摘要
线粒体作为细胞有氧呼吸的主要场所,是为细胞供能的细胞器,具有一套独立于核DNA的遗传物质,即线粒体DNA(mitochondrial DNA, mtDNA). mtDNA编码了37个基因,包括13个呼吸链相关的多肽、22种t RNA以及2种rRNA基因.线粒体异常可直接导致细胞三磷酸腺苷(adenosine triphosphate, ATP)合成减少、细胞能量不足. mtDNA拷贝数及表观遗传的调控对于线粒体行使基本功能至关重要.环境污染物进入生物体内后诱导产生大量活性氧(reactive oxygen species, ROS),造成生物体氧化应激反应,从而引发代谢异常,进而诱发各种疾病.因为靠近氧化磷酸化(oxidative phosphorylation, OXPHOS)发生的场所,并且缺乏组蛋白的保护和足够的DNA损伤修复能力,与核DNA相比, mtDNA更容易受到氧化应激反应的影响.而多种环境污染物暴露可引发过多的活性氧活动,进而可导致mtDNA拷贝数及mtDNA表观遗传修饰的改变. mtDNA异常也正在作为一种可能的环境污染物暴露后的生物标志物,受到越来越多的研究关注.本文简要介绍了mtDNA拷贝数、mtDNA可能的表观遗传修饰以及相关调控机制,并总结了各种类型环境污染物暴露引起mtDNA拷贝数和甲基化变化的研究结果,同时对如何深入研究环境污染物影响mtDNA及分子机制进行了展望.
Mitochondria, as the main site of cellular aerobic respiration, are organelles that provide energy for cells. The mitochondrial genomes are independent of the nuclear genome, known as mitochondrial DNA(mtDNA). mtDNA encodes 37 genes, including 13 respiratory chain-related polypeptides, 22 tRNAs and 2 rRNA genes. Mitochondrial abnormalities can directly reduce cellular ATP synthesis and thus generate insufficient cellular energy. The regulation of mtDNA copy number and epigenetics is crucial for the basic functions of mitochondria. After entering the cells of organisms, environmental pollutants elevate reactive oxygen species(ROS), causing oxidative stress in the organism and resulting in abnormal metabolism and various diseases. Compared with nuclear DNA, mtDNA is more susceptible to oxidative stress because of its proximity to the site of oxidative phosphorylation(OXPHOS) and lack of histone protection and sufficient DNA damage repair capacity. Exposure to various environmental pollutants can induce excessive accumulation of ROS, which leads to changes in mtDNA copy number and epigenetic modifications of mtDNA. An increasing number of studies focus on abnormal mtDNA as a possible biomarker for the exposure and toxicity of environmental pollutants.In this review, we briefly introduce the physiological functions and regulatory mechanisms of mitochondria and mtDNA copy number. Environment pollutant exposures often cause mitochondrial damage, which may alter mtDNA copy number, leading to mitochondrial abnormalities and impairing cell function. Studies have found that mitochondrial dysfunction is related to the occurrence and development of various diseases(e.g., cancer, diabetes, cardiovascular disease, neurodegenerative diseases, etc.).Noteworthily, decreased mtDNA copy number in germ cells blocks embryonic development. Next, along with the associated proteins found in recent studies, possible epigenetic modifications present on mtDNA(e.g., 5-methylcytosine, 5-hydroxymethylcytosine and N~6-methyladenine) are also summarized. A study identified mtDNMT1 in the mitochondrial matrix, which was suggested to be a methyltransferase for mtDNA 5mC. Since 5hmC modification on mtDNA was first reported in 2011, the results of studies on mtDNA 5hmC have been conflicting. However, some research groups found that Tet1 and Tet2 may be involved in the formation of mtDNA 5hmC. A higher level of 6mA modification than nuclear DNA was suggested to be detected in mtDNA, and the METTL4 protein is a potential mtDNA 6mA methyltransferase.Nonetheless, the study on mtDNA methylation is of intensive interest.We reviewed the effects of multiple common environmental pollutants(e.g., PM, black carbon, nicotine, heavy metal particles,etc.) on mitochondrial DNA from two aspects:(1) Environmental pollutants exposure causes mtDNA copy number changes,which may increase disease risk;(2) environmental pollutant exposure alters methylation levels of certain genes in mtDNA. In the first aspect, exposure to different pollutants, or even the same pollutant, resulted in different changes in mtDNA copy number. It suggests that the same environmental pollutants may also affect mtDNA copy number through different mechanisms and pathways. In the second aspect, changes in the methylation levels of D-loop and gene regions on mtDNA caused by pollutant exposure can affect mitochondrial physiological function by affecting mitochondrial DNA replication and mitochondrial-encoded protein expression.We prospect and discuss how to perform further study on the effect of environmental pollutants on mtDNA and its molecular mechanism. The following two aspects should be improved in future pollutants-mtDNA studies:(1) Develop more convenient methods for the extraction of mtDNA from less than million cells to a high purity. This will facilitate the detection and sequencing of mtDNA for diverse purposes;(2) to achieve accurate identification of mtDNA methylation sites in small number of cells and eliminate the interference of mtDNA heterogeneity, the mtDNA methylation sequencing method should be further innovated.
作者
郑婧
刘艳
汪海林
Jing Zheng;Yan Liu;Hailin Wang(State Key Laboratory of Environmental Chemistry and Ecotoxicology,Research Center for Eco-Environmental Sciences,Chinese Academy of Sciences,Beijing 100085,China;University of Chinese Academy of Sciences,Beijing 100049,China)
出处
《科学通报》
EI
CAS
CSCD
北大核心
2022年第35期4170-4179,共10页
Chinese Science Bulletin
基金
国家自然科学基金(22021003)资助。
