How do human cells react to the absence of mitochondrial DNA?
How do human cells react to the absence of mitochondrial DNA?
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DOI：
10.1371/journal.pone.0005713
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发表时间：
2009-05-28
期刊：
影响因子：
3.7
通讯作者：
Tiranti V
中科院分区：
文献类型：
--
作者：
Mineri R;Pavelka N;Fernandez-Vizarra E;Ricciardi-Castagnoli P;Zeviani M;Tiranti V
线粒体的生物发生受两个不同的遗传系统控制：核基因组(NDNA)和线粒体基因组(MtDNA)。线粒体DNA是一个16.6kb的环状基因组，编码组成呼吸链的大约90个亚基中的13个，其余的由nDNA编码。真核细胞能够通过核基因表达的变化来监测和响应线粒体功能的变化，这种现象最初是在酵母中定义的，被称为逆行调节。为了研究线粒体DNA缺失对细胞转录组的影响，我们使用Affymetrix HG-U133A基因芯片阵列研究了线粒体DNA完全缺失的两个人类细胞系143BTK−和A549的基因表达谱，并将其与相应的未耗竭亲本细胞(ρ+细胞)的基因表达谱进行比较。我们的数据表明mtDNA的缺失与以下因素有关：i)细胞周期控制基因的下调和细胞复制率的降低；ii)呼吸链复合体III的核编码亚基的下调；以及iii)一个被描述为大肠杆菌ELAC2的人类同源基因的下调，该基因编码的蛋白质也以线粒体为靶标。我们的结果表明线粒体的生物发生和细胞周期控制之间有很强的相关性，并提示某些蛋白质可能具有双重作用：例如，控制细胞周期进程和线粒体的功能。此外，发现ELAC2和其他位于线粒体中的转录物在ρ°细胞中下调，使它们成为与线粒体DNA复制和表达缺陷相关的人类疾病的良好候选。
Mitochondrial biogenesis is under the control of two different genetic systems: the nuclear genome (nDNA) and the mitochondrial genome (mtDNA). The mtDNA is a circular genome of 16.6 kb encoding 13 of the approximately 90 subunits that form the respiratory chain, the remaining ones being encoded by the nDNA. Eukaryotic cells are able to monitor and respond to changes in mitochondrial function through alterations in nuclear gene expression, a phenomenon first defined in yeast and known as retrograde regulation. To investigate how the cellular transcriptome is modified in response to the absence of mtDNA, we used Affymetrix HG-U133A GeneChip arrays to study the gene expression profile of two human cell lines, 143BTK− and A549, which had been entirely depleted of mtDNA (ρ° cells), and compared it with that of corresponding undepleted parental cells (ρ+ cells). Our data indicate that absence of mtDNA is associated with: i) a down-regulation of cell cycle control genes and a reduction of cell replication rate, ii) a down-regulation of nuclear-encoded subunits of complex III of the respiratory chain and iii) a down-regulation of a gene described as the human homolog of ELAC2 of E. coli, which encodes a protein that we show to also target to the mitochondrial compartment. Our results indicate a strong correlation between mitochondrial biogenesis and cell cycle control and suggest that some proteins could have a double role: for instance in controlling both cell cycle progression and mitochondrial functions. In addition, the finding that ELAC2 and maybe other transcripts that are located into mitochondria, are down-regulated in ρ° cells, make them good candidates for human disorders associated with defective replication and expression of mtDNA.
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影响因子：
12.3
作者：
Gentleman RC;Carey VJ;Bates DM;Bolstad B;Dettling M;Dudoit S;Ellis B;Gautier L;Ge Y;Gentry J;Hornik K;Hothorn T;Huber W;Iacus S;Irizarry R;Leisch F;Li C;Maechler M;Rossini AJ;Sawitzki G;Smith C;Smyth G;Tierney L;Yang JY;Zhang J
通讯作者：
Zhang J
影响因子：
3.7
作者：
Kasashima, Katsumi;Sumitani, Megumi;Endo, Hitoshi
通讯作者：
Endo, Hitoshi
影响因子：
2.2
作者：
Castedo, M;Ferri, K;Kroemer, G
通讯作者：
Kroemer, G
影响因子：
--
作者：
Chen, Y;Beck, A;Tavtigian, SV
通讯作者：
Tavtigian, SV
影响因子：
9.2
作者：
Coates, PJ;Jamieson, DJ;Hall, PA
通讯作者：
Hall, PA