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Nuclear MBL-1 modulates mitochondrial morphology through carnitine palmitoyltransferase in C. elegans with toxic trinucleotide repeats

ABSTRACT: Expansion of nucleotide repeat sequences is linked to a growing number of neuromuscular degenerative disorders. Metabolic changes, including disruptions in mitochondrial function and dynamics, characterize these disorders and are believed to contribute to organismal toxicity. To investigate how toxic RNA repeats affect mitochondria, we used a Caenorhabditis elegans model that expresses expanded CUG repeat RNAs in muscle cells and recapitulates muscle dysfunction. We found that the RNA-binding protein Muscleblind-like 1 (MBL-1) is essential for normal mitochondrial function and regulates organelle morphology. In animals expressing expanded CUG repeats, where MBL-1 function is impaired, we identified two distinct mechanisms of mitochondrial disruption: altered mitochondrial morphology regulated by MBL-1, and oxidative phosphorylation (OxPhos) dysfunction occurring independently of MBL-1. Our data further show that changes in mitochondrial morphology are specifically linked to nuclear MBL-1 dysfunction, which affects cpt-3 expression, a gene encoding carnitine palmitoyl transferase—an enzyme required for fatty acid transport into mitochondria. This mechanism is conserved, with similar disruptions observed in patients with Myotonic Dystrophy type 1. Importantly, our findings indicate that mitochondrial disruption does not result from increased organelle fragmentation. Instead, OxPhos dysfunction appears to be a primary contributor to cellular toxicity.

ORGANISM(S): Caenorhabditis elegans

PROVIDER: GSE311723 | GEO | 2026/01/08

REPOSITORIES: GEO

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Project description:SEPN1 is a type II protein of the endoplasmic reticulum (ER) whose loss of function gives rise to a collection of debilitating autosomal recessive myopathies gathered under the umbrella term of SEPN1-related myopathy (RM). At the moment, SEPN1-RM lacks an effective pharmacological treatment; thus, the medical management of the disease is only supportive. The potentially fatal diaphragmatic weakness leading to respiratory insufficiency in patients still ambulant is the main reason for medical concerns. Thus, studies on SEPN1-RM pathogenesis are necessary to implement a targeted pharmacological therapy aimed at relieving the general muscle weakness and the more worrisome diaphragmatic dysfunction. Here, we show a physical and functional interaction between SEPN1 and the ER stress mediator ERO1 alpha (henceforth, ERO1). Both SEPN1 and ERO1 are involved in the redox regulation of proteins into the ER, although in an opposite way SEPN1 imposes a less oxidant ER poise while ERO1 a more oxidant one, conceivable with a reductase function of SEPN1 and an oxidase one of ERO1. Furthermore, both are mainly localized in a region of the ER in close contact with mitochondria termed mitochondria-associated membranes (MAMs) and their loss impacts oppositely on the short-range MAMs, thereby impinging ER-mitochondria Ca2+ dynamics, OXPHOS, and bioenergetics. We find that ERO1 depletion restores the impaired short-range MAMs due to SEPN1 loss together with mitochondrial ATP. ERO1 knockout in a mouse background of SEPN1 loss blunts ER stress and the consequent Unfolded Protein Response (UPR) while it rescues the diaphragmatic weakness by improving ER/mitochondria contacts, calcium dynamics, and OXPHOS. Importantly, treatments of SEPN1 knock out mice with the chemical chaperone tauroursodeoxycholic acid (TUDCA) mimic the results of ERO1 loss improving calcium dynamics, OXPHOS, ER/mitochondria contacts, thereby rescuing diaphragmatic weakness as well. In addition, TUDCA-treated SEPN1-RM patients-derived myoblasts show a dynamic dose-dependent increase in ATP levels under ER stress conditions suggesting improved mitochondrial function. Thus, our findings point to the ERO1 axis in the pathogenesis of SEPN1-RM thereby impinging on MAMs and mitochondria bioenergetics and recall for the efficacy of a pharmacology therapy with ad hoc ER stress/ERO1 inhibitors for SEPN1-RM.

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Nuclear MBL-1 modulates mitochondrial morphology through carnitine palmitoyltransferase in C. elegans with toxic trinucleotide repeats

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