Mitochondria-associated endoplasmic reticulum membrane (MAM) is a structural link between mitochondria and endoplasmic reticulum (ER). MAM regulates Ca 2+ transport from the ER to mitochondria via an IP3R1-GRP75-VDAC1 complex–dependent mechanism. Excessive MAM formation may cause mitochondrial Ca 2+ 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 Ca 2+ accumulation, mitochondrial dysfunction, and ER stress. Furthermore, Pdk4 2 / 2 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.
Bibliographical noteFunding Information:
This work was supported by National Research Foundation of Korea grants funded by the Korean government (Ministry of Science, ICT and Future Planning) (NRF-2016M3A9B6902872, NRF-2017R1A2B3006406, NRF-2016R1E1A2020567, and NRF-2017R1E1A2A02023467), a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute, funded by the Ministry of Health & Welfare, Republic of Korea (HI16C1501), a grant funded by the Korea Basic Science Institute (T38210), VA Merit Award 1I01CX000361, National Institutes of Health grants U01-AA-021840, R01-DK-107682, R01-AA-025208, and U.S. Department of Defense grant W81XWH-12-1-0497.
All Science Journal Classification (ASJC) codes
- Internal Medicine
- Endocrinology, Diabetes and Metabolism