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.