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Abstract
The work presented herein illustrates the multifaceted role of mitochondria in the survival of different in vitro disease and developmental models, including melanoma cancer cells and developing sympathetic neurons, respectively. In the first study, we sought to investigate the use of mitochondria-targeted therapeutics as an approach to disrupt metabolic reprogramming in poorly targeted melanoma tumor cells with wild-type BRAF. Interestingly, disrupting mitochondrial bioenergetics with the mitochondria-targeted lipophilic cation mitoquinone (MitoQ) induces significant cytotoxic effects, surpassing other investigative and conventional therapeutics. Here, we demonstrate for the first time that divergent targeting of glycolysis and mitochondrial oxidative phosphorylation result in an additive cytotoxic effect in melanoma cells with different genetic backgrounds. Our data suggest that inhibiting glycolysis forces these cells to rely more heavily on mitochondrial oxidative phosphorylation to survive, which makes them more vulnerable to the effects of the lipophilic cation MitoQ. In addition to the role of mitochondria in regulating cellular bioenergetics, cellular redox homeostasis is another crucial function. The mitochondria-derived reactive species (RS) is a central mediator of physiological and pathological apoptotic death of neurons. Many neurons generated during the embryogenesis of the vertebrate nervous system undergo apoptotic death before birth or soon thereafter. Among them are the sympathetic neurons not obtaining sufficient amounts of the nerve growth factor (NGF). Chronic depolarization of the plasma membranes of these neurons promotes their survival in the absence of NGF by an unknown mechanism. In this study, we aimed to identify the mechanism by which chronically depolarized neurons resist apoptotic death following NGF withdrawal. Previous evidence showed that the activation of the intrinsic apoptosis pathway and the Bax-dependent increase of mitochondrial-derived RS are critical events in the death of these cells. Our novel findings demonstrate that chronically depolarized neurons prevent developing pro-oxidant status and therefore resist cell death by upregulating the critical antioxidant glutathione (GSH). These findings strengthen the ever-growing association of mitochondria-derived RS with apoptotic death in neurons. Furthermore, our study will expand our knowledge about the critical players in the development and progression of some neurodegenerative diseases in which electrical activity is profoundly disturbed.