부산대학교 도서관

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. Author summary: We have addressed the controversy of the role of the mitochondrial genome and maintenance exonuclease 1 (MGME1) in mtDNA metabolism by characterization of knockout mice. Our findings show that loss of MGME1 leads to increased de novo formation of linear deleted mtDNA, thus contradicting previous report that MGME1 degrades long linear mtDNA molecules. In addition, we report that loss of MGME1 leads to age-associated pathology manifested as progressive weight loss, cataract and retinopathy. Aged knockout mice also develop kidney inflammation leading to glomerular changes, fibrosis and nephrotic syndrome. Defective mtDNA replication causing the formation of linear deleted mtDNA can thus trigger an immune response that leads to the development of progressive kidney disease in ageing animals. [ABSTRACT FROM AUTHOR]