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LETM1 couples mitochondrial DNA metabolism and nutrient preference

Durigon, R; Mitchell, AL; Jones, AW; Manole, A; Mennuni, M; Hirst, EM; Houlden, H; ... Spinazzola, A; + view all (2018) LETM1 couples mitochondrial DNA metabolism and nutrient preference. EMBO Molecular Medicine , 10 (7) 10.15252/emmm.201708550. Green open access

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Abstract

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.

Type: Article
Title: LETM1 couples mitochondrial DNA metabolism and nutrient preference
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.15252/emmm.201708550
Publisher version: http://doi.org/10.15252/emmm.201708550
Language: English
Additional information: Copyright © 2018 The Authors. Published under the terms of the CC BY 4.0 license
Keywords: LETM1, Wolf–Hirschhorn syndrome, mitochondrial DNA, mitochondrial morphology, nutrient utilization
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Clinical and Movement Neurosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Department of Neuromuscular Diseases
URI: http://discovery.ucl.ac.uk/id/eprint/10053729
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