Combined effects of aging and in vitro non-steroid anti-inflammatory drugs on kidney and liver mitochondrial physiology.

AIMS: Aging and drug-induced side effects may contribute to deteriorate mitochondrial bioenergetics in many tissues, including kidney and liver. One possibility is that the combination of both aging and drug toxicity accelerates the process of mitochondrial degradation, leading to progressive bioenergetic disruption. We therefore analyzed in vitro kidney (KM) and liver (LM) mitochondrial response to salicylate and diclofenac in old and adult animals. MAIN METHODS: Male-Wistar adult (19-wks) and aged (106-wks) rats were used. In vitro endpoints of oxygen consumption and membrane potential were evaluated in non-treated conditions (vehicle) and in the presence of salicylate (0.5mM) and diclofenac (50µM). The susceptibility to calcium-induced permeability transition pore (MPTP) was assessed. Aconitase and C, -SH and MDA contents were measured. Apoptotic signaling was followed by measuring caspase 3, 8 and 9 activities, Bax, Bcl2 and CypD expression. ANT content was semi-quantified. KEY FINDINGS: In general, animal age alone compromised KM state 3 and LM ADP lag phase while resulting in decreased resistance to the MPTP. Aging decreased LM CypD and increased Mn-SOD. Kidney caspase 9-like activity was lower in aged group. Salicylate and diclofenac induced KM and LM dysfunction. ADP lag phase in KM was further increased in the aged group in the presence of diclofenac. No further impairments were observed regarding drug toxicity adding to the aging process. SIGNIFICANCE: Aging impaired KM and LM function despite no detected alterations on oxidative stress and apoptosis. However, aging did not further exacerbate KM and LM frailty induced by salicylate and diclofenac.

Bile acids are toxic for isolated cardiac mitochondria: a possible cause for hepatic-derived cardiomyopathies?

Cholestasis and other liver diseases may affect the heart through the toxic effects of the retained bile acids on cardiac mitochondria, which could explain the origin of hepatic-derived cardiomyopathies. The objective of this work was to test the hypothesis that bile acids are toxic to heart mitochondria for concentrations that are relevant for cholestasis. Heart mitochondria were isolated from rat and subjected to incubation with selected bile acids (litocholic acid [LCA], deoxycholic acid [DCA], chenodeoxycholic acid [CDCA], glycochenodeoxycholic acid [GCDC], taurodeoxycholic acid [TDCA], and glycoursodeoxycholic acid [GUDC]). We observed that the most toxic bile acids were also the most lipophilic ones (LCA, DCA, and CDCA), inducing a decrease on state 3 respiration, respiratory control ratio, and membrane potential and causing the induction of the mitochondrial permeability transition. GUDC was the bile acid with lower indexes of toxicity on isolated heart mitochondria. The results of this research indicate that at toxicologically relevant concentrations, most bile acids (mainly the most lipophilic) alter mitochondrial bioenergetics. The impairment of cardiac mitochondrial function may be an important cause for the observed cardiac alterations during cholestasis.

Enhanced permeability transition explains the reduced calcium uptake in cardiac mitochondria from streptozotocin-induced diabetic rats.

Cardiac dysfunction is associated with diabetes. It was previously shown that heart mitochondria from diabetic rats have a reduced calcium accumulation capacity. The objective of this work was to determine whether the reduction in calcium accumulation by cardiac mitochondria from diabetic rats is related to an enhanced susceptibility to induction of the mitochondrial permeability transition. Streptozotocin-induced diabetic rats were used as a model to study the alterations caused by diabetes in the permeability transition, 21 days after streptozotocin administration. Heart mitochondria were isolated to evaluate respiratory parameters and susceptibility to the calcium-dependent permeability transition. Our results show that streptozotocin diabetes facilitates the mitochondrial permeability transition in cardiac mitochondria, resulting in decreased mitochondrial calcium accumulation. We also observed that heart mitochondria from diabetic rats had depressed oxygen consumption during the phosphorylative state. The reduced mitochondrial calcium uptake observed in heart mitochondria from diabetic rats is related to an enhanced susceptibility to the permeability transition rather than to damage to the calcium uptake machinery.

Diabetes induces metabolic adaptations in rat liver mitochondria: role of coenzyme Q and cardiolipin contents.

Several studies have been carried out to evaluate the alterations in mitochondrial functions of diabetic rats. However, results are sometimes controversial, since experimental conditions diverge, including age and strain of used animals. The purpose of this study was to evaluate the metabolic modifications in liver mitochondria, both in the presence of severe (STZ-treated rats) and mild hyperglycaemia [Goto-Kakizaki (GK) rats], when compared with control animals of similar age. Moreover, metabolic alterations were evaluated also at initial and advanced stages of the disease. We observed that both models of diabetes (type 1 and type 2) presented a decreased susceptibility of liver mitochondria to the induction of permeability transition (MPT). Apparently, there is a positive correlation between the severity of diabetes mellitus (and duration of the disease) and the decline in the susceptibility to MPT induction. We also found that liver mitochondria isolated from diabetic rats presented some metabolic adaptations, such as an increase in coenzyme Q and cardiolipin contents, that can be responsible for the observed decrease in the susceptibility to multiprotein pore (MPTP) opening.