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.