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Summary: The regulation of mitochondrial RNA life cycles and their roles in ribosome biogenesis and energy metabolism are not fully understood. We used CRISPR/Cas9 to generate heart- and skeletal-muscle-specific knockout mice of the pentatricopeptide repeat domain protein 1, PTCD1, and show that its loss leads to severe cardiomyopathy and premature death. Our detailed transcriptome-wide and functional analyses of these mice enabled us to identify the molecular role of PTCD1 as a 16S rRNA-binding protein essential for its stability, pseudouridylation, and correct biogenesis of the mitochondrial large ribosomal subunit. We show that impaired mitoribosome biogenesis can have retrograde signaling effects on nuclear gene expression through the transcriptional activation of the mTOR pathway and upregulation of cytoplasmic protein synthesis and pro-survival factors in the absence of mitochondrial translation. Taken together, our data show that impaired assembly of the mitoribosome exerts its consequences via differential regulation of mitochondrial and cytoplasmic protein synthesis. : Perks et al. engineered intron-exon boundaries using CRISPR/Cas9 to conditionally knock out Ptcd1 in mice. The RNA-binding protein PTCD1 is essential for heart function and regulates the stability and maturation of the 16S rRNA. PTCD1 is required for mitoribosome biogenesis, mitochondrial function, and coordinated nuclear transcription. Keywords: RNA, cardiomyopathy, regulatory RNAs, RNA-seq, mitochondrial ribosome, RNA-binding proteins, mitochondria, mitochondrial gene expression, ribosome biogenesis