Therapeutic potential of targeting mitochondrial dynamics in cancer

Abstract

In the past mitochondria were considered as the "powerhouse" of cell, since they generate more than 90% of ATP in aerobic conditions through the oxidative phosphorylation. However, based on the current knowledge, mitochondria play several other cellular functions, including participation in calcium homeostasis, generation of free radicals and oxidative species, triggering/regulation of apoptosis, among others. Additionally, previous discoveries recognized mitochondria as highly dynamic structures, which undergo morphological alterations resulting in long or short fragments inside the living cells. This highly regulated process was referred as mitochondrial dynamics and involves mitochondrial fusion and fission. Thus, the number of mitochondria and the morphology of mitochondrial networks depend on the mitochondrial dynamics, biogenesis, and mitophagy. In each cell, there is a delicate balance between fusion and fission to allow the maintenance of appropriate mitochondrial functions. It has been proposed that the fusion and fission dynamics process controls cell cycle, metabolism, and survival, being implicated in a wide range of physiological and pathological conditions. Mitochondrial fusion is mediated by dynamin-like proteins, including mitofusin 1 (MFN1), mitofusin 2 (MFN2), and optic atrophy 1 protein (OPA1). Conversely, mitochondrial fission results in a large number of small fragments, which is mediated mainly by dynamin-related protein 1 (DRP1). Interestingly, there is growing evidence proposing that tumor cells modify the mitochondrial dynamics rheostat in order to gain proliferative and survival advantages. Increased mitochondrial fission has been reported in several types of human cancer cells (melanoma, ovarian, breast, lung, thyroid, glioblastoma, and others) and some studies have reported a possible direct correlation between increased mitochondrial fusion and chemoresistance of tumor cells. Here, the current knowledge about alterations of mitochondrial dynamics in cancer will be reviewed and its potential as a target for adjuvant cancer chemotherapy will be discussed.

Keywords: Bioenergetics; Cancer; Cell death; Chemotherapy; Mitochondrial dynamics.