LETM1 couples mitochondrial DNA metabolism and nutrient preference. Issue 9 (16th July 2018)

• Record Type: Journal Article
• Authors: 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
• Is Part Of: EMBO molecular medicine. Volume 10:Issue 9(2018)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2018-07-16
• Subjects: LETM1 -- mitochondrial DNA -- mitochondrial morphology -- nutrient utilization -- Wolf–Hirschhorn syndrome; Molecular biology -- Periodicals; Medical genetics -- Periodicals; Pathology, Molecular -- Periodicals; 616.04205
• DOI: 10.15252/emmm.201708550
• Languages: English
• ISSNs: 1757-4676

Abstract

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. Synopsis: The mitochondrial inner membrane protein LETM1 regulates mitochondrial DNA metabolism according to nutrient availability, which suggests that in the Wolf‐Hirschhorn syndrome and a range of other mitochondrial disorders, dietary control could impact disease development and progression. Nutrients configure mitochondrial nucleoprotein complexes for energy production; for glucose such adaptation is mediated by LETM1. LETM1 and pyruvate dehydrogenase (PDH) are physically associated with mitochondrial nucleoprotein complexes. Monoallelic deletion of LETM1 inactivates PDH and causes aggregation of mitochondrial nucleoids. LETM1 haploinsufficiency permits proliferation on a strict ketone body growth regime, whereas control cells undergo irreversible mitochondrial DNA aggregation and cell death. Mitochondrial translation and ribosome maintenance in human cells requires LETM1 when the organelles utilize glucose and pyruvate. Abstract : The mitochondrial inner membrane protein LETM1 regulates mitochondrial DNA metabolism according to nutrient availability, which suggests that in the Wolf‐Hirschhorn syndrome and a range of other mitochondrial disorders, dietary control could impact disease development and progression.