From mitochondrial cristae pathobiology to metabolic reprogramming in cancer: the α and ω of Malignancies?

Abstract Mitochondrial cristae pathobiology, involving partial or total cristolysis, is a hallmark of human and mammalian cancer. This feature represents the basis of metabolic dysfunction in neoplastic cells. Consequently, most cancer cells with mitochondrial cristae defects would be incapable of producing adequate amounts of energy through oxidative phosphorylation. ATP production through increased glucose-driven cytosolic and glutamine-driven mitochondrial substrate-level phosphorylation thus becomes necessary to compensate for OxPhos insufficiency. The aim of this article is to offer a brief perspective on the link between the mitochondrial cristae pathobiology and the metabolic reprogramming in cancer cells, whose origin is linked to chronic mitochondrial cristae lesion (named α) and its eventual resolution by means of a progressive and continuous process of tumor cell death (named ω), induced by metabolic targeting. Dietary and pharmacological metabolic therapies that restrict the utilization of glucose and glutamine in tumor cells while elevating circulating ketone bodies represent a non-toxic therapeutic strategy for cancer management. Metabolic therapy can induce a persistent state of energy stress with a consequent increase in tumor cell death and reduction of tumor mass while improving the energy efficiency of non-neoplastic cells. Recent clinical studies suggest that ketogenic metabolic therapies may be therapeutically useful and well-tolerated in the long term.