PDK4 Augments ER–Mitochondria Contact to Dampen Skeletal Muscle Insulin Signaling During Obesity
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Dec 06, 2018
- Source ID
- 10.2337/db18-0363
Entities
People
- Chae-myeong Ha
- Dipanjan Chanda
- Hyo-jeong Kim
- Hyun-woo Rhee
- In-Kyu Lee
- Jae-han Jeon
- Jaechan Leem
- Jong-seok Park
- Keun Gyu Park
- Kyu-sang Park
- Robert A. Harris
- Suthat Liangpunsakul
- Tae-hwan Kwon
- Themis Thoudam
- Yang Hoon Huh
- Yeon-kyung Choi
Organizations
- Daegu Catholic University
- Indiana University
- Indiana University School of Medicine
- Korea Basic Science Institute
- Kyungpook National University
- Ministry of Health and Welfare
- Ministry of Science, ICT and Future Planning
- National Institutes of Health
- Richard L. Roudebush VA Medical Center
- Seoul National University
- Ulsan National Institute of Science and Technology
- United States Department of Defense
- Yonsei University