Certain cancer cells within solid tumors experience hypoxia, rendering them incapable
of oxidative phosphorylation (OXPHOS). Despite this oxygen deficiency, these cells
exhibit biochemical pathway activity that relies on NAD+. This mini-review scrutinizes
the persistent, residual Complex I activity that oxidizes NADH in the absence of oxygen
as the electron acceptor. The resulting NAD+ assumes a pivotal role in fueling the
α-ketoglutarate dehydrogenase complex, a critical component in the oxidative decarboxylation
branch of glutaminolysis — a hallmark oncometabolic pathway. The proposition is that
through glutamine catabolism, high-energy phosphate intermediates are produced via
substrate-level phosphorylation in the mitochondrial matrix substantiated by succinyl-CoA
ligase, partially compensating for an OXPHOS deficiency. These insights provide a
rationale for exploring Complex I inhibitors in cancer treatment, even when OXPHOS
functionality is already compromised.
