Icreverzi Amalia, de la Cruz Aida Flor A, Walker David W, Edgar Bruce A
Department of Integrative Biology and Physiology, University of California Los Angeles, Los Angeles, CA, 90095, USA.
Basic Science Division, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA.
Aging Cell. 2015 Oct;14(5):896-906. doi: 10.1111/acel.12376. Epub 2015 Jul 29.
Mitochondrial dysfunction has been implicated in human diseases, including cancer, and proposed to accelerate aging. The Drosophila Cyclin-dependent protein kinase complex cyclin D/cyclin-dependent kinase 4 (CycD/Cdk4) promotes cellular growth by stimulating mitochondrial biogenesis. Here, we examine the neurodegenerative and aging consequences of altering CycD/Cdk4 function in Drosophila. We show that pan-neuronal loss or gain of CycD/Cdk4 increases mitochondrial superoxide, oxidative stress markers, and neurodegeneration and decreases lifespan. We find that RNAi-mediated depletion of the mitochondrial transcription factor, Tfam, can abrogate CycD/Cdk4's detrimental effects on both lifespan and neurodegeneration. This indicates that CycD/Cdk4's pathological consequences are mediated through altered mitochondrial function and a concomitant increase in reactive oxygen species. In support of this, we demonstrate that CycD/Cdk4 activity levels in the brain affect the expression of a set of 'oxidative stress' genes. Our results indicate that the precise regulation of neuronal CycD/Cdk4 activity is important to limit mitochondrial reactive oxygen species production and prevent neurodegeneration.
线粒体功能障碍与包括癌症在内的人类疾病有关，并被认为会加速衰老。果蝇细胞周期蛋白依赖性蛋白激酶复合物细胞周期蛋白D/细胞周期蛋白依赖性激酶4（CycD/Cdk4）通过刺激线粒体生物发生来促进细胞生长。在这里，我们研究了改变果蝇中CycD/Cdk4功能对神经退行性变和衰老的影响。我们发现，全神经元性缺失或增加CycD/Cdk4会增加线粒体超氧化物、氧化应激标志物和神经退行性变，并缩短寿命。我们发现，RNA干扰介导的线粒体转录因子Tfam的缺失可以消除CycD/Cdk4对寿命和神经退行性变的有害影响。这表明CycD/Cdk4的病理后果是通过线粒体功能改变和活性氧随之增加介导的。为此，我们证明大脑中CycD/Cdk4的活性水平会影响一组“氧化应激”基因的表达。我们的结果表明，精确调节神经元CycD/Cdk4的活性对于限制线粒体活性氧的产生和预防神经退行性变很重要。
