Reprogramming of lipid metabolism by PFKL promotes the adaptation of pancreatic ductal adenocarcinoma to glucose deprivation.
TL;DR
PFKL plays a key role in coordinating LD-mitochondria tethering under glucose deprivation in PDAC, and targeting the p38-PFKL-PLIN2-CPT1A axis may represent a promising therapeutic strategy.
Abstract
BACKGROUND/
Objective
Lipid droplet (LD)-mitochondria tethering is essential for fatty acid oxidation (FAO), which sustains tumor cell survival under nutrient-deprivation conditions. However, how LD-mitochondria contact is regulated in pancreatic ductal adenocarcinoma (PDAC) is unclear.
Methods
This study investigated the signaling pathway that regulates lipid droplet-mitochondria interaction in PDAC under conditions of glucose deprivation, utilizing molecular interaction assays, cellular functional experiments, and clinical sample validation.
Results
Glucose deprivation activated p38, leading to phosphorylation of phosphofructokinase, liver type (PFKL) at T331, which in turn phosphorylated the LD protein perilipin 2 (PLIN2) at S159 in PDAC cells. This enhanced the binding of PLIN2 to mitochondrial protein carnitine palmitoyltransferase-1 A (CPT1A), thereby promoting LD-mitochondria tethering. Disruption of this axis impaired LD-mitochondria contact, reduced lipid consumption and ATP production, decreased cell viability, increased apoptosis, and suppressed tumor growth. In human PDAC samples, phosphorylation levels at both PFKL T331 and PLIN2 S159 were elevated and showed a positive correlation.
Conclusion
PFKL plays a key role in coordinating LD-mitochondria tethering under glucose deprivation in PDAC, and targeting the p38-PFKL-PLIN2-CPT1A axis may represent a promising therapeutic strategy.