Mismatch between mtDNA and nuclear DNA determines metabolism and healthy aging

We postulate here that the two singular characteristics of the mitochondrial oxidative phosphorylation system--the integration of three potentially antagonistic functions in the same structure and the double genetic origin of the components that assemble together in these molecular machines--make the evolution of an optimal system impossible. As a consequence the system is intrinsically mismatched and has to be continuously monitored, adjusted and regulated in order to achieve the necessary and variable performance. Systematic transcriptomic, metabolomic and biochemical evaluation of animals with identical nuclear DNA but different mtDNA haplotype strongly support the existence of intrinsic mismatch and reveals profound lifelong metabolic consequences on reactive oxygen species generation, insulin signaling, tendency towards obesity, and healthy ageing parameters, including telomere atresia. Transcriptome analysis of conplastic mice versus WT mice in Liver and Heart tissues. Conplastic strains were obtained after 10 generations of backcrossing to create a new line harboring the nuclear genome of one strain and the mtDNA of another (C57BL/6 and NZB were purchased from Harlan Laboratories).本研究提出，线粒体氧化磷酸化系统（mitochondrial oxidative phosphorylation system）具备两项独特特征：一是在同一结构中整合了三种潜在拮抗的功能，二是组装为该分子机器的组分拥有双重遗传起源，这使得最优系统的演化无从实现。因此该系统存在内在的不匹配性，必须持续进行监测、调整与调控，方能达成所需且可变的性能表现。对核DNA一致但线粒体DNA（mtDNA）单倍型不同的动物开展系统性转录组学、代谢组学与生化评估，有力佐证了内在不匹配现象的存在，并揭示了其对活性氧生成、胰岛素信号通路、肥胖易感性以及包括端粒闭锁在内的健康衰老相关参数的终身深远代谢影响。本研究针对肝脏与心脏组织中的同核异线粒体小鼠（conplastic mice）与野生型（Wild Type）小鼠开展了转录组分析。同核异线粒体品系通过10代回交构建获得，所得新品系携带来自一个品系的核基因组与另一个品系的线粒体DNA（mtDNA）（C57BL/6与NZB品系购自Harlan Laboratories公司）。