Addressing the Core of Carcinogenesis: How a Mitochondrial Mutation Leads to Metabolic Remodeling in Familial Cancers

Appropriate knowledge of the metabolic properties of cancer cells compared with normal ones is a major prerequisite in order to elucidate the mechanisms responsible for abnormal cell proliferation and dysregulated biomass production. A relevant paradigm is the not-yet-fully-perfected basis of the Warburg effect and of the underlying pathways of glucose and glutamine utilization in tumor cells (1). On the other hand, peculiarities in cancer cell metabolism are the result of both germline and somatic mutations, but little is known in general on how these mutations translate into cancer-specific phenotypes, mostly to selected enzyme deficiencies or to imbalances in the regulation and the coordination of metabolic fluxes in tumor cells. This limitation reflects a still-insufficient integration of emerging data from high-throughput technologies and of the various steps of experimental analysis that characterize the “omics” field. While a general advancement in the area is legitimately expected from the development of computational tools (1), it is well documented that wet science, eg, genome-wide association studies and metabolic approaches, is strictly required. To this purpose, it is interesting to note that, for example, cancer-causing mutations associated with enzyme deficiencies are generally investigated according to the following multistep strategy: