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.
Highlights
Mitochondria are major contributors to cellular energy production, converting nutrients to ATP through the oxidative phosphorylation system (OXPHOS)
We demonstrate that mitochondrial abnormalities are evident in primary cells of Wolf–Hirschhorn syndrome (WHS) subjects lacking one allele of LETM1 and that reduced LETM1 expression is associated with the remodeling of nutrient metabolism in a disease state
WHS deletions involve a number of other genes, the loss of which could contribute to the metabolic and mitochondrial phenotypes, the mitochondrial phenotypes were exclusive to the WHS cells lacking a LETM1 allele and were evident in HeLa cells after LETM1 silencing
Summary
Mitochondria are major contributors to cellular energy production, converting nutrients to ATP through the oxidative phosphorylation system (OXPHOS). Thirteen essential proteins of OXPHOS are transcribed from mitochondrial DNA (mtDNA) and synthesized by the mitochondrial ribosomes (mitoribosomes), via a highly specialized system that is tightly coupled to the inner mitochondrial membrane (IMM; Liu & Spremulli, 2000). Mdm is an integral inner membrane protein conserved among eukaryotes, and it is suggested to play a role in multiple facets of mitochondrial metabolism, the precise nature of which remains unclear. Under certain conditions, it co-fractionates with the mitoribosome, on buoyant density gradients (Frazier et al, 2006; Kehrein et al, 2015), and it is proposed to regulate mitochondrial translation (Bauerschmitt et al, 2010). Mdm regulates mitochondrial morphology and volume by controlling ion homeostasis across the mitochondrial inner membrane (Nowikovsky et al, 2004, 2007; Froschauer et al, 2005)
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