LETM1 couples mitochondrial DNA metabolism and nutrient preference

Paolo Niccolo' Doronzio, Marcella Zollino, Serena Lattante, Romina Durigon, Alice L Mitchell, Aleck We Jones, Andreea Manole, Mara Mennuni, Elizabeth Ma Hirst, Henry Houlden, Ilaria Dalla Rosa, Ian J Holt, Antonella Spinazzola

Risultato della ricerca: Contributo in rivistaArticolo in rivista

15 Citazioni (Scopus)

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.
Lingua originaleEnglish
pagine (da-a)e8550-N/A
RivistaEMBO Molecular Medicine
Volume10
DOI
Stato di pubblicazionePubblicato - 2018

Keywords

  • LETM1
  • Molecular Medicine
  • Wolf–Hirschhorn syndrome
  • mitochondrial DNA
  • mitochondrial morphology
  • nutrient utilization

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