3月4日出版的《自然—遗传学》发表了一项关于衰老机制的最新研究成果，即超出正常水平500倍的线粒体DNA点突变不会导致小鼠产生早熟或衰老的迹象。该结论与此前线粒体突变促进衰老的理论相矛盾。
该研究支持了线粒体DNA突变的积累与衰老有关但不是绝对因果关系的观点，而此前的衰老理论表明，突变最终将导致组织功能的衰弱和老化。
在该项研究中，美国华盛顿大学Marc Vermulst和同事利用一种改良的随机突变捕获（Random Mutation Capture，简称RMC）技术对单个分子进行放大探测，从而对线粒体DNA突变积累进行研究。
研究人员发现，小鼠线粒体突变频率比此前的研究结果低10倍，这表明早先的工作可能过分高估了突变发生率。
研究人员将野生小鼠与反常的高线粒体突变水平的“突变”鼠进行了对比，结果发现，纯合子突变基因小鼠比野生鼠线粒体突变频率高2500倍，同时，这些小鼠表现出了寿命减少和早熟等衰老现象。然而，杂合子突变基因小鼠不会表现出提前衰老的信号，尽管它们的线粒体突变频率比野生鼠高500倍。
Vermulst表示，纯合子动物线粒体突变超出了一个临界值，因此突变会导致早熟和衰老；而杂合子动物突变频率尽管也很高，但低于该临界值，不会提前衰老；至于突变率更小的野生动物，或许永远不可能积累足够的能导致衰老的突变。
有专家认为，由于该研究仅仅针对点突变，大规模的线粒体DNA缺失仍可能导致衰老。同时，“突变”鼠早在胚胎发育时期就开始积累突变，而正常动物是在出生后才开始，因此，“突变”鼠可能不是一个理想的模型。美国圣路易斯大学的Peter Zassenhaus表示，“‘突变’鼠胚胎细胞有可能找到了一种方法，来适应成年动物无法忍受的突变……我们需要弄清楚线粒体突变影响组织功能的具体机制。”此外，“突变”鼠有线粒体DNA聚合酶缺陷，因此它们的突变类型也会对结论产生影响。
尽管该研究结论在点突变方面为先前的衰老理论“出了难题”，但是由于各种特定因素，该结论还无法构成实质性的挑战。
部分英文原文：
Nature Genetics - 39, 386 - 390 (2007)
Published online: 11 February 2007; | doi:10.1038/ng1970
The mitochondrial bottleneck occurs without reduction of mtDNA content in female mouse germ cells
Liqin Cao1, 2, 6, Hiroshi Shitara1, 6, Takuro Horii3, Yasumitsu Nagao3, Hiroshi Imai3, Kuniya Abe4, Takahiko Hara5, Jun-Ichi Hayashi2 & Hiromichi Yonekawa1
1 Department of Laboratory Animal Science, Tokyo Metropolitan Institute of Medical Science, Tokyo 113-8613, Japan.
2 Graduate School of Life and Environmental Sciences, University of Tsukuba, Ibaraki 305-8572, Japan.
3 Laboratory of Reproductive Biology, Graduate School of Agriculture, Kyoto University, Kyoto 606-8502, Japan.
4 Technology and Development Team for Mammalian Cellular Dynamics, BioResource Center (BRC), RIKEN Tsukuba Institute, Ibaraki, 305-0074, Japan.
5 Stem Cell Project Group, Tokyo Metropolitan Institute of Medical Science, Tokyo 113-8613, Japan.
6 These authors contributed equally to this work.
Correspondence should be addressed to Hiromichi Yonekawa yonekawa@rinshoken.or.jp
Observations of rapid shifts in mitochondrial DNA (mtDNA) variants between generations prompted the creation of the bottleneck theory. A prevalent hypothesis is that a massive reduction in mtDNA content during early oogenesis leads to the bottleneck1, 2. To test this, we estimated the mtDNA copy number in single germline cells and in single somatic cells of early embryos in mice. Primordial germ cells (PGCs) show consistent, moderate mtDNA copy numbers across developmental stages, whereas primary oocytes demonstrate substantial mtDNA expansion during early oocyte maturation. Some somatic cells possess a very low mtDNA copy number. We also demonstrated that PGCs have more than 100 mitochondria per cell. We conclude that the mitochondrial bottleneck is not due to a drastic decline in mtDNA copy number in early oogenesis but rather to a small effective number of segregation units for mtDNA in mouse germ cells. These results provide new information for mtDNA segregation models and for understanding the recurrence risks for mtDNA diseases.
