Friederich 2018 Nat Commun

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Friederich MW, Timal S, Powell CA, Dallabona C, Kurolap A, Palacios-Zambrano S, Bratkovic D, Derks TGJ, Bick D, Bouman K, Chatfield KC, Damouny-Naoum N, Dishop MK, Falik-Zaccai TC, Fares F, Fedida A, Ferrero I, Gallagher RC, Garesse R, Gilberti M, González C, Gowan K, Habib C, Halligan RK, Kalfon L, Knight K, Lefeber D, Mamblona L, Mandel H, Mory A, Ottoson J, Paperna T, Pruijn GJM, Rebelo-Guiomar PF, Saada A, Sainz B Jr, Salvemini H, Schoots MH, Smeitink JA, Szukszto MJ, Ter Horst HJ, van den Brandt F, van Spronsen FJ, Veltman JA, Wartchow E, Wintjes LT, Zohar Y, Fernández-Moreno MA, Baris HN, Donnini C, Minczuk M, Rodenburg RJ, Van Hove JLK (2018) Pathogenic variants in glutamyl-tRNAGln amidotransferase subunits cause a lethal mitochondrial cardiomyopathy disorder. Nat Commun 9:4065.

» PMID: 30283131 Open Access

Friederich MW, Timal S, Powell CA, Dallabona C, Kurolap A, Palacios-Zambrano S, Bratkovic D, Derks TGJ, Bick D, Bouman K, Chatfield KC, Damouny-Naoum N, Dishop MK, Falik-Zaccai TC, Fares F, Fedida A, Ferrero I, Gallagher RC, Garesse R, Gilberti M, Gonzalez C, Gowan K, Habib C, Halligan RK, Kalfon L, Knight K, Lefeber D, Mamblona L, Mandel H, Mory A, Ottoson J, Paperna T, Pruijn GJM, Rebelo-Guiomar PF, Saada A, Sainz B Jr, Salvemini H, Schoots MH, Smeitink JA, Szukszto MJ, Ter Horst HJ, van den Brandt F, van Spronsen FJ, Veltman JA, Wartchow E, Wintjes LT, Zohar Y, Fernandez-Moreno MA, Baris HN, Donnini C, Minczuk M, Rodenburg RJ, Van Hove JLK (2018) Nat Commun

Abstract: Mitochondrial protein synthesis requires charging mt-tRNAs with their cognate amino acids by mitochondrial aminoacyl-tRNA synthetases, with the exception of glutaminyl mt-tRNA (mt-tRNAGln). mt-tRNAGln is indirectly charged by a transamidation reaction involving the GatCAB aminoacyl-tRNA amidotransferase complex. Defects involving the mitochondrial protein synthesis machinery cause a broad spectrum of disorders, with often fatal outcome. Here, we describe nine patients from five families with genetic defects in a GatCAB complex subunit, including QRSL1, GATB, and GATC, each showing a lethal metabolic cardiomyopathy syndrome. Functional studies reveal combined respiratory chain enzyme deficiencies and mitochondrial dysfunction. Aminoacylation of mt-tRNAGln and mitochondrial protein translation are deficient in patients' fibroblasts cultured in the absence of glutamine but restore in high glutamine. Lentiviral rescue experiments and modeling in S. cerevisiae homologs confirm pathogenicity. Our study completes a decade of investigations on mitochondrial aminoacylation disorders, starting with DARS2 and ending with the GatCAB complex.


Bioblast editor: Plangger M O2k-Network Lab: US CO Denver Van Hove J, ES Madrid Garesse R, NL Nijmegen Rodenburg R


Labels: MiParea: Respiration, mtDNA;mt-genetics, nDNA;cell genetics, Patients  Pathology: Myopathy 

Organism: Human, Fungi  Tissue;cell: Fibroblast  Preparation: Permeabilized cells, Intact cells  Enzyme: Complex I, Complex II;succinate dehydrogenase, Complex III, Complex IV;cytochrome c oxidase, Complex V;ATP synthase 

Coupling state: ROUTINE, OXPHOS, ET  Pathway: N, S, CIV, NS, ROX  HRR: Oxygraph-2k 

2018-12