Mitochondrial performance in heat acclimation—a lesson from ischemia/reperfusion and calcium overload insults in the heart

Abstract

Longterm heat acclimation (LTHA; 30 days, 34°C) causes phenotypic adaptations that render protection against ischemic/reperfusion insult (I/R, 30 min global ischemia and 40 min reperfusion) via heat acclimation-mediated cross-tolerance (HACT) mechanisms. Shortterm acclimation (STHA, 2 days, 34°C), in contrast, is characterized by cellular perturbations, leading to increased susceptibility to insults. Here, we tested the hypothesis that enhanced mitochondrial respiratory function is part of the acclimatory repertoire and that the 30-day regimen is required for protection via HACT. We subjected isolated hearts and mitochondria from controls (C), STHA, or LTHA rats to I/R, hypoxia/reoxygenation, or Ca 2ϩ overload insults. Mitochondrial function was assessed by measuring O2 consumption, membrane potential (⌬⌿m), mitochondrial Ca 2ϩ ([Ca 2ϩ ]m), ATP production, respiratory chain complex activities, and molecular markers of mitochondrial biogenesis. Our results, combining physiological and biochemical parameters, confirmed that mitochondria from LTHA rats subjected to insults, in contrast to C, preserve respiratory functions (e.g., upon I/R, C mitochondria fueled by glutamate-malate, demonstrated decreases of 81%, 13%, 25%, and 50% in O2/P ratio, ATP production, ⌬⌿m, and complex I activity, respectively, whereas the corresponding LTHA parameters remained unchanged). STHA mitochondria maintained ⌬⌿m but did not preserve ATP production. LTHA [Ca 2ϩ ]m was significantly higher than that of C and STHA and was not affected by the hypoxia/reoxygenation protocol compared with C. Enhanced mitochondrial biogenesis markers, switched-on during STHA coincidentally with enhanced membrane integrity (⌬⌿m), were insufficient to confer intact respiratory function upon insult. LTHA was required for respiratory complex I adaptation and HACT. Umschwief et al. (65) proved that the mitochondria, via heat acclimation-mediated cross-tolerance (HACT) mechanisms, in which heat acclimation confers protection against stressors of a different nature, attenuated apoptosis during ischemia/reperfusion (I/R) insult in the heart and following traumatic brain injury. Assayag et al. (3) also demonstrated that basal levels of cytochrome c, an essential electron carrier that transfers electrons from complex III to the COX complex, decreased in the cardiac mitochondria of heat-acclimated rats, whereas heat stress induced a marked elevation of this protein.The former fits with Seebacher's COX activity in warm acclimated reptiles (59). The mitochondrial Bcl XL protein was elevated under both basal-normothermic and heat-stress conditions, implying adaptive properties in the mitochondriaimporting complexes and synthesis systems (2) and marked the mitochondria as essential players in thermotolerance, as well as in HACT. Assayag et al. (3) demonstrated that the adaptive features of the outer mitochondrial membrane (such as an elevated Bcl XL /Bad ratio) are already found after 2 days of heat acclimation, namely short-term heat acclimation (STHA), whereas...

Danshensu protects against ischemia/reperfusion injury and inhibits the apoptosis of H9c2 cells by reducing the calcium overload through the p-JNK-NF-κB-TRPC6 pathway

“…At the same time, the apoptotic rate and the [Ca 2+ ] i level also increased, which is similar to the results of Shen et al (6) and Assayag et al (8). We noted an increase in the basal [Ca 2+ ] i level, and we also noted that the continuous Ca 2+ influx increased slightly following stimulation with OAG, an activator of TRPC6, following the addition of CaCl 2 .…”

“…It is well known that calcium overload is an important event for cellular apoptosis (6)(7)(8). The TRP superfamily is highly permeable to calcium.…”

“…The authors observed that reperfusion accelerated the development of myocardial necrosis, and the degree of myocardial necrosis following I/R for 30-60 min was similar to that observed 24 h after coronary occlusion. To date, various studies have shown that I/R injury is associated with calcium overload (6)(7)(8), the production of free radicals (9,10) and mitochondrial alterations (10,11). Cytosolic calcium overload is now well known as an essential pathophysiological mechanism which is involved in reperfusion injury, although the source and origin of the calcium remains to be determined (12).…”

Heat Acclimation, Epigenetics, and Cytoprotection Memory

“…In contrast to the rapid neural adaptive responses, the build-up cytoprotective protein reserves takes time, hence, despite the seemingly "acclimated" physiological phenotype upon STHA [the profound drop in T-Tsh for heat dissipation and increased endurance due to greater evaporative cooling (77)], cytoprotection per se has not yet evolved, it is only achieved upon LTHA (6,7). In this section, essential/sufficient genes in heat acclimation mediated thermotolerance and delayed thermal injury will be discussed.…”

“…Classical preconditioning involves short term events (∼2d) and differs from the cross-tolerance conferred by heat acclimation, which depends on the kinetics of acclimation/deacclimation, and lasts for several weeks. In contrast to classical preconditioning, 2d acclimation (where apparent acclimation depends on neural activity) reduces tolerance to novel stressors despite several rapid adaptive responses, probably related to phosphorylation processes (6) [detailed in Assayag et al (6,7)]. This suggests that heat acclimation mediated cross-tolerance depends on long-term translational processes which establish reserves of cytoprotective proteins [e.g., HSP72, see sec above and adjustment of electron transfer in mitochondrial proteins (7)].…”