Figure 3.

Scheme of oxidative phosphorylation and its link to de novo pyrimidine synthesis and tumor formation. In cells with functional mitochondria, electrons are fed into the ETC by CI and CII, and by DHODH, which catalyzes conversion of dihydroorotate (DHO) to orotate in the fourth reaction of de novo pyrimidine synthesis. The electrons are intercepted by the oxidized form of CoQ, which is reduced and carries the electrons to CIII and CIV. CoQ is re-oxidized to accept more electrons from the entry points. This includes DHODH, which allows for de novo pyrimidine synthesis to occur, so that cells can transit the S-phase and eventually undergo cytokinesis, facilitating tumor initiation and progression. In cells devoid of mtDNA (ρ⁰ cells), respiration is completely inhibited, so that DHODH does not function, de novo pyrimidine synthesis is halted, and tumors cannot develop or progress. DHODH^KO cells with functional respiration cannot transit the S-phase of the cell cycle since DHODH is inhibited. Restoration of the function of CIII and CIV, for example, by transfecting ρ⁰ cells with alternative oxidase (AOX), results in redox-cycling of CoQ, which restores the DHODH activity so that tumors can form and progress. Modified from Bajzikova et al. (2019). OMM, outer mitochondrial membrane; IMS inter-membrane space; IMM, inner mitochondrial space; UMP, uridine monophosphate.