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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)

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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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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

ISSN (print) / ISBN 1553-7390

e-ISSN 1553-7404

Journal PLoS Genetics

Quellenangaben Volume: 18, Issue: 5, Article Number: e1010190

Publisher Public Library of Science (PLoS)

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute of Experimental Genetics (IEG)

Grants 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