Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: EC:2.7.11.2 (
PDK1
)
2,238
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
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.
...
PMID:PDK4 Augments ER-Mitochondria Contact to Dampen Skeletal Muscle Insulin Signaling During Obesity. 3052 25
