Inherited mitochondrial DNA variants can affect complement, inflammation and apoptosis pathways: insights into mitochondrial-nuclear interactions
Inherited mitochondrial DNA variants can affect complement, inflammation and apoptosis pathways: insights into mitochondrial-nuclear interactions
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DOI：
10.1093/hmg/ddu065
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发表时间：
2014-07-01
影响因子：
3.5
通讯作者：
Udar, Nitin
中科院分区：
文献类型：
--
作者：
Kenney, M. Cristina;Chwa, Marilyn;Udar, Nitin
视网膜相关性黄斑变性（AMD）是发达国家视力丧失的主要原因。虽然与补体途径中的遗传多态性有关，但有许多具有高风险等位基因的个体不会发生AMD，这表明可能涉及其他“修饰剂”。线粒体（mt）单倍型群，定义为特定的mtDNA单核苷酸多态性（SNPs）的积累，代表人口的起源，可能是这样一个修改器。J单倍群与AMD的高风险相关，而H单倍群具有保护性。很难为单倍型群分配生物学后果，因此我们创造了人类ARPE-19胞质杂种（细胞质杂种），其具有相同的细胞核，但具有J或H单倍型群的线粒体，以研究它们对生物能量学和分子途径的影响。J型胞质杂交体与H型胞质杂交体相比具有改变的生物能量分布。Q-PCR分析显示，由mtDNA编码的7个呼吸复合体基因的表达水平显着降低。J和H胞质杂交体显著改变了替代补体、炎症和凋亡途径的8个核基因的表达。对所有胞质杂种进行整个mtDNA的测序，以鉴定单倍型群和非单倍型群定义的SNP。线粒体DNA可以调节细胞生物能量学和与补体、炎症和凋亡相关的核基因的表达水平。测序数据表明，观察到的影响是由于罕见的mtDNA变异，而是代表J与H单倍型组的SNP的组合。这些发现代表了我们对线粒体-核相互作用概念的范式转变。
Age-related macular degeneration (AMD) is the leading cause of vision loss in developed countries. While linked to genetic polymorphisms in the complement pathway, there are many individuals with high risk alleles that do not develop AMD, suggesting that other 'modifiers' may be involved. Mitochondrial (mt) haplogroups, defined by accumulations of specific mtDNA single nucleotide polymorphisms (SNPs) which represent population origins, may be one such modifier. J haplogroup has been associated with high risk for AMD while the H haplogroup is protective. It has been difficult to assign biological consequences for haplogroups so we created human ARPE-19 cybrids (cytoplasmic hybrids), which have identical nuclei but mitochondria of either J or H haplogroups, to investigate their effects upon bioenergetics and molecular pathways. J cybrids have altered bioenergetic profiles compared with H cybrids. Q-PCR analyses show significantly lower expression levels for seven respiratory complex genes encoded by mtDNA. J and H cybrids have significantly altered expression of eight nuclear genes of the alternative complement, inflammation and apoptosis pathways. Sequencing of the entire mtDNA was carried out for all the cybrids to identify haplogroup and non-haplogroup defining SNPs. mtDNA can mediate cellular bioenergetics and expression levels of nuclear genes related to complement, inflammation and apoptosis. Sequencing data suggest that observed effects are not due to rare mtDNA variants but rather the combination of SNPs representing the J versus H haplogroups. These findings represent a paradigm shift in our concepts of mt-nuclear interactions.