Mice lacking the mitochondrial exonuclease MGME1 develop inflammatory kidney disease with glomerular dysfunction

Abstract

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.

The 5′-phosphate enhances the DNA-binding and exonuclease activities of human mitochondrial genome maintenance exonuclease 1 (MGME1)

“…The preference for a 5′-phosphate may be an important factor in regulating the activity of MGME1 to cooperate with the 3′–5′ exonuclease activity of pol γ in degrading linear mtDNA ( 32 ). In addition, MGME1 has also been proposed to remove flaps formed when mtDNA replication is reaching completion ( 20 , 23 ). The preferential processing of flaps from the 5′-end would facilitate the formation of ligatable ends, which are necessary for the completion of mtDNA replication.…”

“…The superfamily includes a variety of enzymes involved in DNA and RNA cleavage. MGME1 interacts with all three components (POLG, SSBP1, and TWNK) of the minimal mitochondrial replisome ( 18 , 19 ) and therefore is considered a component of the mitochondrial replication machinery ( 20 ). MGME1 has a documented role in maintaining 7S DNA ( 11 , 17 , 18 , 21 ).…”

The immune system as a driver of mitochondrial disease pathogenesis: a review of evidence

“…Similarly, the polymerase gamma (PolG) deficient 'mutator' mouse model of mtDNA instability has been shown to have aberrantly hyperactive innate immune responses, with type-I interferon responses contributing at significantly to the phenotype [120]. In a more recent third model of mtDNA instability, loss of the mitochondrial genome maintenance exonuclease Mgme1, which causes adult-onset mitochondrial disease in humans, results in severe autoimmune disease with prominent inflammatory renal disease [121]. Infiltrating T-and B-cells were present in these renal lesions, and elevated levels of circulating blood IL-6, TNFα, IL-10, and IL-2 indicating systemic inflammation.…”

Roles of Mitochondrial DNA Damage in Kidney Diseases: A New Biomarker

“…A decrease in mtDNA content was the main cause of reduced OXPHOS in chromophobe renal cancer (ChRCC) [ 96 ]. The latest study showed that mtDNA replication defects led to the formation of mtDNA linear deletion, which triggered an immune response and led to progressive kidney disease in aging animals [ 97 ].…”