Manczak Maria, Sesaki Hiromi, Kageyama Yusuke, Reddy P Hemachandra
Neurogenetics Laboratory, Neuroscience Division, Oregon National Primate Research Center, Oregon Health & Science University, 505 NW 185th Avenue, Beaverton, OR 97006, USA.
Biochim Biophys Acta. 2012 Jun;1822(6):862-74. doi: 10.1016/j.bbadis.2012.02.017. Epub 2012 Feb 23.
The objective of this study was to elucidate the effect of partial reduction of the mitochondrial fission protein, dynamin-related protein 1 (Drp1) on mitochondrial activity and synaptic viability. Recent knockout studies of Drp1 revealed that homozygote Drp1 knockout mice are embryonic lethal due to reduced mitochondrial fission, and that this reduced fission leads to developmental defects in the brain. In contrast, heterozygote Drp1 knockout mice appear to be normal in terms of lifespan, fertility, and viability, and phenotypically these animals are not different from wild-type mice. However, the effects of partial Drp1 reduction on mitochondrial function and synaptic activity are not well understood. In the present study, we sought to characterize synaptic, dendritic and mitochondrial proteins, and mitochondrial function and GTPase enzymatic activity, in Drp1 heterozygote knockout mice. Interestingly, we found no significant changes in synaptic, dendritic, and mitochondrial proteins in the Drp1 heterozygote knockout mice compared to the wild-type mice. Further, mitochondrial function and GTPase enzymatic activity appeared to be normal. However, H(2)O(2) and lipid peroxidation levels were significantly reduced in the Drp1 heterozygote knockout mice compared to the wild-type mice. These findings suggest that partial Drp1 reduction does not affect mitochondrial and synaptic viability and may have therapeutic use in treating patients with Alzheimer's disease and Huntington's disease.
本研究的目的是阐明线粒体分裂蛋白——动力相关蛋白1（Drp1）部分减少对线粒体活性和突触活力的影响。最近对Drp1的基因敲除研究表明，纯合子Drp1基因敲除小鼠由于线粒体分裂减少而胚胎致死，且这种减少的分裂会导致大脑发育缺陷。相比之下，杂合子Drp1基因敲除小鼠在寿命、生育能力和活力方面似乎正常，并且在表型上这些动物与野生型小鼠没有差异。然而，Drp1部分减少对线粒体功能和突触活性的影响尚未得到充分了解。在本研究中，我们试图对Drp1杂合子基因敲除小鼠的突触、树突和线粒体蛋白以及线粒体功能和GTP酶活性进行表征。有趣的是，与野生型小鼠相比，我们发现Drp1杂合子基因敲除小鼠的突触、树突和线粒体蛋白没有显著变化。此外，线粒体功能和GTP酶活性似乎正常。然而，与野生型小鼠相比，Drp1杂合子基因敲除小鼠中的过氧化氢和脂质过氧化水平显著降低。这些发现表明，Drp1部分减少不会影响线粒体和突触活力，可能对治疗阿尔茨海默病和亨廷顿病患者具有治疗用途。
