生殖細胞ミトコンドリアDNA変異のマクロファージにおける役割

抄録

Accumulation of mutated mitochondrial DNA (mtDNA) results in mitochondrial dysfunction. We have previously reported that accumulation of mtDNA mutation increases inflammasome-mediated innate immune response in vitro and in vivo. Emerging evidences suggest that accumulation of maternally-transmitted mtDNA (m-mtDNA) mutation contributes to aggravating ageing. Meanwhile it remains unclear whether m-mtDNA mutation affects immune function in offspring mice. We generated a series of inbred mutant mice by intercrossing of mice heterozygous for the mtDNA mutator allele (PolgAwt/mut), which can generate mice harboring m-mtDNA (PolgAwt1). Bone marrow-derived macrophages (BMDM) from the first generation (N1) of PolgAwt1 (PolgAwt1-N1) display ~1.4 times more mtDNA mutation than cells from the control mice (Polgwt0-N1). However, inflammasome activation in BMDM was comparable between the two groups. There were no significant differences on the number of mtDNA mutation as well as inflammasome activation between cells from PolgAwt1-N2 and PolgAwt0-N2. Although the number of mtDNA mutation in BMDM from PolgAwt1-N3 was comparable to PolgAwt0-N3, inflammasome activation was further increased in BMDM from PolgAwt1-N3, compared to PolgAwt0-N3. These results suggest that m-mtDNA mutation may have an immunomodulatory effect to offspring.