St John Justin C
Centre for Genetic Diseases, Hudson Institute of Medical Research, and the Department of Molecular and Translational Science, Monash University, 27-31 Wright Street, Clayton, VIC 3168, Australia.
Semin Cell Dev Biol. 2016 Apr;52:93-101. doi: 10.1016/j.semcdb.2016.01.028. Epub 2016 Jan 28.
Until recently, it was thought that the role of the mitochondrial genome was confined to encoding key proteins that generate ATP through the process of oxidative phosphorylation in the electron transfer chain. However, with increasing new evidence, it is apparent that the mitochondrial genome has a major role to play in a number of diseases and phenotypes. For example, mitochondrial variants and copy number have been implicated in the processes of fertilisation outcome and development and the onset of tumorigenesis. On the other hand, mitochondrial DNA (mtDNA) haplotypes have been implicated in a variety of diseases and most likely account for the adaptation that our ancestors achieved in order that they were fit for their environments. The mechanisms, which enable the mitochondrial genome to either protect or promote the disease phenotype, require further elucidation. However, there appears to be significant 'crosstalk' between the chromosomal and mitochondrial genomes that enable this to take place. One such mechanism is the regulation of DNA methylation by mitochondrial DNA, which is often perturbed in reprogrammed cells that have undergone dedifferentiation and affects mitochondrial DNA copy number. Furthermore, it appears that the mitochondrial genome interacts with the chromosomal genome to regulate the transcription of key genes at certain stages during development. Additionally, the mitochondrial genome can accumulate a series of mtDNA variants, which can lead to diseases such as cancer. It is likely that a combination of certain mitochondrial variants and aberrant patterns of mtDNA copy number could indeed account for many diseases that have previously been unaccounted for. This review focuses on the role that the mitochondrial genome plays especially during early stages of development and in cancer.
直到最近，人们还认为线粒体基因组的作用仅限于编码关键蛋白质，这些蛋白质通过电子传递链中的氧化磷酸化过程产生三磷酸腺苷（ATP）。然而，随着越来越多新证据的出现，很明显线粒体基因组在许多疾病和表型中发挥着重要作用。例如，线粒体变异和拷贝数与受精结果、发育过程以及肿瘤发生的起始有关。另一方面，线粒体DNA（mtDNA）单倍型与多种疾病有关，很可能解释了我们的祖先为适应环境而实现的适应性变化。线粒体基因组能够保护或促进疾病表型的机制，还需要进一步阐明。然而，染色体基因组和线粒体基因组之间似乎存在显著的“串扰”，使得这种情况得以发生。一种这样的机制是线粒体DNA对DNA甲基化的调控，这在经历去分化的重编程细胞中经常受到干扰，并影响线粒体DNA拷贝数。此外，线粒体基因组似乎在发育的某些阶段与染色体基因组相互作用，以调控关键基因的转录。此外，线粒体基因组可以积累一系列mtDNA变异，这可能导致癌症等疾病。某些线粒体变异和异常的mtDNA拷贝数模式的组合很可能确实可以解释许多以前无法解释的疾病。这篇综述重点关注线粒体基因组特别是在发育早期和癌症中所起的作用。
