Ingvi Karl Jónsson, Margrét Helga Ögmundsdóttir and Ottar Rolfsson
Autophagy is a vital recycling process, clearing cells of old and damaged contents and contributing to homeostasis. ATG7, in addition to its vital role in autophagy, plays a role in tumorigenesis and metabolic disease. A short isoform of ATG7 (ATG7(2)) does not have an autophagic function and its expression is increased in tumors. ATG7(2) interacts with metabolic proteins and has been shown to decrease glycolysis and mitochondrial activity.
To study the metabolic effects further, the full-length ATG7(1) isoform, the short ATG7(2) isoform and empty vector (EV), were overexpressed in mouse embryonic fibroblasts with Atg7 knockout (MEF) and in a human hepatocellular carcinoma cell line, HuH7. The MEF cells are widely used in autophagy and ATG7 research, providing a comparable background to previous literature. The HuH7 cells were chosen due to the importance of ATG7 and autophagy in the liver. Metabolomic profiling was performed in both cell lines in addition to a metabolic flux analysis in the MEF.
Both ATG7 isoforms alter central carbon metabolite profiles: ATG7(1) alters amino acid and energy metabolite levels whereas ATG7(2) increases global central carbon metabolite levels. Both isoforms cause accumulations of oncometabolites – metabolites with tumorigenic effects. Flux analysis confirmed previous findings, suggesting ATG7(2) decreases glycolysis. A novel discovery of ATG7(2) was discovered as well: reduced nucleotide and glutathione synthesis.
ATG7(2) is increased in tumors, possibly conveying tumorigenic effects via metabolic alterations. ATG7(2) may play a role in metabolic reprogramming, potentially increasing cancer cell survival.
