Abstract
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.
Highlights
Hibernating species are well known for their ability to initiate safe metabolic suppression and to resist ischemia and hypothermia, even outside the hibernation season [1,2,3,4,5]
Even more interesting is that outside the hibernation season, hibernators withstand iatrogenic damage, such as ischemia/reperfusion injury (IRI) and energy deprivation [8,9,10,11], whereas IRI in humans leads to organ failure as found, for example, in organ transplantation [12] and myocardial infarction [13]
We suggest that the more recently discovered ferroptosis pathway, a form of regulated cell death initiated after an overload of lipid peroxidation [25], plays an important role in hypothermia
Summary
Hibernating species are well known for their ability to initiate safe metabolic suppression and to resist ischemia and hypothermia, even outside the hibernation season [1,2,3,4,5]. Even more interesting is that outside the hibernation season, hibernators withstand iatrogenic damage, such as ischemia/reperfusion injury (IRI) and energy deprivation [8,9,10,11], whereas IRI in humans leads to organ failure as found, for example, in organ transplantation [12] and myocardial infarction [13]. Because of these features, hibernation is a highly interesting model to define new preservation techniques in conditions such as organ transplantation [14,15] and cardiac arrest [16]. We sought to determine the cause of cell death by exploring ferroptosis in both hibernator and non-hibernator cells
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