3月4日出版的《自然—遺傳學(xué)》發(fā)表了一項(xiàng)關(guān)于衰老機(jī)制的最新研究成果,，即超出正常水平500倍的線粒體DNA點(diǎn)突變不會導(dǎo)致小鼠產(chǎn)生早熟或衰老的跡象,。該結(jié)論與此前線粒體突變促進(jìn)衰老的理論相矛盾,。
該研究支持了線粒體DNA突變的積累與衰老有關(guān)但不是絕對因果關(guān)系的觀點(diǎn),，而此前的衰老理論表明,，突變最終將導(dǎo)致組織功能的衰弱和老化,。
在該項(xiàng)研究中,，美國華盛頓大學(xué)Marc Vermulst和同事利用一種改良的隨機(jī)突變捕獲（Random Mutation Capture,，簡稱RMC）技術(shù)對單個分子進(jìn)行放大探測,，從而對線粒體DNA突變積累進(jìn)行研究。
研究人員發(fā)現(xiàn),，小鼠線粒體突變頻率比此前的研究結(jié)果低10倍,，這表明早先的工作可能過分高估了突變發(fā)生率。
研究人員將野生小鼠與反常的高線粒體突變水平的“突變”鼠進(jìn)行了對比,，結(jié)果發(fā)現(xiàn),，純合子突變基因小鼠比野生鼠線粒體突變頻率高2500倍，同時,，這些小鼠表現(xiàn)出了壽命減少和早熟等衰老現(xiàn)象,。然而，雜合子突變基因小鼠不會表現(xiàn)出提前衰老的信號,，盡管它們的線粒體突變頻率比野生鼠高500倍,。
Vermulst表示，純合子動物線粒體突變超出了一個臨界值,，因此突變會導(dǎo)致早熟和衰老,；而雜合子動物突變頻率盡管也很高，但低于該臨界值,，不會提前衰老,；至于突變率更小的野生動物，或許永遠(yuǎn)不可能積累足夠的能導(dǎo)致衰老的突變,。
有專家認(rèn)為,，由于該研究僅僅針對點(diǎn)突變，大規(guī)模的線粒體DNA缺失仍可能導(dǎo)致衰老。同時,，“突變”鼠早在胚胎發(fā)育時期就開始積累突變,，而正常動物是在出生后才開始，因此,，“突變”鼠可能不是一個理想的模型,。美國圣路易斯大學(xué)的Peter Zassenhaus表示，“‘突變’鼠胚胎細(xì)胞有可能找到了一種方法,，來適應(yīng)成年動物無法忍受的突變……我們需要弄清楚線粒體突變影響組織功能的具體機(jī)制,。”此外,，“突變”鼠有線粒體DNA聚合酶缺陷,，因此它們的突變類型也會對結(jié)論產(chǎn)生影響。
盡管該研究結(jié)論在點(diǎn)突變方面為先前的衰老理論“出了難題”,，但是由于各種特定因素,，該結(jié)論還無法構(gòu)成實(shí)質(zhì)性的挑戰(zhàn)。
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.
