Open AccessLETM 1 couples mitochondrial DNA metabolism and nutrient preference
Author(s) -
Durigon Romina,
Mitchell Alice L,
Jones Aleck WE,
Manole Andreea,
Mennuni Mara,
Hirst Elizabeth MA,
Houlden Henry,
Maragni Giuseppe,
Lattante Serena,
Doronzio Paolo Niccolo’,
Dalla Rosa Ilaria,
Zollino Marcella,
Holt Ian J,
Spinazzola Antonella
Publication year - 2018
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.201708550
Subject(s) - neurology , library science , medicine , neuroscience , psychology , computer science
The diverse clinical phenotypes of Wolf–Hirschhorn syndrome ( WHS ) are the result of haploinsufficiency of several genes, one of which, LETM 1 , encodes a protein of the mitochondrial inner membrane of uncertain function. Here, we show that LETM 1 is associated with mitochondrial ribosomes, is required for mitochondrial DNA distribution and expression, and regulates the activity of an ancillary metabolic enzyme, pyruvate dehydrogenase. LETM 1 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 LETM 1, 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.