Mitochondrial dysfunction is associated with a pro-apoptotic cellular environment in senescent cardiac muscle
Mitochondrial dysfunction is associated with a pro-apoptotic cellular environment in senescent cardiac muscle
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DOI：
10.1016/j.mad.2009.12.004
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发表时间：
2010-02-01
影响因子：
5.3
通讯作者：
Hood, David A.
中科院分区：
文献类型：
--
作者：
Ljubicic, Vladimir;Menzies, Keir J.;Hood, David A.
随着年龄的增长，心肌会发生显著的重塑。这可能部分是由于线粒体生物发生和功能的进行性损害。我们的目的是研究衰老是如何影响心肌细胞死亡中致凋亡因子的亚细胞定位的。使用6个月和36个月大的Fischer 344xBN动物，我们评估了细胞器内容和功能的标志物，以及与细胞凋亡有关的蛋白质的线粒体和细胞溶质区室化。衰老与心脏线粒体含量和呼吸功能的减少有关。这些变化伴随着细胞色素c和AIF的更大的胞质积累，以及更高的线粒体Bax和更快的渗透性转换孔开放速率。来自老年心脏的线粒体表现出p66Shc和p46Shc的更大富集，提供了增强的致凋亡信号传导的进一步证据。蛋白石是更大的衰老心肌，而Drp1是更高的老年人的线粒体分数，相比年轻的动物。此外，衰老动物心脏中的DNA片段水平更高。因此，致凋亡蛋白的特异性区室化意味着在老年心肌中，血管介导的细胞死亡信号传导高度活跃，这可能有助于进行性心脏病理生理学。(C)2010爱思唯尔爱尔兰有限公司版权所有。
Cardiac muscle undergoes significant remodeling with aging. This may be partly due to the progressive impairment of mitochondrial biogenesis and function. Our purpose was to examine how aging affects the subcellular localization of apoptogenic factors involved in mitochondrially mediated cell death in cardiac muscle. Employing 6- and 36-month-old Fischer 344xBN animals, we assessed markers of organelle content and function, as well as the mitochondrial and cytosolic compartmentalization of proteins implicated in apoptosis. Aging was associated with decrements in cardiac mitochondrial content and respiratory function. These changes were accompanied by a greater cytosolic accumulation of cytochrome c and AIF, as well as a higher mitochondrial Bax and a faster rate of permeability transition pore opening. Mitochondria from aged hearts demonstrated a greater enrichment of p66Shc and p46Shc providing further evidence of enhanced apoptogenic signaling. Opal was greater in the senescent myocardium, while Drp1 was higher in the mitochondrial fraction of aged, compared to the young animals. Furthermore, the level of fragmented DNA was greater in the hearts of senescent animals. Thus, the specific compartmentalization of apoptogenic proteins implies that mitochondrially mediated cell death signaling is highly active in the aged myocardium, which may contribute to progressive cardiac pathophysiology. (C) 2010 Elsevier Ireland Ltd. All rights reserved.