Perks 2018 Cell Rep

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Perks KL, Rossetti G, Kuznetsova I, Hughes LA, Ermer JA, Ferreira N, Busch JD, Rudler DL, Spahr H, Schöndorf T, Shearwood AJ, Viola HM, Siira SJ, Hool LC, Milenkovic D, Larsson NG, Rackham O, Filipovska A (2018) PTCD1 is required for 16S rRNA maturation complex stability and mitochondrial ribosome assembly. Cell Rep 23:127-42.

» PMID: 29617655 Open Access

Perks KL, Rossetti G, Kuznetsova I, Hughes LA, Ermer JA, Ferreira N, Busch JD, Rudler DL, Spahr H, Schoendorf T, Shearwood AJ, Viola HM, Siira SJ, Hool LC, Milenkovic D, Larsson NG, Rackham O, Filipovska A (2018) Cell Rep

Abstract: 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.

Keywords: RNA, RNA-binding proteins, RNA-seq, cardiomyopathy, Mitochondria, Mitochondrial gene expression, Mitochondrial ribosome, Regulatory RNAs, Ribosome biogenesis Bioblast editor: Kandolf G O2k-Network Lab: AU Perth Filipovska A, DE Cologne Larsson NG


Labels: MiParea: Respiration, mt-Biogenesis;mt-density, Genetic knockout;overexpression 


Organism: Mouse  Tissue;cell: Heart  Preparation: Isolated mitochondria  Enzyme: Complex I, Complex II;succinate dehydrogenase, Complex III, Complex IV;cytochrome c oxidase, Complex V;ATP synthase 

Coupling state: LEAK, OXPHOS, ET  Pathway: N, S, Gp  HRR: Oxygraph-2k 

2018-05