Restoring mitochondrial DNA copy number preserves mitochondrial function and delays vascular aging in mice.
Restoring mitochondrial DNA copy number preserves mitochondrial function and delays vascular aging in mice.
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DOI：
10.1111/acel.12773
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发表时间：
2018-08
期刊：
影响因子：
7.8
通讯作者：
Bennett MR
中科院分区：
文献类型：
--
作者：
Foote K;Reinhold J;Yu EPK;Figg NL;Finigan A;Murphy MP;Bennett MR
衰老是心血管疾病的最大危险因素，但血管衰老的分子机制仍不清楚。线粒体DNA（mtDNA）损伤与衰老有关，但mtDNA损伤或线粒体功能障碍是否存在并直接促进血管衰老尚不清楚。此外，在小鼠中的机制研究受到长的研究时间和缺乏在标准化的早期时间点的动脉老化的敏感的、可重复的和可再现的参数的严重阻碍。我们研究了小鼠动脉衰老的多个侵入性和非侵入性动脉生理参数和结构变化的时间过程，衰老如何影响血管线粒体功能，以及线粒体功能的获得或丧失对血管衰老的影响。在44周龄时首次检测到血管老化，颈动脉顺应性和扩张性降低，β僵硬指数增加，主动脉脉搏波速度（PWV）增加。主动脉胶原含量和弹性蛋白断裂也增加，在44周。动脉mtDNA拷贝数（mtCN）和mtCN-调节蛋白TFAM、PGC 1 α和Twinkle在44周时减少，与线粒体呼吸减少相关。线粒体解旋酶Twinkle（Tw+）的过表达增加了动脉中的线粒体CN，改善了线粒体呼吸，并在所有研究参数中延迟了生理和结构老化。相反，线粒体聚合酶-γ（PolG）缺陷和mtDNA完整性降低的小鼠表现出加速的血管老化。我们的研究确定了多个早期和可重复的参数，用于评估小鼠血管老化。动脉线粒体呼吸随着年龄的增长而显著降低，线粒体DNA完整性和线粒体功能的降低直接促进血管老化。
Aging is the largest risk factor for cardiovascular disease, yet the molecular mechanisms underlying vascular aging remain unclear. Mitochondrial DNA (mtDNA) damage is linked to aging, but whether mtDNA damage or mitochondrial dysfunction is present and directly promotes vascular aging is unknown. Furthermore, mechanistic studies in mice are severely hampered by long study times and lack of sensitive, repeatable and reproducible parameters of arterial aging at standardized early time points. We examined the time course of multiple invasive and noninvasive arterial physiological parameters and structural changes of arterial aging in mice, how aging affects vessel mitochondrial function, and the effects of gain or loss of mitochondrial function on vascular aging. Vascular aging was first detected by 44 weeks (wk) of age, with reduced carotid compliance and distensibility, increased β‐stiffness index and increased aortic pulse wave velocity (PWV). Aortic collagen content and elastin breaks also increased at 44 wk. Arterial mtDNA copy number (mtCN) and the mtCN‐regulatory proteins TFAM, PGC1α and Twinkle were reduced by 44 wk, associated with reduced mitochondrial respiration. Overexpression of the mitochondrial helicase Twinkle (Tw+) increased mtCN and improved mitochondrial respiration in arteries, and delayed physiological and structural aging in all parameters studied. Conversely, mice with defective mitochondrial polymerase‐gamma (PolG) and reduced mtDNA integrity demonstrated accelerated vascular aging. Our study identifies multiple early and reproducible parameters for assessing vascular aging in mice. Arterial mitochondrial respiration reduces markedly with age, and reduced mtDNA integrity and mitochondrial function directly promote vascular aging.
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影响因子：
5.3
作者：
Mengel-From, Jonas;Thinggaard, Mikael;Dalgard, Christine;Kyvik, Kirsten Ohm;Christensen, Kaare;Christiansen, Lene
通讯作者：
Christiansen, Lene
DOI：
10.1073/pnas.0505551102
发表时间：
2005-12-06
影响因子：
11.1
作者：
Tyynismaa, H;Mjosund, KP;Suomalainen, A
通讯作者：
Suomalainen, A
影响因子：
3.5
作者：
Ylikallio, Emil;Tyynismaa, Henna;Suomalainen, Anu
通讯作者：
Suomalainen, Anu
影响因子：
3.5
作者：
Ekstrand, MI;Falkenberg, M;Larsson, NG
通讯作者：
Larsson, NG
DOI：
10.1007/978-1-62703-739-6_31
发表时间：
2014
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
--
作者：
Furda, Amy;Santos, Janine H;Meyer, Joel N;Van Houten, Bennett
通讯作者：
Van Houten, Bennett