Pathogenic PTCD1 variants cause mitochondrial protein aggregation and cardiomyopathy
Disorders of mitochondrial oxidative phosphorylation affecting multiple respiratory chain complexes are among the most common causes of mitochondrial disease in humans. However, impaired energy metabolism alone does not fully account for tissue-specific vulnerability and disease progression, suggesting that additional molecular mechanisms contribute to disease pathology. We previously identified PTCD1 variants in a child with infantile cardiomyopathy associated with a combined respiratory chain deficiency. Here, we establish the pathogenicity of three PTCD1 (NM_015545.4) variants in which p.(Arg113Trp) and p.(Gly184Arg) segregate in cis whereas p.(Arg130*) is present in trans, demonstrating that disrupted mitochondrial proteostasis contributes to tissue damage in PTCD1 deficiency. PTCD1 patient cardiac tissue characterisation revealed impaired mitoribosome biogenesis, alongside increased aggregation of selective mitochondrial matrix proteins. Cell models expressing individual and combined PTCD1 missense variants, coupled with proteomics, recapitulated the protein aggregation, with the cis p.(Arg113Trp);p.(Gly184Arg) combination showing the most severe effect. Protein aggregation was accompanied by altered OPA1 processing and mitochondrial network remodelling. Our findings establish accumulating proteotoxic stress arising from impaired mitoribosome assembly as a pathogenic mechanism in post-mitotic tissues, driving PTCD1 cardiomyopathy.