生物
线粒体DNA
物候学
遗传学
基因剔除小鼠
表型
线粒体
肾病
疾病
粒线体疾病
基因
病理
糖尿病
内分泌学
医学
作者
Adrián Sanz-Moreno,Oana V. Amarie,Raffaele Gerlini,Jelena Misic,Marie‐Lune Simard,Eckhard Wolf,Martin Hrabě de Angelis,Nils‐Göran Larsson
出处
期刊:PLOS Genetics
日期:2022-05-09
卷期号:18 (5): e1010190-e1010190
被引量:6
标识
DOI:10.1371/journal.pgen.1010190
摘要
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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