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 mito-chondrial 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 mito-chondrial import motor. Accordingly, ablation of LPGAT1 or TIMM14 not only causes aberrant fatty acyl com-positions but also ER retention of newly remodeled PG, leading to profound loss in mitochondrial crista struc-ture 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 prema-ture death, which are highly reminiscent of those caused by TIMM14 mutations in humans.

Automated summary

Phosphatidylglycerol (PG) is a mitochondrial phospholipid that needs to be remodeled at the endoplasmic reticulum (ER) after mitochondrial biosynthesis to function properly. Defects in PG remodeling can lead to MEGDEL syndrome. LPGAT1, an acyltransferase, is identified as a candidate gene for MEGDEL syndrome and is involved in PG remodeling through interaction with the prohibitin/TIMM14 mitochondrial import motor. Deletion of LPGAT1 in mice results in features resembling MEGDEL syndrome.