Mitochondria and the Metabolic Logic of Oncocytic Tumors.

Abstract

Background: Oncocytic tumors, long recognized for their distinctive granular cytoplasm and exceptional mitochondrial burden, have historically posed challenges to classical cancer models due to their enigmatic molecular profiles. The understanding of mitochondria has evolved significantly, from early histological observations of ill-defined cytoplasmic "granules" to their recognized central role in cellular bioenergetics and, more recently, in modern metabolic theories of oncogenesis. This review revisits this historical trajectory to contextualize the unique pathology of oncocytic neoplasms.

Summary: Drawing parallels between the historical understanding of mitochondria and the pathology of oncocytic tumors, this article explores how profound mitochondrial dysfunction, rather than primary nuclear genomic instability, may fundamentally underlie the oncocytic phenotype. The Somatic Mutation Theory is critically re-examined in light of the emerging Mitochondrial Metabolic Theory (MMT), highlighting MMT's potential to provide a more comprehensive explanation for tumorigenesis through bioenergetic disruption. Despite their striking and consistent mitochondrial characteristics, including structurally abnormal mitochondria with disrupted cristae and impaired respiratory complexes, oncocytic tumors, particularly those of the thyroid, remain notably underrepresented in mainstream metabolic cancer models. By integrating insights from historical cytology, modern diagnostic pathology, and molecular oncology, this article proposes that oncocytic neoplasms serve as morphologically overt and biochemically aligned exemplars of the MMT, pointing the critical need for deeper cross-disciplinary dialog in cancer research. This article serves as a foundational contribution to this special issue of Acta Cytologica, which aims to re-center mitochondria in the discussion of oncocytic lesions. By providing this essential metabolic and historical context, it sets the stage for the subsequent organ-specific studies on oncocytic neoplasms, bridging the fields of cytopathology, pathology, and molecular biology. Its inclusion in Acta Cytologica highlights the journal's dedication to multidisciplinary synthesis, offering a comprehensive understanding of oncocytic lesions from their cellular presentation to their molecular underpinnings.

Key messages: Oncocytic tumors represent a compelling model for understanding cancer through the lens of mitochondrial metabolic dysfunction, challenging the primacy of nuclear genomic mutations. Their unique morphological and functional mitochondrial abnormalities provide visible evidence of underlying bioenergetic disruption and might functionally align with the biochemical phenotype described by the MMT. Integrating historical pathological observations with contemporary molecular and metabolic research is crucial for advancing the understanding of these enigmatic tumors and cancer biology more broadly. Oncocytic tumors should be recognized not only as diagnostic challenges but also as vital "metabolic sentinels" in the ongoing quest to unravel the origins and progression of cancer.