The evolving metabolic landscape of a cell. Schematic representation of the evolutionary process of a cancer cell driven by metabolic cues. The high bioenergetic flexibility of mitochondria allows cells to adapt to ever-changing environments, acquiring different metabolic configurations within the metabolic landscape. This metabolic flexibility is achieved by mutations of mtDNA and further shaped by the degree of heteroplasmy of the mutations itself. According to pre-existing metabolic adaptations (mitochondrial phenotypes) and to nutrient availability, there might be a selective pressure on the acquisition of genetic mutations that can sustain a certain metabolic configuration (gray dashed lines). The nDNA mutation is then passed to the progeny. The fixation of a specific metabolic configuration (e.g. aerobic glycolysis) could then lead to tumorigenic transformation (orange dashed lines) by yet unidentified mechanisms. This scenario could be used to trace the metabolic evolution of cancer based on an evolving metabolic landscape.