LETM 1 couples mitochondrial DNA metabolism and nutrient preference

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.

International meeting on Wolf‐Hirschhorn syndrome: Update on the nosology and new insights on the pathogenic mechanisms for seizures and growth delay

“…They also found that those phenotypes segregated with seizures in their WHS cohort. A recent work by Durigon et al () seemed to support these findings.…”

Recurrent De Novo NAHR Reciprocal Duplications in the ATAD3 Gene Cluster Cause a Neurogenetic Trait with Perturbed Cholesterol and Mitochondrial Metabolism

“…6,8 ATAD3 also co-purifies with the mitochondrial protein synthesis machinery, mtDNA, and mitochondrial cholesterol, 7,8,20 and there is evidence that the mitochondrial nucleoprotein complexes are interlinked. 21,22 Hence perturbed cholesterol-containing micro-domains could be the common factor linking all the features associated with ATAD3 deficiency.…”

Homozygous variant in OTX2 and possible genetic modifiers identified in a patient with combined pituitary hormone deficiency, ocular involvement, myopathy, ataxia, and mitochondrial impairment

“…Very recently researchers have recognized an important role for LETM1 in mitochondrial ribosome function. Moreover, fibroblasts from WHS patients displayed clear abnormalities in mitochondrial morphology, mtDNA organization and a remodeling of oxidative metabolism (Durigon et al, ). The emerging importance of LETM1 in mitochondrial morphology maintenance and function, suggests a possible role of the p.Arg294Gln variant in the determination or worsening of at least a portion of our patient's symptoms, and may contribute to the severe mitochondrial dysfunction revealed by studies on muscle biopsy of our proband.…”