Abstract
Temperature (T) reduction increases lifespan, but the mechanisms are not understood. Because reactive oxygen species (ROS) contribute to aging, we hypothesized that lowering T might decrease mitochondrial ROS production. We measured respiratory response and ROS production in isolated mitochondria at 32, 35, and 37 °C. Lowering T decreased the rates of resting (state 4) and phosphorylating (state 3) respiration phases. Surprisingly, this respiratory slowdown was associated with an increase of ROS production and hydrogen peroxide release and with elevation of the mitochondrial membrane potential, ΔΨ(m). We also found that at lower T mitochondria produced more carbon-centered lipid radicals, a species known to activate uncoupling proteins. These data indicate that reduced mitochondrial ROS production is not one of the mechanisms mediating lifespan extension at lower T. They suggest instead that increased ROS leakage may mediate mitochondrial responses to hypothermia.
Highlights
Reactive oxygen species (ROS)3 are byproducts of normal oxygen metabolism and can serve as signaling molecules [1] or mediate molecular and cellular damage [2, 3]
These assays were performed at three different temperatures selected as representative of the physiological core temperature of mice during the dark:active phase of the day (37 °C), the light:resting phase (35 °C), and the temperature reached under calorie restriction (32 °C)
Experiments typically involved parallel measurements of oxygen consumption by identical amounts of a given mitochondria sample using two independent Clark-type electrodes where one of them is tightly controlled at a specific temperature, T Ϯ 0.1 °C, in reference to the second electrode which is stabilized at 37 °C
Summary
Reactive oxygen species (ROS) are byproducts of normal oxygen metabolism and can serve as signaling molecules [1] or mediate molecular and cellular damage [2, 3]. A balanced dietary regimen demonstrated to prolong lifespan and retard aging [6, 7], reduced both oxidative damage and core body temperature [8]. Modest but prolonged reduction of core body temperature increased lifespan independently of calorie restriction in poikilotherms [9]. To obtain mechanistic clues on causes and dynamics of ROS leakage we studied the effect of temperature on mitochondrial membrane potential. These assays were performed at three different temperatures selected as representative of the physiological core temperature of mice during the dark:active phase of the day (37 °C), the light:resting phase (35 °C), and the temperature reached under calorie restriction (32 °C)
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