Functional linkage between mitochondrial electron transport, glycolysis, and AMP-activated protein kinase signaling underlying cancer cell survival

Mitochondrial metabolism has emerged as a potential target for cancer therapy because of its essential role in cell proliferation and survival beyond ATP production. However, translation into clinical practice is challenging owing to several limitations, including the difficulty in distinguishing cancerous mitochondria from noncancerous mitochondria. The heterogeneity of cancerous mitochondria further complicates this effort. Herein, we focused on cancerous mitochondria exhibiting low DNA/RNA levels and respiratory function compared with those exhibited by normal cells and determined the effect of low mitochondrial respiratory activity on cancer cells. Interestingly, mitochondria low-type (mt-Low) cancer cells derived from hepatocellular carcinoma were selectively and highly 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-Normal), although ATP levels were sustained in both types of cells under these conditions. In mt-Normal cells, glycolysis increased and AMP-activated protein kinase was activated upon ETC inhibition, which critically contributed toward cell survival. However, mt-Low cells could not induce these responses, which resulted in cell death. Based on these results, therapeutics targeting respiratory function have emerged as promising precision medicines for mt-Low cancers. Similar to conventional ETC inhibitors, small interfering RNAs targeting core subunits of respiratory complex I or III were effective in inhibiting cell proliferation (complex I and III) and survival (complex I) of mt-Low cancer cells, encouraging pionerring anticancer approaches using the next-generation modality.