Opening of the mitochondrial permeability transition pore links mitochondrial dysfunction to insulin resistance in skeletal muscle

Abstract

Insulin resistance is associated with mitochondrial dysfunction, but the mechanism by which mitochondria inhibit insulin-stimulated glucose uptake into the cytoplasm is unclear. The mitochondrial permeability transition pore (mPTP) is a protein complex that facilitates the exchange of molecules between the mitochondrial matrix and cytoplasm, and opening of the mPTP occurs in response to physiological stressors that are associated with insulin resistance. In this study, we investigated whether mPTP opening provides a link between mitochondrial dysfunction and insulin resistance by inhibiting the mPTP gatekeeper protein cyclophilin D (CypD) in vivo and in vitro. Mice lacking CypD were protected from high fat diet-induced glucose intolerance due to increased glucose uptake in skeletal muscle. The mitochondria in CypD knockout muscle were resistant to diet-induced swelling and had improved calcium retention capacity compared to controls; however, no changes were observed in muscle oxidative damage, insulin signaling, lipotoxic lipid accumulation or mitochondrial bioenergetics. In vitro, we tested 4 models of insulin resistance that are linked to mitochondrial dysfunction in cultured skeletal muscle cells including antimycin A, C2-ceramide, ferutinin, and palmitate. In all models, we observed that pharmacological inhibition of mPTP opening with the CypD inhibitor cyclosporin A was sufficient to prevent insulin resistance at the level of insulin-stimulated GLUT4 translocation to the plasma membrane. The protective effects of mPTP inhibition on insulin sensitivity were associated with improved mitochondrial calcium retention capacity but did not involve changes in insulin signaling both in vitro and in vivo. In sum, these data place the mPTP at a critical intersection between alterations in mitochondrial function and insulin resistance in skeletal muscle.

Lactosylceramide contributes to mitochondrial dysfunction in diabetes

“…Perturbation in intracellular Ca 2+ homeostasis resulting from decreased expression/ activity of sarco/ER calcium ATPase (SERCA) and compromised mitochondrial Ca 2+ handling in STZ-induced diabetic hearts ( 76 ) can potentially modulate ceramide metabolism. However, variations in activity of SERCA and mitochondrial Ca 2+ controlling mPTP opening/closure do not affect the levels of diacylglycerol or ceramide ( 77,78 ). This suggests that deregulation of Ca 2+ homeostasis and mPTP activity is likely downstream of ceramide metabolism, or they are independent factors.…”

Skeletal muscle insulin resistance: role of mitochondria and other ROS sources

“…A link between MPT pore opening and mitochondrial dysfunction and IR was demonstrated by inhibiting in vivo and in vitro the protein cyclophilin D (CypD) that regulates MTP pore opening by directly binding to pore constituent proteins (Taddeo et al 2014). Indeed, mice lacking CypD were protected from high-fat diet-induced glucose intolerance due to increased glucose uptake in skeletal muscle.…”

“…Indeed, mice lacking CypD were protected from high-fat diet-induced glucose intolerance due to increased glucose uptake in skeletal muscle. Furthermore, in in vitro models of skeletal muscle IR, it was observed that pharmacological inhibition of MTP pore opening with the CypD inhibitor cyclosporine A prevented IR at the level of insulinstimulated GLUT4 translocation to the plasma membrane (Taddeo et al 2014).…”

Mechanisms of Asthma in Obesity. Pleiotropic Aspects of Obesity Produce Distinct Asthma Phenotypes

“…These data suggest that airway epithelial mitochondrial dysfunction may contribute to allergic asthma, even in lean individuals. Mitochondrial dysfunction is a characteristic of obesity, and many studies, particularly in liver and muscle cells, suggest that obesity increases mitochondrial oxidative stress (55,56). Interestingly, airway mitochondria are altered in animals fed a high-fat diet (33).…”