期刊
EMBO MOLECULAR MEDICINE
卷 10, 期 9, 页码 -出版社
WILEY
DOI: 10.15252/emmm.201708550
关键词
LETM1; mitochondrial DNA; mitochondrial morphology; nutrient utilization; Wolf-Hirschhorn syndrome
资金
- UK Medical Research Council [MC_PC_13029]
- European Commission (MEET project grant) [317433]
- UK Medical Research Council
- Catholic University of Rome
- Ikerbasque Science Foundation
- Carlos III Health Program
- Biodonostia Research Institute
- MRC [MC_PC_13029/2, MC_UP_1202/14] Funding Source: UKRI
The diverse clinical phenotypes of Wolf-Hirschhorn syndrome (WHS) are the result of haploinsufficiency of several genes, one of which, LETM1, encodes a protein of the mitochondrial inner membrane of uncertain function. Here, we show that LETM1 is associated with mitochondrial ribosomes, is required for mitochondrial DNA distribution and expression, and regulates the activity of an ancillary metabolic enzyme, pyruvate dehydrogenase. LETM1 deficiency in WHS alters mitochondrial morphology and DNA organization, as does substituting ketone bodies for glucose in control cells. While this change in nutrient availability leads to the death of fibroblasts with normal amounts of LETM1, WHS-derived fibroblasts survive on ketone bodies, which can be attributed to their reduced dependence on glucose oxidation. Thus, remodeling of mitochondrial nucleoprotein complexes results from the inability of mitochondria to use specific substrates for energy production and is indicative of mitochondrial dysfunction. However, the dysfunction could be mitigated by a modified diet-for WHS, one high in lipids and low in carbohydrates.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据