Effects of cold on murine brain mitochondrial function

Abstract

Therapeutic hypothermia is a strategy that reduces metabolic rate and brain damage during clinically-relevant hypoxic events. Mitochondrial respiration is compromised by hypoxia, with deleterious consequences for the mammalian brain; however, little is known about the effects of reduced temperature on mitochondrial metabolism. Therefore, we examined how mitochondrial function is impacted by temperature using high resolution respirometry to assess electron transport system (ETS) function in saponin-permeabilized mouse brain at 28 and 37°C. Respirometric analysis revealed that, at the colder temperature, ETS respiratory flux was ~ 40–75% lower relative to the physiological temperature in all respiratory states and for all fuel substrates tested. In whole brain tissue, the enzyme maximum respiratory rates for complexes I-V were similarly reduced by between 37–88%. Complexes II and V were particularly temperature-sensitive; a temperature-mediated decrease in complex II activity may support a switch to complex I mediated ATP-production, which is considerably more oxygen-efficient. Finally, the mitochondrial H+-gradient was more tightly coupled, indicating that mitochondrial respiration is more efficient at the colder temperature. Taken together, our results suggest that improvements in mitochondrial function with colder temperatures may contribute to energy conservation and enhance cellular viability in hypoxic brain.

Tracking the Formation and Degradation of Fatty-Acid-Accumulated Mitochondria Using Label-Free Chemical Imaging

“…It was reported that ADP phosphorylation is much more e cient at physiological temperature 38 . Studies also found that at lower temperatures, the maximum respiratory rates for the membrane-bound complexes were signi cantly reduced compared to those at the physiological temperature 39 . The increased concentration of NADH and FAD might slow down the β-oxidation process, causing the accumulation of FAs in these mitochondria 40,41 .…”

Cold Exposure After Exercise Impedes the Neuroprotective Effects of Exercise on Thermoregulation and UCP4 Expression in an MPTP-Induced Parkinsonian Mouse Model

“…In addition, our results indicated that preventing persistent brain hypothermia through exercise ( Figure 2 ) or cold exposure ( Figure 3 ) is associated with the improvement of MPTP-induced nigrostriatal dopaminergic neurodegeneration (loss of TH ir neurons in the SN and reduction of DAT immunoreactivity in the striatum, Figure 6 ) and movement disorders (short latency to fall in rotarod performance, Figure 5 ). Both exercise training and cold acclimation have been demonstrated to be able to promote mitochondrial biogenesis ( Marques-Aleixo et al, 2015 ; Pamenter et al, 2018 ; Salamon et al, 2019 ). Accordingly, lasting brain hypothermia may be the result of mitochondrial dysfunction and may contribute to MPTP-induced nigrostriatal dopaminergic neurodegeneration.…”

“…Brain UCP4 mRNA expression was shown to be upregulated after acute exposure to temperatures of 4°C ( Yu et al, 2000 ), and UCP4 overexpression has been shown to prevent ATP deficiency and oxidative insult in PD cell models ( Chu et al, 2009 ; Wu et al, 2014 ; Xu et al, 2018 ). Mitochondrial biogenesis can be elevated by exercise training or cold adaptation ( Marques-Aleixo et al, 2015 ; Pamenter et al, 2018 ; Salamon et al, 2019 ). Accordingly, it is reasonable to infer that the prevention of UCP4 downregulation related to mitochondrial dysfunction contributes to exercise training- or cold adaptation-induced neuroprotection against MPTP toxicity.…”

Neuroprotective Potential of Mild Uncoupling in Mitochondria. Pros and Cons

“…Moreover, hypothermia has protective properties, which imposes requirements, not only to prevent anything that causes an increase in temperature in the brain, but also to use hypothermia in experimental and clinical conditions to prevent the development of neurological damage [137]. A reasonable explanation was given in that hypothermia suppresses mitochondrial activity, in particular, increasing the degree of coupling of oxidation and phosphorylation as the antipode of uncoupling [138].…”