Mitochondria and the Metabolic Logic of Oncocytic Tumours.

Oncocytic tumors, long recognized for their distinctive granular cytoplasm, have historically posed challenges to classical cancer models due to their enigmatic molecular profiles and exceptional mitochondrial burden. This review revisits the path from the early histological discovery of mitochondria to their central role in modern metabolic theories of oncogenesis. Drawing parallels between mitochondrial history and oncocytic tumor pathology, we explore how mitochondrial dysfunction, rather than nuclear genomic instability, may underlie the oncocytic phenotype. Revisiting the Somatic Mutation Theory (SMT) alongside the emerging Mitochondrial Metabolic Theory (MMT), we highlight the explanatory potential of mitochondrial bioenergetic disruption in tumorigenesis. Despite being rich in structurally abnormal mitochondria, oncocytic tumors, particularly in the thyroid, remain underrepresented in mainstream metabolic cancer models. By integrating insights from historical cytology, modern pathology, and molecular oncology, this article proposes that oncocytic neoplasms serve as morphologically overt and biochemically aligned exemplars of MMT, underlining the need for deeper cross-disciplinary dialogue. This contribution lays the conceptual groundwork for the organ-specific studies featured in this special issue, positioning oncocytic tumors as both diagnostic challenges and metabolic sentinels in cancer biology.