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

Simple Summary Mitochondria are organelles involved in different biological processes, including tumorigenesis. Accumulating evidence strongly supports that, despite the presence of an active glycolytic pathway (the Warburg effect), cancer cells undergo a mitochondrial metabolic rewiring towards the OXPHOS pathway, leading to the production of high levels of ATP to sustain their uncontrolled proliferation and aggressive behavior. Alterations of the mitochondrial structural dynamics (biogenesis, fusion, fission, mitophagy) are also involved in cancer growth and progression. The mechanisms underlying this mitochondrial plasticity, now considered as a hallmark of cancer, were shown to occur with specific features in different cancer cell types and contexts. In this review, we provide an incisive description of the peculiar metabolic rewiring and structural dynamics occurring in prostate cancer cells during the different phases of their transformation from healthy cells to early- and late-stage cancer cells. We also address the role of these mitochondrial dynamics as effective targets of therapeutic approaches. 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.