Kavazis Andreas N, Morton Aaron B, Hall Stephanie E, Smuder Ashley J
School of Kinesiology, Auburn University, Auburn, AL, United States.
Department of Applied Physiology and Kinesiology, University of Florida, Room 25 Florida Gym, , Gainesville, FL 32611, United States.
Mitochondrion. 2017 May;34:9-19. doi: 10.1016/j.mito.2016.10.008. Epub 2016 Nov 8.
Doxorubicin (DOX) is a highly effective chemotherapeutic used in the treatment of a broad spectrum of malignancies. However, clinical use of DOX is highly limited by cumulative and irreversible cardiomyopathy that occurs following DOX treatment. The pathogenesis of DOX-induced cardiac muscle dysfunction is complex. However, it has been proposed that the etiology of this myopathy is related to mitochondrial dysfunction, as a result of the dose-dependent increase in the mitochondrial accumulation of DOX. In this regard, cardiac muscle possesses two morphologically distinct populations of mitochondria. Subsarcolemmal (SS) mitochondria are localized just below the sarcolemma, whereas intermyofibrillar (IMF) mitochondria are found between myofibrils. Mitochondria in both regions exhibit subtle differences in biochemical properties, giving rise to differences in respiration, lipid composition, enzyme activities and protein synthesis rates. Based on the heterogeneity of SS and IMF mitochondria, we hypothesized that acute DOX administration would have distinct effects on each cardiac mitochondrial subfraction. Therefore, we isolated SS and IMF mitochondria from the hearts of female Sprague-Dawley rats 48h after administration of DOX. Our results demonstrate that while SS mitochondria appear to accumulate greater amounts of DOX, IMF mitochondria demonstrate a greater apoptotic and autophagic response to DOX exposure. Thus, the divergent protein composition and function of the SS and IMF cardiac mitochondria result in differential responses to DOX, with IMF mitochondria appearing more susceptible to damage after DOX treatment.
阿霉素（DOX）是一种高效的化疗药物，用于治疗多种恶性肿瘤。然而，DOX的临床应用受到其治疗后发生的累积性和不可逆性心肌病的严重限制。DOX诱导的心肌功能障碍的发病机制很复杂。然而，有人提出这种肌病的病因与线粒体功能障碍有关，这是由于DOX在线粒体中的积累呈剂量依赖性增加所致。在这方面，心肌拥有两种形态上不同的线粒体群体。肌膜下（SS）线粒体位于肌膜下方，而肌原纤维间（IMF）线粒体则位于肌原纤维之间。这两个区域的线粒体在生化特性上表现出细微差异，导致呼吸、脂质组成、酶活性和蛋白质合成速率存在差异。基于SS和IMF线粒体的异质性，我们假设急性给予DOX会对每个心脏线粒体亚组分产生不同的影响。因此，我们在给予DOX 48小时后，从雌性Sprague-Dawley大鼠的心脏中分离出SS和IMF线粒体。我们的结果表明，虽然SS线粒体似乎积累了更多的DOX，但IMF线粒体对DOX暴露表现出更大的凋亡和自噬反应。因此，SS和IMF心脏线粒体不同的蛋白质组成和功能导致对DOX的反应不同，DOX治疗后IMF线粒体似乎更容易受到损伤。
