Congratulations to Roger Shi, PhD and the Shi Lab on their upcoming publication in Cell Reports!
The paper will be a spotlight article with a preview in an upcoming issue. Dr. Shi is the Joe R. and Teresa Lozano Long Distinguished Chair in Metabolic Biology and a Professor with the Department of Pharmacology and the Sam and Ann Barshop Institute for Longevity and Aging Studies.
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
Cell Rep. 2023 Nov 1;42(11):113214. doi: 10.1016/j.celrep.2023.113214. Online ahead of print. Spotlight article with a preview.
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.
Keywords: CP: Cell biology; LPGAT1; MEGDEL syndrome; mitochondrial dysfunction; phosphatidylglycerol; prohibitin/TIM complex.