Mitochondrial gateways to cancer

Mitochondria are required for cellular survival, yet can also orchestrate cell death. The peculiar biochemical properties of these organelles, which are intimately linked to their compartmentalized ultrastructure, provide an optimal microenvironment for multiple biosynthetic and bioenergetic pathways. Most intracellular ATP is generated by mitochondrial respiration, which also represents the most relevant source of intracellular reactive oxygen species. Mitochondria participate in a plethora of anabolic pathways, including cholesterol, cardiolipin, heme and nucleotide biosynthesis. Moreover, mitochondria integrate numerous pro-survival and pro-death signals, thereby exerting a decisive control over several biochemical cascades leading to cell death, in particular the intrinsic pathway of apoptosis. Therefore, it is not surprising that cancer cells often manifest the deregulation of one or several mitochondrial functions. The six classical hallmarks of cancer (i.e., limitless replication, self-provision of proliferative stimuli, insensitivity to antiproliferative signals, disabled apoptosis, sustained angiogenesis, invasiveness/metastatic potential), as well as other common features of tumors (i.e., avoidance of the immune response, enhanced anabolic metabolism, disabled autophagy) may directly or indirectly implicate deregulated mitochondria. In this review, we discuss several mechanisms by which mitochondria can contribute to malignant transformation and tumor progression.