Metabolic design in a mammalian model of extreme metabolism, the North American least shrew (Cryptotis parva).
Metabolic design in a mammalian model of extreme metabolism, the North American least shrew (Cryptotis parva).
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DOI：
10.1113/jp282153
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发表时间：
2022-02
影响因子：
5.5
通讯作者：
Balaban, Robert S.
中科院分区：
文献类型：
--
作者：
Chung, Dillon J.;Madison, Grey P.;Aponte, Angel M.;Singh, Komudi;Li, Yuesheng;Pirooznia, Mehdi;Bleck, Christopher K. E.;Darmani, Nissar A.;Balaban, Robert S.
线粒体适应是哺乳动物细胞分化功能和能量稳态的基础。但这些关系背后的机制仍然知之甚少。在这里，我们研究了极端哺乳动物新陈代谢模型（最小的鼩鼱（Cryptotis parva））中器官特异性的线粒体形态、连接性和蛋白质组成。这是通过高分辨率 3D 聚焦离子束电子显微镜成像和串联质量标签质谱蛋白质组学的结合实现的。我们证明肝脏和肾脏的线粒体含量与心脏相当，从而可以评估具有相似代谢需求的不同器官中的线粒体适应。肌肉线粒体网络（心脏和骨骼）广泛，纳米隧道的发生率很高，它们共同支持大肌肉细胞的新陈代谢。在肝脏和肾脏中未检测到线粒体网络，因为单个线粒体位于 ATP 消耗位点。在横纹肌中没有观察到这种配置，可能是由于均匀的 ATP 酶分布和收缩的结构要求。这些结果表明，针对类似代谢需求的独特的基本线粒体结构适应取决于哺乳动物极端代谢模型中能量利用过程的拓扑结构。这项研究调查了线粒体形态和蛋白质组成在设定现存最小哺乳动物之一——北美最小鼩鼱（Cryptotis parva）的极端代谢率中的作用。为此，对肝脏、肾脏、骨骼肌和心脏组织的线粒体特征进行了比较，因为这些组织是基础代谢状态和最大代谢状态的主要贡献者。肝脏和肾脏的线粒体体积密度和蛋白质含量接近心脏中观察到的水平，表明这些以前的组织是小型哺乳动物高基础代谢率的主要贡献者。尽管线粒体含量很高，但肝脏和肾脏并不表现出线粒体网络——这种结构被认为是在细胞尺度上传导线粒体质子动力的结构。鼩鼱骨骼肌和心脏线粒体网络组织与在大型哺乳动物中观察到的网络一致，同时也表现出纳米级连接性的增强。肾和肝线粒体不形成网络，而是直接与 ATP 利用位点相关。这些结果确定了决定线粒体网络形成的条件和驱动哺乳动物代谢率异速生长的过程。
Mitochondrial adaptations are fundamental to differentiated function and energetic homeostasis in mammalian cells. But the mechanisms that underlie these relationships remain poorly understood. Here, we investigated organ-specific mitochondrial morphology, connectivity and protein composition in a model of extreme mammalian metabolism, the least shrew (Cryptotis parva). This was achieved through a combination of high-resolution 3D focused ion beam electron microscopy imaging and tandem mass tag mass spectrometry proteomics. We demonstrate that liver and kidney mitochondrial content are equivalent to the heart, permitting assessment of mitochondrial adaptations in different organs with similar metabolic demand. Muscle mitochondrial networks (cardiac and skeletal) are extensive, with a high incidence of nanotunnels – which collectively support the metabolism of large muscle cells. Mitochondrial networks were not detected in the liver and kidney as individual mitochondria are localized with sites of ATP consumption. This configuration is not observed in striated muscle, likely due to a homogeneous ATPase distribution and the structural requirements of contraction. These results demonstrate distinct, fundamental mitochondrial structural adaptations for similar metabolic demand that are dependent on the topology of energy utilization process in a mammalian model of extreme metabolism. This study investigates the role of mitochondrial morphology and protein composition in setting the extreme metabolic rates of one of the smallest extant mammals, the North American least shrew (Cryptotis parva). To do this, mitochondrial characteristics from liver, kidney, skeletal muscle and heart tissues were compared as these tissues are major contributors to basal and maximum metabolic states. Liver and kidney mitochondrial volume density and protein content approach levels observed in the heart, indicating that these former tissues are major contributors to the high basal metabolic rates of small mammals. Despite this high mitochondrial content, the liver and kidney do not exhibit mitochondrial networking – structures that are proposed to conduct mitochondrial proton motive force at the scale of the cell. Shrew skeletal muscle and cardiac mitochondrial network organization is consistent with networks observed in larger mammals while also exhibiting increased connectivity at the nanometre scale. Instead of forming networks, kidney and liver mitochondria are directly associated with sites of ATP utilization. These results identify conditions that dictate the formation of mitochondrial networks and processes that drive mammalian allometric scaling of metabolic rates.