Comparative studies on the physiological adaption of mitochondria and endoplasmic reticulum to envirnmental xenobiotics from invertebrate to mammals

Abstract

Mitochondria are critical for numerous cellular and biochemical processes. The reciprocal interaction between mitochondria and the endoplasmic reticulum impacts several cellular functions. In cellular and animal models, exposure to a series of pharmaceuticals or environmental pollutants has been shown to alter energy homeostasis resulting in a predisposition to common metabolism-related pathologies. Instead, it has been shown that mitochondria are exquisitely sensitive to environmental stress and act both as a target of stress and the coordinating center for the adaptive cellular response. The present Ph.D. thesis's first aim was to evaluate the dose-dependence effect of the endocrine disruptor DDE, the primary metabolite of DDT, on viability and mitochondrial dynamics in human liver cells (HepG2) in vitro, ranging between 0.5 and 100 µM. Its toxic effects on cells could be associated with mitochondrial network impairment associated with an imbalance between mitochondrial fusion and fission processes. Mitochondrial fusion and fission processes are critical to maintain the mitochondrial network and allow the cell to respond to external stressors such as environmental pollutants. Fusion processes are associated with the optimization of mitochondrial function, whereas fission processes are associated with removing damaged mitochondria. Results showed that DDE induced a decrease in cell viability in a dose-dependent manner and enhanced its effects in coincubation conditions with dietary fatty acids. The fusion protein markers Mitofusin 2 (MFN2) and Optical Atrophy 1 (OPA1) exhibited an inverted U-shape dose-response curve, showing the highest content in the 2.5-25 μM DDE dose range. On the other hand, the fission protein marker dynamin related protein1 (DRP1) was found significantly increased, leading to an increased fission/fusion ratio, with high DDE doses. A similar trend was observed for glucose regulated protein 75 (GRP75), a chaperon involved in mitochondria-endoplasmic reticulum interaction. Our results suggested that low DDE doses elicited cell adaption stimulating mitochondrial dynamics machinery to counteract the DDE effect. ... [edited by Author]