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Milenkovic, D.* ; Sanz-Moreno, A. ; Calzada-Wack, J. ; Rathkolb, B. ; Amarie, O.V. ; Gerlini, R. ; Aguilar-Pimentel, J.A. ; Misic, J.* ; Simard, M.L.* ; Wolf, E.* ; Fuchs, H. ; Gailus-Durner, V. ; Hrabě de Angelis, M. ; Larsson, N.-G.*

Mice lacking the mitochondrial exonuclease MGME1 develop inflammatory kidney disease with glomerular dysfunction.

PLoS Genet. 18:e1010190 (2022)
Verlagsversion Forschungsdaten DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
Mitochondrial DNA (mtDNA) maintenance disorders are caused by mutations in ubiquitously expressed nuclear genes and lead to syndromes with variable disease severity and tissue-specific phenotypes. Loss of function mutations in the gene encoding the mitochondrial genome and maintenance exonuclease 1 (MGME1) result in deletions and depletion of mtDNA leading to adult-onset multisystem mitochondrial disease in humans. To better understand the in vivo function of MGME1 and the associated disease pathophysiology, we characterized a Mgme1 mouse knockout model by extensive phenotyping of ageing knockout animals. We show that loss of MGME1 leads to de novo formation of linear deleted mtDNA fragments that are constantly made and degraded. These findings contradict previous proposal that MGME1 is essential for degradation of linear mtDNA fragments and instead support a model where MGME1 has a critical role in completion of mtDNA replication. We report that Mgme1 knockout mice develop a dramatic phenotype as they age and display progressive weight loss, cataract and retinopathy. Surprisingly, aged animals also develop kidney inflammation, glomerular changes and severe chronic progressive nephropathy, consistent with nephrotic syndrome. These findings link the faulty mtDNA synthesis to severe inflammatory disease and thus show that defective mtDNA replication can trigger an immune response that causes age-associated progressive pathology in the kidney.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
ISSN (print) / ISBN 1553-7390
e-ISSN 1553-7404
Zeitschrift PLoS Genetics
Quellenangaben Band: 18, Heft: 5, Seiten: , Artikelnummer: e1010190 Supplement: ,
Verlag Public Library of Science (PLoS)
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Experimental Genetics (IEG)
Förderungen German Center for Diabetes Research (DZD)
German Federal Ministry of Education and Research
Diabetesfonden
Knut and Alice Wallenberg Foundation
Novo Nordisk Foundation
European Research Council
Swedish Cancer Foundation
Swedish Research Council