Dysregulated Ribonucleoprotein Granules Impair Mitochondrial Function in RBM20-Related Dilated Cardiomyopathy.

Rbm20 gain-of-function variants mislocalize RBM20 to cytoplasmic ribonucleoprotein granules and impair mitochondrial function, linked to reduced soluble mitochondrial proteins and oxidative phosphorylation failure.

• Why it matters: RBM20 mislocalization is associated with more aggressive dilated cardiomyopathy, but how it leads to cardiac dysfunction is unclear, especially relative to splicing loss-of-function.
• What they did: Mouse models carrying Rbm20 GoF or loss-of-function variants were analyzed with proteomic profiling, protein solubility assays, mitochondrial respiration and calcium flux tests, and electron microscopy; human iPSC-derived cardioids validated variant-specific phenotypes.
• The result: GoF models showed posttranscriptional downregulation of soluble mitochondrial proteins, including TMEM65, reduced membrane protein solubility, enlarged mitochondria with cristae disorganization, and impaired oxidative phosphorylation and calcium handling; cardioids supported that cytoplasmic mislocalization, not splicing deficiency, drives mitochondrial dysfunction.

AI summary of the abstract · may contain errors · not medical advice · read the paper.