PISD acts as a switch between lipophagy and fatty acid transfer to mitochondria.

Authors

Hanbing Xue, Xingwen Hu, Zhenni Yang, Yiqing Cao, Qi Zhu, Hongyu Zhao, Xiaoli Ma, Tianxin Lei, Dian Zhuang, Jing Zheng, Siqi Guo, Xiaochuan Fu, Ka Kit Chung, Pingsheng Liu, Xiaohong Zhuang, Zhengyu Liang, Sicong He, Hui Jiang, Yan G Zhao

Published in

The Journal of cell biology. Volume 225. Issue 9. Sep 07, 2026. Epub Jul 13, 2026.

Abstract

Fatty acids (FAs) are transported from lipid droplets (LDs) to mitochondria for β-oxidation during cell starvation. Starvation also triggers engulfment of LDs by autophagosomes and their subsequent degradation by lysosomes (lipophagy). The mechanisms coordinating these pathways remain unclear. Here, we demonstrate that PISD-LD, an LD-localized isoform of phosphatidylserine decarboxylase, facilitates FA transfer while inhibiting lipophagy. PISD-LD mediates LD-mitochondrion (LD-mito) contacts via interaction with mitochondrial PISD. In PISD-LD KD cells, LDs are larger, and FA trafficking and mitochondrial FA β-oxidation are suppressed. The lipid transfer proteins ATG2A/B are recruited by PISDs to mediate FA transfer from LDs to mitochondria. Disruption of PISD-LD-mediated LD-mito contacts activates lipophagy, aiding LD degradation. PISD-LD binds the lipophagy receptor Spartin and inhibits lipophagy by impeding Spartin-LC3 interaction. PISD-LD also regulates LD-mito contacts and lipid metabolism in mouse liver. Thus, PISD-LD serves as a switch between LD-to-mitochondrion FA transfer and lipophagy, ensuring efficient energy production.

PMID:
42439896
Bibliographic data and abstract were imported from PubMed on 13 Jul 2026.

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