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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 <jats:italic>in vivo<\/jats:italic> function of MGME1 and the associated disease pathophysiology, we characterized a <jats:italic>Mgme1<\/jats:italic> mouse knockout model by extensive phenotyping of ageing knockout animals. We show that loss of MGME1 leads to <jats:italic>de novo<\/jats:italic> 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 <jats:italic>Mgme1<\/jats:italic> 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.<\/jats:p>","DOI":"10.1371\/journal.pgen.1010190","type":"journal-article","created":{"date-parts":[[2022,5,9]],"date-time":"2022-05-09T17:45:24Z","timestamp":1652118324000},"page":"e1010190","update-policy":"https:\/\/doi.org\/10.1371\/journal.pgen.corrections_policy","source":"Crossref","is-referenced-by-count":19,"title":["Mice lacking the mitochondrial exonuclease MGME1 develop inflammatory kidney disease with glomerular 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