LETM1 couples mitochondrial DNA metabolism and nutrient preference.
EMBO Mol Med
; 10(9)2018 09.
Article
em En
| MEDLINE
| ID: mdl-30012579
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.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Complexo Piruvato Desidrogenase
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Proteínas de Ligação ao Cálcio
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DNA Mitocondrial
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Ribossomos Mitocondriais
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Glucose
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Corpos Cetônicos
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Proteínas de Membrana
Limite:
Humans
Idioma:
En
Ano de publicação:
2018
Tipo de documento:
Article