Unraveling the Peculiar Features of Mitochondrial Metabolism and Dynamics in Prostate Cancer.

Prostate cancer (PCa) is the second leading cause of cancer deaths among men in Western countries. Mitochondria, the "powerhouse" of cells, undergo distinctive metabolic and structural dynamics in different types of cancer. PCa cells experience peculiar metabolic changes during their progression from normal epithelial cells to early-stage and, progressively, to late-stage cancer cells. Specifically, healthy cells display a truncated tricarboxylic acid (TCA) cycle and inefficient oxidative phosphorylation (OXPHOS) due to the high accumulation of zinc that impairs the activity of m-aconitase, the enzyme of the TCA cycle responsible for the oxidation of citrate. During the early phase of cancer development, intracellular zinc levels decrease leading to the reactivation of m-aconitase, TCA cycle and OXPHOS. PCa cells change their metabolic features again when progressing to the late stage of cancer. In particular, the Warburg effect was consistently shown to be the main metabolic feature of late-stage PCa cells. However, accumulating evidence sustains that both the TCA cycle and the OXPHOS pathway are still present and active in these cells. The androgen receptor axis as well as mutations in mitochondrial genes involved in metabolic rewiring were shown to play a key role in PCa cell metabolic reprogramming. Mitochondrial structural dynamics, such as biogenesis, fusion/fission and mitophagy, were also observed in PCa cells. In this review, we focus on the mitochondrial metabolic and structural dynamics occurring in PCa during tumor development and progression; their role as effective molecular targets for novel therapeutic strategies in PCa patients is also discussed.