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

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. Overall design: Comparison of gene expression profiles between wild-type C. elegans (N2) and muscleblind splicing factor mutant mbl-1(tm1563) at different development stages – as L4s and as 2 days old adults. Comparison of gene expression profiles between C. elegans expressing RNAs with 123CUG repeats in the body wall muscle cells, and controls expressing 0CUGs. Two independent strains of each - 123CUG and 0CUG animals – were analyzed. Animals were analyzed at differential developmental stages: as L4s and as 2 days old adults.