Proline and dihydroorotate dehydrogenase promote a hyper-proliferative state and dampen ferroptosis in cancer cells by rewiring mitochondrial redox metabolism.

Redox realignment is integral to the initiation, progression, and metastasis of cancer. This requires considerable metabolic rewiring to induce aberrant shifts in redox homeostasis that favor high hydrogen peroxide (HO) generation for the induction of a hyper-proliferative state. The ability of tumor cells to thrive under the oxidative burden imposed by this high HO is achieved by increasing antioxidant defenses. This shift in the redox stress signaling threshold (RST) also dampens ferroptosis, an iron (Fe)-dependent form of cell death activated by oxidative distress and lipid peroxidation reactions. Mitochondria are central to the malignant transformation of normal cells to cancerous ones since these organelles supply building blocks for anabolism, govern ferroptosis, and serve as the major source of cell HO. This review summarizes advances in understanding the rewiring of redox reactions in mitochondria to promote carcinogenesis, focusing on how cancer cells hijack the electron transport chain (ETC) to promote proliferation and evasion of ferroptosis. I then apply emerging concepts in redox homeodynamics to discuss how the rewiring of the Krebs cycle and ETC promotes shifts in the RST to favor high rates of HO generation for cell signaling. This discussion then focuses on proline dehydrogenase (PRODH) and dihydroorotate dehydrogenase (DHODH), two enzymes over expressed in cancers, and how their link to one another through the coenzyme Q (CoQ) pool generates a redox connection that forms a HO signaling platform and pyrimidine synthesome that favors a hyper-proliferative state and disables ferroptosis.

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