Delic Vedad, Brownlow Milene, Joly-Amado Aurelie, Zivkovic Sandra, Noble Kenyaria, Phan Tam-Anh, Ta Yen, Zhang Yumeng, Bell Stephen D, Kurien Crupa, Reynes Christian, Morgan Dave, Bradshaw Patrick C
Department of Cell Biology, Microbiology and Molecular Biology, University of South Florida, Tampa, FL 33620, United States.
University of South Florida College of Medicine, Department of Molecular Pharmacology and Physiology, Tampa, FL 33613, United States; USF Health Byrd Alzheimer's Institute, Tampa, FL 33613, United States.
Mol Cell Neurosci. 2015 Jul;67:46-54. doi: 10.1016/j.mcn.2015.06.001. Epub 2015 Jun 3.
Calorie restriction (CR) has been shown to increase lifespan and delay aging phenotypes in many diverse eukaryotic species. In mouse models of Alzheimer's disease (AD), CR has been shown to decrease amyloid-beta and hyperphosphorylated tau levels and preserve cognitive function. Overexpression of human mutant tau protein has been shown to induce deficits in mitochondrial electron transport chain complex I activity. Therefore, experiments were performed to determine the effects of 4-month CR on brain mitochondrial function in Tg4510 mice, which express human P301L tau. Expression of mutant tau led to decreased ADP-stimulated respiratory rates, but not uncoupler-stimulated respiratory rates. The membrane potential was also slightly higher in mitochondria from the P301L tau mice. As shown previously, tau expression decreased mitochondrial complex I activity. The decreased complex I activity, decreased ADP-stimulated respiratory rate, and increased mitochondrial membrane potential occurring in mitochondria from Tg4510 mice were not restored by CR. However, the CR diet did result in a genotype independent decrease in mitochondrial F0F1-ATPase activity. This decrease in F0F1-ATPase activity was not due to lowered levels of the alpha or beta subunits of F0F1-ATPase. The possible mechanisms through which CR reduces the F0F1-ATPase activity in brain mitochondria are discussed.
热量限制（CR）已被证明能延长多种真核生物的寿命并延缓衰老表型。在阿尔茨海默病（AD）的小鼠模型中，CR已被证明可降低β淀粉样蛋白和过度磷酸化tau蛋白水平，并维持认知功能。人类突变tau蛋白的过表达已被证明会导致线粒体电子传递链复合体I活性缺陷。因此，进行了实验以确定4个月的CR对表达人类P301L tau的Tg4510小鼠脑线粒体功能的影响。突变tau的表达导致ADP刺激的呼吸速率降低，但解偶联剂刺激的呼吸速率未降低。P301L tau小鼠线粒体的膜电位也略高。如先前所示，tau表达降低了线粒体复合体I的活性。CR并未恢复Tg4510小鼠线粒体中出现的复合体I活性降低、ADP刺激的呼吸速率降低以及线粒体膜电位升高的情况。然而，CR饮食确实导致线粒体F0F1 - ATP酶活性出现与基因型无关的降低。F0F1 - ATP酶活性的这种降低并非由于F0F1 - ATP酶的α或β亚基水平降低。文中讨论了CR降低脑线粒体中F0F1 - ATP酶活性的可能机制。
