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PDK4 Augments ER-Mitochondria Contact to Dampen Skeletal Muscle Insulin Signaling During Obesity.

Diabetes (2018-12-14)
Themis Thoudam, Chae-Myeong Ha, Jaechan Leem, Dipanjan Chanda, Jong-Seok Park, Hyo-Jeong Kim, Jae-Han Jeon, Yeon-Kyung Choi, Suthat Liangpunsakul, Yang Hoon Huh, Tae-Hwan Kwon, Keun-Gyu Park, Robert A Harris, Kyu-Sang Park, Hyun-Woo Rhee, In-Kyu Lee
ABSTRACT

Mitochondria-associated endoplasmic reticulum membrane (MAM) is a structural link between mitochondria and endoplasmic reticulum (ER). MAM regulates Ca2+ transport from the ER to mitochondria via an IP3R1-GRP75-VDAC1 complex-dependent mechanism. Excessive MAM formation may cause mitochondrial Ca2+ overload and mitochondrial dysfunction. However, the exact implication of MAM formation in metabolic syndromes remains debatable. Here, we demonstrate that PDK4 interacts with and stabilizes the IP3R1-GRP75-VDAC1 complex at the MAM interface. Obesity-induced increase in PDK4 activity augments MAM formation and suppresses insulin signaling. Conversely, PDK4 inhibition dampens MAM formation and improves insulin signaling by preventing MAM-induced mitochondrial Ca2+ accumulation, mitochondrial dysfunction, and ER stress. Furthermore, Pdk4-/- mice exhibit reduced MAM formation and are protected against diet-induced skeletal muscle insulin resistance. Finally, forced formation and stabilization of MAMs with synthetic ER-mitochondria linker prevented the beneficial effects of PDK4 deficiency on insulin signaling. Overall, our findings demonstrate a critical mediatory role of PDK4 in the development of skeletal muscle insulin resistance via enhancement of MAM formation.

MATERIALS
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Brand
Product Description

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