Preferential amplification of a human mitochondrial DNA deletion in vitro and in vivo.
Preferential amplification of a human mitochondrial DNA deletion in vitro and in vivo.
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DOI：
10.1038/s41598-018-20064-2
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发表时间：
2018-01-29
影响因子：
4.6
通讯作者：
Helliwell SB
中科院分区：
文献类型：
--
作者：
Russell OM;Fruh I;Rai PK;Marcellin D;Doll T;Reeve A;Germain M;Bastien J;Rygiel KA;Cerino R;Sailer AW;Lako M;Taylor RW;Mueller M;Lightowlers RN;Turnbull DM;Helliwell SB
我们从患者成纤维细胞中诱导出多能干细胞(IPSC)，以产生含有不同程度异质性的细胞系，其中m.13514 A >； G线粒体DNA点突变(2株)和~6 kb单一大规模线粒体DNA缺失(3株)。对含有单一大规模mtDNA缺失的iPSCs进行长期培养，发现mtDNA缺失水平随着时间的推移而持续增加。线粒体DNA异质性水平较高与呼吸衰竭增加相关。为了确定在分化过程中缺失水平发生了什么变化，从低(20%)和中等异质性(55%)mtDNA缺失克隆中产生了包含所有三个胚层的畸胎瘤。无论使用的是含有低或中等mtDNA异质性的IPSCs，所有畸胎瘤生殖层中的异质性最终水平都增加到类似的高水平(>；60%)。因此，在人类干细胞分裂过程中，细胞不仅耐受高mtDNA缺失量，而且似乎优先复制缺失的mtDNA基因组。这意味着线粒体DNA缺失与疾病和衰老有关。
We generated induced pluripotent stem cells (iPSCs) from patient fibroblasts to yield cell lines containing varying degrees of heteroplasmy for a m.13514 A > G mtDNA point mutation (2 lines) and for a ~6 kb single, large scale mtDNA deletion (3 lines). Long term culture of the iPSCs containing a single, large-scale mtDNA deletion showed consistent increase in mtDNA deletion levels with time. Higher levels of mtDNA heteroplasmy correlated with increased respiratory deficiency. To determine what changes occurred in deletion level during differentiation, teratomas comprising all three embryonic germ layers were generated from low (20%) and intermediate heteroplasmy (55%) mtDNA deletion clones. Regardless of whether iPSCs harbouring low or intermediate mtDNA heteroplasmy were used, the final levels of heteroplasmy in all teratoma germ layers increased to a similar high level (>60%). Thus, during human stem cell division, cells not only tolerate high mtDNA deletion loads but seem to preferentially replicate deleted mtDNA genomes. This has implications for the involvement of mtDNA deletions in both disease and ageing.
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