Elsevier

Molecular Metabolism

Volume 3, Issue 2, April 2014, Pages 124-134
Molecular Metabolism

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

https://doi.org/10.1016/j.molmet.2013.11.003Get rights and content
Under a Creative Commons license
open access

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.

Abbreviations

MPTP
mitochondrial permeability transition pore
CYPD
cyclophilin D
HFD
high fat diet
LFD
low fat diet
WT
wild type
KO
knockout
CSA
cyclosporin A
BKA
bongkrekic acid
O2radical dot
superoxide
[3H]-2-DOG
[3H]-2-deoxyglucose
Rg′
rate of glucose transport
FFA
free fatty acid
DAG
diacylglycerol
TEM
transmission electron microscopy
PDH
pyruvate dehydrogenase
PDHa
active PDH
PDHt
total PDH
MCAD
medium chain acyl-CoA dehydrogenase
β-HAD
β-hydroxyacyl-CoA dehydrogenase
PM
plasma membrane
ANT
adenine nucleotide translocator
VDAC
voltage-dependent anion channel
HK2
hexokinase 2
ETC
electron transport chain
OXPHOS
oxidative phosphorylation
MnSOD
mitochondrial manganese superoxide dismutase
MIRKO
muscle insulin receptor knockout
MHC
myosin heavy chain
TBARS
thiobarbituric acid reactive substances

Keywords

Glucose
Insulin resistance
Mitochondrial dysfunction
Mitochondrial permeability transition pore
Cyclophilin D
Skeletal muscle

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