Effects of environmental metals on mitochondrial bioenergetics of the CD-1 mice pancreatic beta-cells.

Environmental metals are believed to have diabetogenic effects without any clear underlying mechanisms. The study investigated the effects of metals, lead (Pb), mercury (Hg), cadmium (Cd), and molybdenum (Mo), on the bioenergetics of isolated pancreatic ß-cells from CD-1 mice via different functional and structural techniques. The tested metals caused significant decrease in ATP production in concentration and exposure duration-dependent pattern; Cd was the most potent cytotoxic metal. In ATP assay estimated effective concentration 50 (EC50) (25, 40, 20, and 100 µM for Pb, Hg, Cd, and Mo, respectively), the metals also significantly inhibited the glucose-stimulated insulin secretion (GSIS), mitochondrial complexes activity, mitochondrial membranes potential, and oxygen consumption rates of the treated cells with parallel increases in their lactate production and in the mitochondrial swelling and permeation of their inner mitochondrial membranes to potassium (K+) and hydrogen (H+) ions. In addition, Cd, Pb, and Hg produced significant increases in mitochondrial membrane fluidity (MMF) with significant decreases in saturated/unsaturated fatty acid ratios. In 10 µM concentration, away from Mo, the three metals showed inhibitory effects on the mitochondrial functions to variable degrees. Only Cd showed significant effect on MMF and fatty acid ratios at a concentration of 10 µM. In conclusion, the tested metals significantly affected the bioenergetics of the pancreatic ß-cells with significant effect on GSIS. Cd showed the most significant functional and structural effects on their mitochondria followed by Pb, then Hg, while Mo was almost safe up to 10 µM concentration. Hence, bioenergetic mitochondrial disruption can be considered as an underlying mechanism of the diabetogenic effects of the tested metals.

Carbamazepine induces a bioenergetics disruption to microvascular endothelial cells from the blood-brain barrier.

Carbamazepine (CBZ) is a widely employed anti-seizure medication that crosses the blood-brain barrier (BBB) to exert its anti-convulsant action. The effects of CBZ on components of the BBB have yet to be completely delineated. Hence the current study evaluated the effects of CBZ upon mitochondrial functionality of BBB-derived microvascular endothelial cells isolated from Albino rats. The influence of CBZ on cell viability and barrier functions were evaluated by 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT), lactate dehydrogenase, and electrophysiological assays over a drug concentration range of 0.1-1000 µM. Bioenergetics effects were measured via ATP production, mitochondrial complexes I and III activities, lactate production, and oxygen consumption rates (OCRs), and mitochondrial membrane potential, fluidity and lipid content. CBZ was cytotoxic to microvascular endothelial cells in a concentration and duration dependent manner. CBZ significantly diminished the endothelial cell's barrier functions, and impacted upon cellular bioenergetics: reducing mitochondrial complex activities with a parallel decrease in OCRs and increased anaerobic lactate production. CBZ significantly decreased mitochondrial membrane potential and induced an increase of membrane fluidity and decrease in levels of mitochondrial saturated and unsaturated fatty acids. In summary, CBZ disrupted functional activity of BBB endothelial cells via damage and modification of mitochondria functionality at therapeutically relevant concentrations.

Effect of antipsychotics on mitochondrial bioenergetics of rat ovarian theca cells.

BACKGROUND: Antipsychotics (APs) are widely prescribed drugs, which are well known to cause reproductive adverse effects through mechanisms yet to be determined. The purpose of this study was to investigate the effect of antipsychotics on mitochondrial bioenergetics of rat ovarian theca cells as a possible mechanism of reproductive toxicity. METHODS: Isolated rat theca interstitial cells (TICs) were treated with two typical (chlorpromazine [CPZ] and haloperidol [HAL]) and two atypical APs (risperidone [RIS] and clozapine [CLZ]). The effects of these APs on TICs bioenergetics (ATP content, mitochondrial complexes I and III activities, oxygen consumption rates (OCRs), mitochondrial membrane potential (MPP) and lactate production) and on steroidogenesis (androstenedione and progesterone synthesis) were investigated. RESULTS: All APs resulted in a concentration-dependent decrease in the ATP content of TICs. All APs at their estimated IC50s (6µM, 21µM, 35µM and 37µM for CPZ, HAL, CLZ and RIS respectively) significantly decreased TICs OCRs (p<0.0001), MPP (p<0.0001) and significantly (p=0.0003) inhibited mitochondrial complex I activity. Only typical APs inhibited complex III (p=0.005). Also, APs at IC50s increased TICs lactate production to varying degrees. All APs used at their IC50s significantly inhibited progesterone (p=0.0022) and androstenedione (p=0.0027) production. Only CPZ was found to inhibit these hormones at the low concentration (1µM). CONCLUSION: All four antipsychotics seem to inhibit mitochondrial bioenergetics and steroidogenesis in rat's ovarian theca cells. These findings support the hypothesis that APs-induced reproductive toxicity may be through mechanisms involving mitochondrial insult>. Further research is required to establish the link between APs-induced mitochondrial dysfunction and disordered steroidogenesis.