Abstract
The mitochondrial permeability transition pore (mPTP) is a key regulator of mitochondrial function that has been implicated in the pathogenesis of metabolic disease. Cyclophilin D (CypD) is a critical regulator that directly binds to mPTP constituents to facilitate the pore opening. We previously found that global CypD knockout mice (KO) are protected from diet-induced glucose intolerance; however, the tissue-specific function of CypD and mPTP, particularly in the control of glucose homeostasis, has not been ascertained. To this end, we performed calcium retention capacity (CRC) assay to compare the importance of CypD in the liver versus skeletal muscle. We found that liver mitochondria are more dependent on CypD for mPTP opening than skeletal muscle mitochondria. To ascertain the tissue-specific role of CypD in metabolic homeostasis, we generated liver-specific and muscle-specific CypD knockout mice (LKO and MKO, respectively) and fed them either a chow diet or 45% high-fat diet (HFD) for 14 weeks. MKO mice displayed similar body weight gain and glucose intolerance compared with wild type littermates (WT), whereas LKO mice developed greater visceral obesity, glucose intolerance and pyruvate intolerance compared with WT mice. These findings demonstrate that loss of muscle CypD is not sufficient to alter whole body glucose metabolism, while the loss of liver CypD exacerbates obesity and whole-body metabolic dysfunction in mice fed HFD.
Highlights
Impaired mitochondrial function due to increased damage and/or impaired maintenance is associated with a plethora of disease conditions affecting multiple organ systems
Loss of Cyclophilin D (CypD) in the liver mitochondria had a profound impact on calcium retention capacity (CRC) such that up to 12 rounds of Ca2+ addition (83 nM per mg mitochondrial protein) were required to trigger Ca2+ overload-induced mitochondrial permeability transition pore (mPTP) opening compared to wild type littermates (WT) mitochondria (Fig 1B and 1C)
The fact that liver-specific CypD knockout mice had exacerbated glucose intolerance suggests that normal mPTP in hepatocytes is critical for them to deal with lipid overload and maintain metabolic homeostasis under the condition of high-fat diet (HFD)
Summary
Impaired mitochondrial function due to increased damage and/or impaired maintenance is associated with a plethora of disease conditions affecting multiple organ systems. The contribution of mitochondrial dysfunction to obesity and type 2 diabetes is important since these two related disease conditions are reaching epidemic levels and are primarily
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