Annual Report of Activities CNC 2008 - Center for Neuroscience and ...

Mitochondrial Toxicology and Pharmacology | Head: Paulo OliveiraObjectivesMitochondria are the energy powerplants of cellsby producing the majority of the chemical energycell use for their processes. The majorbreakthrough happened with the discovery thatmitochondria play an important role in cell deathprocesses. Together with the fact that mitochondriaalso are active players in cytosolic calciumhomeostasis and in intermediate metabolism, it ispertinent to question if different molecules, whichcan interact with living systems, or even diseaseconditions, promote their biological effects throughmitochondrial‐mediated effects. In fact, numerousexamples of mitochondria‐mediated cell injury canbe found in the literature; not only chemicals cannegatively affect mitocondrial function but also theorigin and progression of several pathologies isclosely related with disruption of mitochondrialhomeostasis. The main and general objective of the“Mitochondrial Toxicology and PharmacologyGroup” is to provide an insight into the role ofmitochondria as a primary intracellular target inthe initiation of drug‐ and disease‐induced celldysfunction. The main particular objective is tounderstand how mitochondria are involved in thepathophysiology of several diseases, includingdiabetes and cholestasis and how mitochondrialfunction can be altered by chemotherapy, not onlyto decrease the side effects of agents commonlyused in oncology, but also to specifically identifynew mitochondrial targets in tumor cells. We usedifferent in vitro (isolated mitochondrial fractions,cultured cell lines) and in vivo models (animalmodels of stress or disease‐induced mitochondrialalterations) in order to gather information on howmitochondria are affected by xenobiotics orstressful situations (e.g. exercise, differentpathologies) and the relevance for the tissuehomeostasis.Main AchievementsOur research group has provided several seminalworks in different lines of research, in which thefollowing:1) Mitochondrial toxicity of anticancer agents: Wehave investigated the role of mitochondria, notonly as a plausible target of novelchemotherapeutics in cancer cells, but also as amediator of toxicity of clinically used antineoplasticagents. We have demonstrated that twoplant alkaloids, berberine and sanguinarine,present a selective cytotoxic effect on human andmouse metastatic melanoma cells by targetingmitochondria, which can be a breakthrough in thetreatment of advanced melanoma. We haveidentified the adenine nucleotide translocator as acritical target of berberine. We also concluded thatthe activation of the p53‐Bax axis occurs upstreamof mitochondrial dysfunction induced by thecardiotoxicant doxorubicin in H9c2 myoblasts.2) Mitochondrial alterations during hepaticdiseases: Non‐alcoholic fatty liver disease(NAFLD) is an increasingly reported pathology,characterized by fat accumulation within thehepatocyte. We have demonstrated that cholinedeficientanimals have disturbed mitochondrialcalcium accumulation and bioenergetics, as well asincreased oxidative stress, which suggests amechanism for the development of NALFDassociated with altered mitochondrial function.3) Xenobiotic‐induced mitochondrial alterations:We have screened the toxicity of severalcompounds with clinical relevance in both heartand liver mitochondrial fractions. Of specialrelevance, we tested Indirubin‐3ʹ‐oxime, whichimpairs mitochondrial oxidative phosphorylationand prevents mitochondrial permeability transitioninduction, the insecticide methoprene, whichshowed a lower toxicity when compared withother compounds of the same family,mildronate, which was shown to prevent AZTinducedmitochondrial toxicity and Sildenafilcitrate, which was shown to decreasemitochondrial oxidative stress atconcentrations that did not affectmitochondrial bioenergetics.49