Department of Clinical Pharmacy and Pharmacology, University Medical Centre Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands.
Department of Surgery, University Medical Centre Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands.
Int J Mol Sci. 2020 Mar 9;21(5):1864. doi: 10.3390/ijms21051864.
Mitochondrial failure is recognized to play an important role in a variety of diseases. We previously showed hibernating species to have cell-autonomous protective mechanisms to resist cellular stress and sustain mitochondrial function. Here, we set out to detail these mitochondrial features of hibernators. We compared two hibernator-derived cell lines (HaK and DDT1MF2) with two non-hibernating cell lines (HEK293 and NRK) during hypothermia (4 °C) and rewarming (37 °C). Although all cell lines showed a strong decrease in oxygen consumption upon cooling, hibernator cells maintained functional mitochondria during hypothermia, without mitochondrial permeability transition pore (mPTP) opening, mitochondrial membrane potential decline or decreased adenosine triphosphate (ATP) levels, which were all observed in both non-hibernator cell lines. In addition, hibernator cells survived hypothermia in the absence of extracellular energy sources, suggesting their use of an endogenous substrate to maintain ATP levels. Moreover, hibernator-derived cells did not accumulate reactive oxygen species (ROS) damage and showed normal cell viability even after 48 h of cold-exposure. In contrast, non-hibernator cells accumulated ROS and showed extensive cell death through ferroptosis. Understanding the mechanisms that hibernators use to sustain mitochondrial activity and counteract damage in hypothermic circumstances may help to define novel preservation techniques with relevance to a variety of fields, such as organ transplantation and cardiac arrest.
线粒体功能衰竭被认为在多种疾病中发挥着重要作用。我们之前曾发现，一些冬眠物种具有细胞自主的保护机制，以抵抗细胞应激并维持线粒体功能。在这里，我们详细研究了冬眠动物的这些线粒体特征。我们比较了两种冬眠衍生的细胞系（HaK 和 DDT1MF2）和两种非冬眠细胞系（HEK293 和 NRK）在低温（4°C）和复温（37°C）期间的线粒体功能。尽管所有细胞系在冷却时耗氧量均明显下降，但冬眠动物细胞在低温下仍能维持功能正常的线粒体，而不会发生线粒体通透性转换孔（mPTP）开放、线粒体膜电位下降或三磷酸腺苷（ATP）水平降低，这些变化在两种非冬眠细胞系中均有观察到。此外，在没有细胞外能量来源的情况下，冬眠动物细胞能够在低温下存活，这表明它们利用内源性底物来维持 ATP 水平。此外，即使在 48 小时的冷暴露后，冬眠动物衍生的细胞也不会积累活性氧（ROS）损伤，并且保持正常的细胞活力。相比之下，非冬眠细胞会积累 ROS，并通过铁死亡导致广泛的细胞死亡。了解冬眠动物在低温环境下维持线粒体活性和对抗损伤的机制，可能有助于定义与多种领域相关的新型保存技术，如器官移植和心脏骤停。
