Mitochondria: From Bacteria to Cancer, the Dedifferentiation Hypothesis of Mitochondria to Immortal Multipotent Cancer Stem Cells

Background: Carcinogenesis has traditionally been attributed to the accumulation of somatic mutations in nuclear genes regulating cell proliferation, survival, and apoptosis. Although hereditary genetic predispositions account for less than 10% of cases, the extensive heterogeneity of the somatic mechanisms driving tumorigenesis—including subsets of neoplasms lacking canonical nuclear mutations—suggests that non-mutational mechanisms and organelle dynamics significantly influence tumor onset. Emerging evidence increasingly supports the concept that mitochondrial dysfunction and metabolic reprogramming are essential factors in tumor development, rather than merely downstream consequences of nuclear genetic alterations. While current literature establishes mitochondrial alterations as crucial co-initiators and facilitators of early transformation, defining whether metabolic failures may eventually act as primary trigger remains an ongoing area of investigation. Within this perspective, the “Endosymbiotic/Evolutionary Theory” provides a useful heuristic model, since it conceptualizes metabolic rewiring not as a literal genetic reversal, but as an adaptive shift toward ancestral, highly glycolytic survival programs when oxidative microenvironments are compromised. Methods: We conducted a comprehensive theoretical and comparative analysis of mitochondrial biology, interrogating the structural, functional, and evolutionary parallels between mitochondria, intracellular bacteria, and viruses within the conceptual context of the endosymbiotic theory. Particular attention was given to mitochondrial proteins associated with organellogenesis, bioenergetic control, and molecular mechanisms facilitating mitochondrial–nuclear communication, including the integration of mitochondrial DNA (mtDNA) into nuclear DNA (nDNA) as nuclear mitochondrial DNA segments (NUMTs). Results: Under sustained bioenergetic stress, mitochondrial retrograde signaling can achieve regulatory dominance over the nucleus, driving a functional dissociation between organellar metabolic state and nuclear control. While not autonomous in a strict sense, this shift echoes the evolutionary legacy described by the endosymbiotic theory, whereby mitochondria act as semi-independent bioenergetic systems capable of imposing profound effects on nuclear gene expression and cellular fate. The resulting state is characterized by metabolic reconfiguration, loss of differentiation fidelity, and the acquisition of cancer stem cell–like properties. This process may unfold through a sequence of interrelated events: (1) persistent endogenous or exogenous stressors that challenge cellular homeostasis; (2) establishment of a chronic inflammatory state and sustained redox imbalance; (3) progressive disruption of the cellular microenvironment and inter-organelle communication; (4) emergence of a permissive pre-neoplastic niche characterized by impaired oxidative phosphorylation (OXPHOS), altered mitochondrial dynamics, and sustained retrograde signaling; (5) activation of adaptive survival pathways and escape from canonical cell death and checkpoint controls; and (6) progression toward a dedifferentiated, stem-like cellular phenotype associated with metabolic plasticity and increased resilience. Conclusions: We recommend that cancer be reframed as a dedifferentiated cellular state primarily driven by mitochondria-derived signaling, reflecting the organelle’s ancestral autonomy and the reactivation of evolutionarily conserved mechanisms involving transposons, retrotransposons, Long Interspersed Nuclear Element-1 (L1), transposable elements (TEs), reactive oxygen species (ROS), and mtDNA–nDNA crosstalk, including the generation of nuclear mitochondrial DNA segments (NUMTs). This perspective extends the canonical view of predominantly nuclear-driven oncogenesis by reframing carcinogenesis as a bioenergetic and bio-evolutionary process, thereby highlighting mtDNA–nDNA interactions and mitochondrial signaling as central targets for cancer prevention, diagnosis, and therapy.