Institute of Functional and Applied Anatomy, Hannover Medical School, Hannover, Germany.
Research Core Unit Electron Microscopy, Hannover Medical School, Hannover, Germany.
J Anat. 2023 Jan;242(1):91-101. doi: 10.1111/joa.13618. Epub 2021 Dec 27.
Aging is associated with cardiac hypertrophy and progressive decline in heart function. One of the hallmarks of cellular aging is the dysfunction of mitochondria. These organelles occupy around 1/4 to 1/3 of the cardiomyocyte volume. During cardiac aging, the removal of defective or dysfunctional mitochondria by mitophagy as well as the dynamic equilibrium between mitochondrial fusion and fission is distorted. Here, we hypothesized that these changes affect the number of mitochondria and alter their three-dimensional (3D) characteristics in aged mouse hearts. The polyamine spermidine stimulates both mitophagy and mitochondrial biogenesis, and these are associated with improved cardiac function and prolonged lifespan. Therefore, we speculated that oral spermidine administration normalizes the number of mitochondria and their 3D morphology in aged myocardium. Young (4-months old) and old (24-months old) mice, treated or not treated with spermidine, were used in this study (n = 10 each). The number of mitochondria in the left ventricles was estimated by design-based stereology using the Euler-Poincaré characteristic based on a disector at the transmission electron microscopic level. The 3D morphology of mitochondria was investigated by 3D reconstruction (using manual contour drawing) from electron microscopic z-stacks obtained by focused ion beam scanning electron microscopy. The volume of the left ventricle and cardiomyocytes were significantly increased in aged mice with or without spermidine treatment. Although the number of mitochondria was similar in young and old control mice, it was significantly increased in aged mice treated with spermidine. The interfibrillar mitochondria from old mice exhibited a lower degree of organization and a greater variation in shape and size compared to young animals. The mitochondrial alignment along the myofibrils in the spermidine-treated mice appeared more regular than in control aged mice, however, old mitochondria from animals fed spermidine also showed a greater diversity of shape and size than young mitochondria. In conclusion, mitochondria of the aged mouse left ventricle exhibited changes in number and 3D ultrastructure that is likely the structural correlate of dysfunctional mitochondrial dynamics. Spermidine treatment reduced, at least in part, these morphological changes, indicating a beneficial effect on cardiac mitochondrial alterations associated with aging.
衰老是与心脏肥大和心脏功能进行性下降相关的。细胞衰老的一个标志是线粒体功能障碍。这些细胞器占据心肌细胞体积的 1/4 到 1/3 左右。在心脏衰老过程中，受损或功能失调的线粒体通过自噬作用被清除，以及线粒体融合和裂变之间的动态平衡被破坏。在这里，我们假设这些变化会影响线粒体的数量，并改变它们在老年小鼠心脏中的三维（3D）特征。多胺亚精胺既能刺激自噬又能刺激线粒体生物发生，而这与改善心脏功能和延长寿命有关。因此，我们推测口服亚精胺可以使衰老心肌中线粒体的数量及其 3D 形态正常化。本研究使用了年轻（4 个月大）和年老（24 个月大）的小鼠（每组 10 只），并对其进行了亚精胺处理或未处理。通过基于电子显微镜水平的切割器的 Euler-Poincaré 特征，基于设计的体视学估计左心室中线粒体的数量。通过聚焦离子束扫描电子显微镜获得的电子显微镜 z 堆栈进行 3D 重建（使用手动轮廓绘图）来研究线粒体的 3D 形态。无论是否接受亚精胺治疗，年老小鼠的左心室和心肌细胞体积均明显增加。尽管年轻和年老的对照组小鼠中线粒体数量相似，但接受亚精胺治疗的年老小鼠中线粒体数量明显增加。与年轻动物相比，来自年老小鼠的纤维间线粒体的组织程度较低，形状和大小的变化较大。与对照组年老小鼠相比，用亚精胺处理的小鼠中线粒体沿着肌原纤维的排列似乎更规则，但接受亚精胺喂养的年老线粒体的形状和大小也比年轻线粒体更具多样性。总之，衰老小鼠左心室的线粒体数量和 3D 超微结构发生了变化，这可能是线粒体动力学功能障碍的结构相关因素。亚精胺治疗至少部分减少了这些形态变化，表明其对与衰老相关的心脏线粒体改变具有有益作用。
