LPGAT1 controls MEGDEL syndrome by coupling phosphatidylglycerol remodeling with mitochondrial transport

Haoran Sun, Jun Zhang, Qianqian Ye, Ting Jiang, Xueling Liu, Xiaoyang Zhang, Fanyu Zeng, Jie Li, Yue Zheng, Xianlin Han, Chuan Su, Yuguang Shi

Research output: Contribution to journalArticlepeer-review

1 Scopus citations


Phosphatidylglycerol (PG) is a mitochondrial phospholipid required for mitochondrial cristae structure and cardiolipin synthesis. PG must be remodeled to its mature form at the endoplasmic reticulum (ER) after mitochondrial biosynthesis to achieve its biological functions. Defective PG remodeling causes MEGDEL (non-alcohol fatty liver disease and 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like) syndrome through poorly defined mechanisms. Here, we identify LPGAT1, an acyltransferase that catalyzes PG remodeling, as a candidate gene for MEGDEL syndrome. We show that PG remodeling by LPGAT1 at the ER is closely coordinated with mitochondrial transport through interaction with the prohibitin/TIMM14 mitochondrial import motor. Accordingly, ablation of LPGAT1 or TIMM14 not only causes aberrant fatty acyl compositions but also ER retention of newly remodeled PG, leading to profound loss in mitochondrial crista structure and respiration. Consequently, genetic deletion of the LPGAT1 in mice leads to cardinal features of MEGDEL syndrome, including 3-methylglutaconic aciduria, deafness, dilated cardiomyopathy, and premature death, which are highly reminiscent of those caused by TIMM14 mutations in humans.

Original languageEnglish (US)
Article number113214
JournalCell Reports
Issue number11
StatePublished - Nov 28 2023


  • CP: Cell biology
  • LPGAT1
  • MEGDEL syndrome
  • mitochondrial dysfunction
  • phosphatidylglycerol
  • prohibitin/TIM complex

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology


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