title: Loss of the mitochondrial protein-only ribonuclease P complex causes aberrant tRNA processing and lethality in Drosophila.
abstract: Proteins encoded by mitochondrial DNA are translated using mitochondrially encoded tRNAs and rRNAs. As with nuclear encoded tRNAs, mitochondrial tRNAs must be processed to become fully functional. The mitochondrial form of ribonuclease P (mt:RNase P) is responsible for 5'-end maturation and is comprised of three proteins; mitochondrial RNase P protein (MRPP) 1 and 2 together with proteinaceous RNase P (PRORP). However, its mechanism and impact on development is not yet known. Using homology searches, we have identified the three proteins composing Drosophila mt:RNase P: Mulder (PRORP), Scully (MRPP2) and Roswell (MRPP1). Here, we show that each protein is essential and localizes with mitochondria. Furthermore, reducing levels of each causes mitochondrial deficits, which appear to be due at least in part to defective mitochondrial tRNA processing. Overexpressing two members of the complex, Mulder and Roswell, is also lethal, and in the case of Mulder, causes abnormal mitochondrial morphology. These data are the first evidence that defective mt:RNase P causes mitochondrial dysfunction, lethality and aberrant mitochondrial tRNA processing in vivo, underscoring its physiological importance. This in vivo mt:RNase P model will advance our understanding of how loss of mitochondrial tRNA processing causes tissue failure, an important aspect of human mitochondrial disease.
authors.affiliation: Department of Biochemistry and Molecular Biology, Uniformed Services University, Bethesda, MD, 20814, USA.
authors.forename: Aditya
authors.initials: A
authors.lastname: Sen
authors.affiliation: Department of Biochemistry and Molecular Biology, Uniformed Services University, Bethesda, MD, 20814, USA.
authors.forename: Agnes
authors.initials: A
authors.lastname: Karasik
authors.affiliation: Department of Biochemistry and Molecular Biology, Uniformed Services University, Bethesda, MD, 20814, USA.
authors.forename: Aranganathan
authors.initials: A
authors.lastname: Shanmuganathan
authors.affiliation: Walt Whitman High School, Bethesda, MD, 20817, USA.
authors.forename: Elena
authors.initials: E
authors.lastname: Mirkovic
authors.affiliation: Department of Biochemistry and Molecular Biology, Uniformed Services University, Bethesda, MD, 20814, USA markos.koutmos@usuhs.edu.
authors.forename: Markos
authors.initials: M
authors.lastname: Koutmos
authors.affiliation: Department of Biochemistry and Molecular Biology, Uniformed Services University, Bethesda, MD, 20814, USA rachel.cox@usuhs.edu.
authors.forename: Rachel T
authors.initials: RT
authors.lastname: Cox
mesh_terms: D015094:3-Hydroxyacyl CoA Dehydrogenases / Q000235:genetics*; D000818:Animals; D004272:DNA, Mitochondrial / Q000235:genetics*; D004330:Drosophila / Q000235:genetics; D029721:Drosophila Proteins / Q000235:genetics*; D005786:Gene Expression Regulation; D006801:Humans; D008928:Mitochondria / Q000235:genetics / Q000473:pathology; D024101:Mitochondrial Proteins / Q000235:genetics*; D012343:RNA, Transfer / Q000235:genetics; D043262:Ribonuclease P / Q000235:genetics*; D000072020:Synthetic Lethal Mutations / Q000235:genetics
chemical_list: D004272:DNA, Mitochondrial; D029721:Drosophila Proteins; D024101:Mitochondrial Proteins; C000620158:Mldr protein, Drosophila; C000620157:Rswl protein, Drosophila; D012343:RNA, Transfer; D015094:3-Hydroxyacyl CoA Dehydrogenases; C112473:scu protein, Drosophila; D043262:Ribonuclease P