p53 Regulates Mitochondrial Respiration

TLDR

Cancer cells preferentially use glycolysis, a hallmark Warburg effect that confers a survival advantage, and the COX complex regulator SCO2 is essential for oxygen utilization. We demonstrate that p53 regulates the switch between respiration and glycolysis via SCO2, and loss of SCO2 in p53‑competent cells induces a glycolytic phenotype, linking p53 to mitochondrial respiration and providing insight into the Warburg effect, aging, and metabolism.

Abstract

The energy that sustains cancer cells is derived preferentially from glycolysis. This metabolic change, the Warburg effect, was one of the first alterations in cancer cells recognized as conferring a survival advantage. Here, we show that p53, one of the most frequently mutated genes in cancers, modulates the balance between the utilization of respiratory and glycolytic pathways. We identify Synthesis of Cytochrome c Oxidase 2 (SCO2) as the downstream mediator of this effect in mice and human cancer cell lines. SCO2 is critical for regulating the cytochrome c oxidase (COX) complex, the major site of oxygen utilization in the eukaryotic cell. Disruption of the SCO2 gene in human cancer cells with wild-type p53 recapitulated the metabolic switch toward glycolysis that is exhibited by p53-deficient cells. That SCO2 couples p53 to mitochondrial respiration provides a possible explanation for the Warburg effect and offers new clues as to how p53 might affect aging and metabolism.