Metabolic links between mitochondrial electron transport, glycolysis, and AMP-activated protein kinase signaling modulate hepatocellular carcinoma cell survival.

Beyond ATP production, mitochondrial metabolism, due to its essential role in cell proliferation and survival, is a potential target for cancer therapy. However, translation into clinical practice is challenging owing to several limitations, including difficulty in distinguishing cancerous and non-cancerous mitochondria, which is further complicated by the heterogeneity of the former. Herein, we focused on cancerous mitochondria exhibiting low DNA/RNA levels and respiratory function compared with those demonstrated by normal cells, and determined the effects of low respiratory activity on the metabolic phenotypes of cancer cells. Interestingly, mitochondria low-type (mt-Low) cells derived from hepatocellular carcinomas were relatively sensitive to electron transport chain (ETC) inhibition. Specifically, cells died under the treatment with the ETC inhibitors, rotenone and antimycin A, at lower doses compared with cells exhibiting normal respiratory activity (mt-psNormal), although ATP levels were sustained in both cell types under these conditions. In mt-psNormal cells, upon ETC inhibition, glycolytic activity increased, and AMP-activated protein kinase was activated, which critically contributed to cell survival. However, these responses were not effectively induced in ETC inhibition-sensitive mt-Low cells. Similar to conventional ETC inhibitors, small interfering RNAs targeting core subunits of respiratory complexes I or III effectively inhibited proliferation (complexes I and III) or survival (complex I) of the tested mt-Low cancer cells, supporting innovative anticancer approaches that target respiratory function using next-generation technology.