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 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 −/− 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.

Metabolic implications of organelle–mitochondria communication

“…In contrast to these results, Arruda et al found an increase in the MAM proteins MCU and RyR in soleus muscles from ob/ob and HFD‐fed mice, suggesting an enrichment in MAMs under these conditions. In line with these results, Thoudam et al found increased levels of IP3R1, VDAC1, and GRP75 in the MAM fraction of skeletal muscle of HFD‐fed mice and ob/ob mice. Furthermore, they observed increased levels of MFN2 in HFD‐fed mice.…”

“…Furthermore, they observed increased levels of MFN2 in HFD‐fed mice. Moreover, using proximity ligation assays, they detected increased IP3R1–GRP75–VDAC1 interactions in HFD‐fed mice and ob/ob mice . Transmission electron microscopy of muscle MAM surface revealed increased MAM area in HFD‐fed mice compared to animals on a chow diet .…”

“…Moreover, using proximity ligation assays, they detected increased IP3R1–GRP75–VDAC1 interactions in HFD‐fed mice and ob/ob mice . Transmission electron microscopy of muscle MAM surface revealed increased MAM area in HFD‐fed mice compared to animals on a chow diet . Interestingly, the authors quantified the distance between juxtaposed ER and mitochondria and found that in HFD‐fed mice the proportion of loose contacts between the ER and mitochondria was increased.…”

“…IP3R1 silencing in hepatocytes does not alter the protein levels of the other IP3Rs . Pdk4 ablation in mice results in decreased MAM formation in skeletal muscle . Tg2 ablation in mouse embryonic fibroblasts (MEF) decreases the quantity of mitochondria–ER contact sites .…”

Reduction of mitochondria and up regulation of pyruvate dehydrogenase kinase 4 of skeletal muscle in patients with chronic kidney disease

“…e, the difference of mRNA expression of each isoenzyme between non‐CKD group and ESRD group was not statistically significant. As PDK4 is predominantly expressed in skeletal muscle and myocardium in mammals, therefore we examined the PDK4 protein level. The PDK4 protein expression in ESRD and non‐CKD patients was 2.355 ± 0.721 versus 1.000 ± 0.692 ( P = 0.004; Fig.…”