Carcinogenesis is the progressive transformation of a normal cell into a neoplastic cell. This multistep process, underlying tumor initiation, promotion, and progression, involves diverse and complex mechanisms that remain incompletely understood: oncogenic mutations, genomic instability, epigenetic alterations, and metabolic reprogramming. The latter is among the fundamental hallmarks of cancer, as defined by Hanahan and Weinberg in 2011, and concerns not only glucose and glutamine metabolism but also that of amino acids, lipids, and nucleic acids. By reconfiguring their metabolism, cancer cells manage to survive despite genetic alterations, low nutrient availability, and a hypoxic environment. This literature review highlights the central role of mitochondria across all of these stages.
For a long time, the Warburg hypothesis, formulated nearly a century ago, suggested that cancer cells favored aerobic glycolysis at the expense of mitochondrial respiration owing to irreversible mitochondrial damage. Subsequent work, on the contrary, established that these organelles remain functional in most tumor cells and actively contribute to their metabolic plasticity. Beyond their bioenergetic role, mitochondria constitute an integrative hub controlling ATP production, amino acid synthesis, redox homeostasis, the production of reactive oxygen species (ROS), calcium signaling, and apoptotic pathways. The authors detail how they promote tumor initiation, notably through mitochondrial DNA mutations and the production of oncometabolites, and then how they support progression by controlling metabolic reprogramming and mitochondrial dynamics.
The review also emphasizes the non-cell-autonomous dimension of the mitochondrial contribution. Tumors display metabolic heterogeneity, with some cells adopting a glycolytic phenotype while others remain in a more oxidative state depending on oxygen and nutrient availability. A metabolic dialogue is thus established with the microenvironment: the concept of the "reverse Warburg effect" accounts for a mutual metabolic dependence between cancer cells and stromal cells, which can extend to the intercellular transfer of metabolites, and even of mitochondria.
Finally, mitochondrial metabolism is presented as a promising therapeutic target. Several strategies are reviewed: inhibition of mitochondrial translation (tigecycline), inhibition of the respiratory chain and complex I (metformin, ME-344, IACS010759), targeting of the Krebs cycle (CPI-613, or the IDH inhibitors enasidenib and ivosidenib approved in certain acute myeloid leukemias), glutaminase inhibition, as well as modulation of redox homeostasis through ROS-generating compounds and "mitocans" that selectively target tumor mitochondria. Several of these molecules are currently undergoing clinical trials. The mechanisms regulating the mitochondrial metabolic plasticity of tumors therefore constitute an active field of research for the development of new anticancer approaches.