrial respiration and mitochondrial biogenesis as compared to control cells, leading in consequence to an insufficient energy supply and finally oncotic cell death, which does not occur in ATG12-deficient fibroblasts. ATG12, that we could detect partly at a mitochondrial localization, was upregulated in diverse types of solid tumors compared to the normal tissues in a multi-organ tissue microarray (TMA), thus suggesting a potential role for ATG12 in regulating cancer cell metabolism. Inducing oncosis by imposing an ATG12 deficiency in solid tumors might represent an anti-cancer therapy preferable to conventional caspase-dependent apoptosis that often shows undesirable consequences, such as incomplete cancer cell killing and silencing of the host immune system.