LPGAT1 controls MEGDEL syndrome by coupling phosphatidylglycerol remodeling with mitochondrial transport

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. [Display omitted] •LPGAT1 specifically interacts with PHB/TIM translocon•LPGAT1 coordinates with PHB/TIM translocon for mitochondrial PG transport•Loss of LPGAT1 or TIMM14 causes similar aberrant PG acyl compositions•Ablation of LPGAT1 causes cardinal features of MEGDEL syndrome in mice Phosphatidylglycerol is a mitochondrial phospholipid but is remodeled in the ER. Little is known about how the remodeled phosphatidylglycerol is transported back to mitochondria. Sun et al. demonstrate that phosphatidylglycerol remodeling by LPGAT1 closely coordinates with the mitochondrial PHB/TIM translocon and that ablation of LPGAT1 or disruption of the coordination process causes MEGDEL syndrome.