Exploring mitochondrial central dogma in cancer from a metabolic perspective

Abstract Mitochondria are metabolic hubs that house their own genomes (mitochondrial DNA [mtDNA]), which encode components of the oxidative phosphorylation (OXPHOS) machinery. The mitochondrial central dogma not only governs compartmentalised metabolism but also intensively intertwines with multiple biological processes, and its dysregulation is a hallmark of cancer and metabolic diseases. In this review, we highlight recent advances in mitochondrial biogenesis from a metabolic perspective, with a particular emphasis on cancer. Metabolites act as donors for diverse chemical modifications, which have been systematically identified on mtDNA, rRNA, and tRNA. Besides, post-translational modifications of proteins involved in mtDNA replication, transcription, and translation has been revealed to connect metabolic signals with mitochondrial biogenesis. A comprehensive landscape of the mitochondrial central dogma has deepened our understanding of how mitochondria coordinate OXPHOS with other organelle-specific processes to obtain a flexible metabolic network, which potentiates tumor growth. Notably, non-canonical products and biological functions of the mitochondrial central dogma further reshape our concepts of cancer initiation and progression. Given that dysregulated mitochondrial biogenesis is found in multiple human disorders, including cancer, targeting this pathway offers new therapeutic opportunities. Genome-wide studies and drug screens have identified metabolic nodes and small molecules with potential to correct mitochondrial dysfunction in cancer, while emerging tools such as mtDNA editing enable precise intervention. Despite a maturing picture of mitochondrial biogenesis, many hidden players and functions remain to be uncovered to fully decipher mitochondrial biology in cancer.