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• Pathogenic RBM20 gain-of-function variants mislocalize to cytoplasmic ribonucleoprotein granules, disrupting mitochondrial protein homeostasis.
• This mislocalization causes reduced mitochondrial protein abundance, cristae disorganization, and impaired mitochondrial respiration.
• Loss-of-function RBM20 variants cause splicing defects but do not impair mitochondrial function to the same extent.
• These findings elucidate a distinct mechanism for the aggressive phenotype in RBM20-related dilated cardiomyopathy (DCM) and identify mitochondrial mRNA/protein regulation as a therapeutic target.
