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Determination of calcium-induced swelling by rat heart mitochondria from male (open triangle) and female (open square) rats. Extent of swelling was calculated from the swelling curves (A) and expressed as the decrease of absorbance at 520 nm during 5 min after addition of 200 μM CaCl2. Maximum rate of swelling (B) was calculated from curves obtained after derivatization of curves presented in A. Inset in B indicates digital values obtained from particular curves. Experimental conditions are described in methods
Source publication
Most of the experimental studies have revealed that female heart is more tolerant to ischemia/reperfusion (I/R) injury as compared with the male myocardium. It is widely accepted that mitochondrial dysfunction, and particularly mitochondrial permeability transition pore (MPTP) opening, plays a major role in determining the extent of cardiac I/R inj...
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The voltage-dependent anion channel (VDAC) is the major protein of the mitochondrial outer membrane (MOM). It is now generally accepted that this channel is responsible for most of the metabolite flux in and out of mitochondria. Small ions, adenine nucleotides such as ATP and ADP, and other water soluble mitochondrial respiratory substrates cross t...
Citations
... Together with the Center for Experimental Medicine of IKEM, we have also addressed questions concerning the influence of comorbidities, especially various forms of systemic hypertension, on myocardial ischemic tolerance and new possibilities of therapeutic pharmacological interventions [98][99][100][101][102]. The merger with the Department of Cardiac Morphogenesis has led to the expansion of the studied topics to include the development of the structure and function of the cardiac conduction system and to the enrichment of the methodological tools [103][104][105][106]. Special attention was paid to the developmental and sex differences in cardiac tolerance to ischemia/reperfusion injury and the possible role of mitochondria in this process [107][108][109][110][111][112][113][114][115][116]. A newly established international collaboration with the Medical College of Wisconsin, Milwaukee, has yielded new findings with translational potential on the beneficial effects of eicosanoids on cardiac injury by ischemia and on the development of post-ischemic heart failure [117][118][119][120]. ...
... However, only a limited number of studies investigated the effects of sex hormones on mitochondrial function. Either sex differences have been described in the heart or the effects of estrogen and progesterone on mitochondrial function and the generation of reactive oxygen species (ROS) have been described, but mostly in the brain (11) and not in the heart (12)(13)(14). Consequently, there is still limited knowledge about the influence of sex and sex hormones on mitochondrial respiration in the cardiovascular system (15). ...
... They may however be related to previously described sex-dependent effects that concern the lower ROS production reported in human and murine female cardiac mitochondria (13), better antioxidant protection (24) and better calcium handling (25) compared with male cardiac mitochondria. These mechanisms contribute to the observed female resilience of HF or slower progression toward HF (14). ...
Introduction
Sex differences in the adaptation to pressure overload have been described in humans, as well as animal models, and have been related to sex-specific expression of mitochondrial genes. We therefore tested whether sex differences in cardiac mitochondrial respiration exist in humans with aortic stenosis (AS). We also examined whether these potential differences may be at least partially due to sex hormones by testing if mitochondrial respiration is affected by estrogen (17ß-estradiol (E2)).
Methods
Consecutive patients undergoing transapical aortic valve implantation (TAVI) (women, n = 7; men, n = 10) were included. Cardiac biopsies were obtained during TAVI and used directly for mitochondrial function measurements. Male and female C57BL/6J mice (n = 8/group) underwent sham surgery or gonadectomy (GDX) at the age of 2 months. After 14 days, mice were treated once with intraperitoneally injected vehicle (placebo), 17ß-estradiol (E2), estrogen receptor alpha (ERα) agonist [propyl pyrazole triol (PPT)], or ER beta (ERβ) agonist (BAY-1214257). Thereafter, mitochondrial measurements were performed directly in cardiac skinned fibers from isolated left ventricles and musculus solei.
Results
Mitochondrial State-3 respiration was higher in female than that in male human heart biopsies (15.0 ± 2.30 vs. 10.3 ± 2.05 nmol/mL/min/mg, p< 0.05). In the mouse model, mitochondrial State-3 respiration decreased significantly after GDX in female (27.6 ± 1.55 vs. 21.4 ± 1.71 nmol/mL/min/mg; p< 0.05) and male hearts (30.7 ± 1,48 vs. 23.7 ± 2,23 nmol/mL/min/mg; p< 0.05). In ovariectomized female mice, E2 and ERβ-agonist treatment restored the State-3 respiration to intact placebo level, whereas ERα-agonist treatment did not modulate State-3 respiration. The treatment with E2, ERα-, or ERβ-agonist did not modulate the State-3 respiration in GDX male mice.
Conclusion
We identified sex differences in mitochondrial respiration in the diseased human heart. This is in alignment with known sex differences in the gene expression and proteome level at the functional level. E2 and ERβ affect cardiac mitochondrial function in the mouse model, suggesting that they may also contribute to the sex differences in the human heart. Their roles should be further investigated.
... We used this innovative methodology to evaluate the effects of ROS and triiodothyronine on calcium-induced mitochondrial swelling [69]. We also assessed tissue specificity [117], age-dependent differences [118,119], and differences between male and female tissues [120] to calcium-and ROS-induced pore opening and evaluated ischemia/reperfusion injury [121]. Mitochondrial swelling is also used in our laboratory of experimental hepatology to evaluate changes in mitochondrial metabolism after exposure to hepatotoxic and hepatoprotective substances. ...
... triiodothyronine on calcium-induced mitochondrial swelling [69]. We also assessed tissue specificity [117], age-dependent differences [118,119], and differences between male and female tissues [120] to calcium-and ROS-induced pore opening and evaluated ischemia/reperfusion injury [121]. Mitochondrial swelling is also used in our laboratory of experimental hepatology to evaluate changes in mitochondrial metabolism after exposure to hepatotoxic and hepatoprotective substances. ...
The mitochondrial permeability transition pore (MPTP) is a calcium-dependent, ion non-selective membrane pore with a wide range of functions. Although the MPTP has been studied for more than 50 years, its molecular structure remains unclear. Short-term (reversible) opening of the MPTP protects cells from oxidative damage and enables the efflux of Ca2+ ions from the mitochondrial matrix and cell signaling. However, long-term (irreversible) opening induces processes leading to cell death. Ca2+ ions, reactive oxygen species, and changes in mitochondrial membrane potential regulate pore opening. The sensitivity of the pore to Ca2+ ions changes as an organism ages, and MPTP opening plays a key role in the pathogenesis of many diseases. Most studies of the MPTP have focused on elucidating its molecular structure. However, understanding the mechanisms that will inhibit the MPTP may improve the treatment of diseases associated with its opening. To evaluate the functional state of the MPTP and its inhibitors, it is therefore necessary to use appropriate methods that provide reproducible results across laboratories. This review summarizes our current knowledge of the function and regulation of the MPTP. The latter part of the review introduces two optimized methods for evaluating the functional state of the pore under standardized conditions.
... There were no differences in functional measurements of respiratory chain activities in mitochondria isolated from male and female rat hearts [51]. To determine the role of sex in mitochondrial bioenergetic function in a cellular context, we performed the Seahorse Cell Mito Stress test in intact cardiomyocytes isolated from age-matched adult male and female mice in this study. ...
... While sex differences have been observed in mitochondrial ROS production/oxidative damage [61][62][63] and in calcium-induced mitochondrial swelling (mitochondrial permeability transition pore opening) [51,64], there is little information available regarding the role of sex in mitochondrial bioenergetic function in adult cardiomyocytes. It is noteworthy that sex-specific differences have been reported in metabolic responses following acute injury, such as trauma, shock, and sepsis [65,66]. ...
... We observed that during normal conditions, there were no differences in the mitochondrial bioenergetic response in cardiomyocytes isolated from age-matched adult male and female mice. In fact, comparable mitochondrial respiratory chain activities in substrate oxidation and coupled ATP generation have been reported in mitochondria from male and female rat hearts, with similar amounts of respiratory chain complexes I-IV [51]. However, there was better mitochondrial metabolic function with higher maximal respiration capacity in cardiomyocytes from female mice when compared to those from male ones in response to TNFα or H 2 O 2 , indicating better performance and less damage in cardiomyocytes from female animals during such stress. ...
Cardiac dysfunction/damage following trauma, shock, sepsis, and ischemia impacts clinical outcomes. Acute inflammation and oxidative stress triggered by these injuries impair mitochondria, which are critical to maintaining cardiac function. Despite sex dimorphisms in consequences of these injuries, it is unclear whether mitochondrial bioenergetic responses to inflammation/oxidative stress are sex-dependent. We hypothesized that sex disparity in mitochondrial bioenergetics following TNFα or H2O2 exposure is responsible for reported sex differences in cardiac damage/dysfunction. Methods and Results: Cardiomyocytes isolated from age-matched adult male and female mice were subjected to 1 h TNFα or H2O2 challenge, followed by detection of mitochondrial respiration capacity using the Seahorse XF96 Cell Mito Stress Test. Mitochondrial membrane potential (ΔΨm) was analyzed using JC-1 in TNFα-challenged cardiomyocytes. We found that cardiomyocytes isolated from female mice displayed a better mitochondrial bioenergetic response to TNFα or H2O2 than those isolated from male mice did. TNFα decreased ΔΨm in cardiomyocytes isolated from males but not from females. 17β-estradiol (E2) treatment improved mitochondrial metabolic function in cardiomyocytes from male mice subjected to TNFα or H2O2 treatment. Conclusions: Cardiomyocyte mitochondria from female mice were more resistant to acute stress than those from males. The female sex hormone E2 treatment protected cardiac mitochondria against acute inflammatory and oxidative stress.
... In addition, only male rats were examined in the present study, despite data indicating female hearts are protected from ischemia-reperfusion damage compared with male hearts (49)(50)(51). Some investigations have revealed functional differences between male and female cardiac mitochondria (52)(53)(54), particularly in terms of calcium handling (52,53), and therefore, future studies should expand the whole pathway analysis employed in the present study to mitochondria from female hearts, both with and without ischemic damage. ...
Myocardial ischemia has long-lasting negative impacts on cardiomyocyte mitochondrial ATP production. However, the location(s) of damage to the oxidative phosphorylation pathway responsible for altered mitochondrial function is unclear. Mitochondrial reactive oxygen species (ROS) production increases following ischemia, but the specific factors controlling this increase are unknown. To determine how ischemia affects the mitochondrial energy conversion cascade and ROS production, mitochondrial driving forces (redox potential and membrane potential (ΔΨ)) were measured at resting, intermediate, and maximal respiration rates in mitochondria isolated from rat hearts after 60 minutes of control flow (Control) or no-flow ischemia (Ischemia). The effective activities of the dehydrogenase enzymes, the electron transport chain (ETC), and ATP synthesis and transport were computed using the driving forces and flux. Ischemia lowered maximal mitochondrial respiration rates and diminished the responsiveness of respiration to both redox potential and ΔΨ. Ischemia decreased the activities of every component of the oxidative phosphorylation pathway: the dehydrogenase enzymes, the ETC, and ATP synthesis and transport. ROS production was linearly related to driving force down the ETC; however, Ischemia mitochondria demonstrated a greater driving force down the ETC and higher ROS production. Overall, results indicate that ischemia ubiquitously damages the oxidative phosphorylation pathway, reduces mitochondrial sensitivity to driving forces, and augments the propensity for electrons to leak from the ETC. These findings underscore that strategies to improve mitochondrial function following ischemia must target the entire mitochondrial energy conversion cascade.
... Indeed, in mitochondria isolated from both ventricles and septum of adult male and female Wistar rats, mitochondrial permeability transition pore sensitivity to Ca 2+ load showed sex differences: female mitochondria are more resistant, both in the extent and in the rate of the mitochondrial swelling at higher Ca 2+ concentration (200 µM). At low Ca 2+ concentration (50 µM) no differences were detected [111]. Female rat ventricles have been found to present higher levels of α-and β-myosin heavy chain (MHC) mRNA and of actin mRNA in comparison to males, but no differences were found in the ratio of α-to β-MHC between female and male rats [112]. ...
Heart failure (HF) is growing in prevalence, due to an increase in aging and comorbidities. Heart failure with reduced ejection fraction (HFrEF) is more common in men, whereas heart failure with preserved ejection fraction (HFpEF) has a higher prevalence in women. However, the reasons for these epidemiological trends are not clear yet. Since HFpEF affects mostly postmenopausal women, sex hormones should play a pivotal role in HFpEF development. Furthermore, for HFpEF, contrary to HFrEF, effective therapeutic approaches are missing. Interestingly, studies evidenced that some therapies can have better results in women than in HFpEF men, emphasizing the necessity of understanding these observations at a molecular level. Thus, herein, we review the molecular mechanisms of estrogen and androgen actions in the heart in physiological conditions and explain how its dysregulation can lead to disease development. This clarification is essential in the road for an effective personalized management of HF, particularly HFpEF, towards the development of sex-specific therapeutic approaches.
... Necrosome formation, along with a drop in mitochondrial membrane potential, induces the opening of a small pore, known as the mitochondrial permeability transition pore (MPTP), which increases the mitochondrial permeability to cause swelling, ultimately leading to cell death [80]. The extent of necrosis differs between males and females, as female mitochondria have higher Ca 2+ capacity and as a result, present less Ca 2+ -induced swelling and MPTP [81]. The E2 protection against MPTP opening has been observed to occur mainly through the function of ERβ [82]. ...
Biological sex influences disease development and progression. The steroid hormone 17β-oestradiol (E2), along with its receptors, is expected to play a major role in the manifestation of sex differences. E2 exerts pleiotropic effects in a system-specific manner. Mitochondria are one of the central targets of E2, and their biogenesis and respiration are known to be modulated by E2. More recently, it has become apparent that E2 also regulates mitochondrial fusion–fission dynamics, thereby affecting cellular metabolism. The aim of this article is to discuss the regulatory pathways by which E2 orchestrates the activity of several components of mitochondrial dynamics in the cardiovascular and nervous systems in health and disease. We conclude that E2 regulates mitochondrial dynamics to maintain the mitochondrial network promoting mitochondrial fusion and attenuating mitochondrial fission in both the cardiovascular and nervous systems.
... Interestingly, we found male sparrows had significantly higher activities of HK and CS than females, independent of altitude. Our results are inconsistent with the finding showing no differences in CS and HK activities in the myocardium between sexes in rats (Milerová et al. 2016). Generally, the sex-based differences for animals in behavior, neuroendocrinology, and physiology are generally related to stress response, locomotor ability and body composition, etc. (Blanchard et al. 1995;Koolhaas et al. 1995;Martinez et al. 1998). ...
Background
Efficient and selective utilization of metabolic substrates is one of the key strategies in high-altitude animals to cope with hypoxia and hypothermia. Previous findings have shown that the energy substrate utilization of highland animals varies with evolutionary history and phylogeny. The heart is a proxy for the cardiopulmonary system, and the metabolic substrate utilization in the myocardium is also under the strong selective pressure of chronically hypoxic and hypothermic environments. However, little information is available on the physiological adjustments in relation to metabolic substrate utilization in the myocardium for coping with high-altitude environments.
Methods
We compared the metabolic enzyme activities, including hexokinase (HK), phosphofructokinase (PFK), pyruvate kinase (PK), citrate synthase (CS), carnitine palmitoyl transferase 1 (CPT-1), lactic dehydrogenase (LDH), and creatine kinase (CK), and metabolic substrate contents including glucose (Glu), triglyceride (TG), and free fatty acid (FFA) in the myocardium of a typical human commensal species, Eurasian Tree Sparrows ( Passer montanus ) between the Qinghai-Tibet Plateau (the QTP, 3230 m) and low altitude population (Shijiazhuang, 80 m), and between sexes.
Results
Among the seven metabolic enzymes and three substrates investigated, we identified no significant differences in PK, CPT-1, HK, CS, LDH, and CK activities and TG content of the myocardium between high and low altitude populations. However, the QTP sparrows had significantly lower Glu content and PFK activities but higher FFA content relative to their lowland counterparts. In addition, male sparrows had higher myocardial HK and CS activities relative to females, independent of altitude.
Conclusions
Our results showed that the QTP sparrows elevated fatty acid utilization rather than glucose preference in the myocardium relative to lowland counterpart, which contributes to uncovering both the physiological adjustments for adapting to the extreme conditions of the QTP, intraspecifically.
... Compared with females, males have a lower capacity for calcium retention and greater sensitivity to Ca 2+ -induced mitochondrial permeability transition pore opening, further supporting the cardioprotective role of oestrogen in the heart [105][106][107] . Gene expression analyses in mice and rats support these findings, revealing considerable sexual dimorphism in cardiac mitochondria at the transcriptional level for genes related to fatty acid metabolism, oxidative phosphorylation and apoptosis 108,109 . ...
The convergence of tissue engineering and patient-specific stem cell biology has enabled the engineering of in vitro tissue models that allow the study of patient-tailored treatment modalities. However, sex-related disparities in health and disease, from systemic hormonal influences to cellular-level differences, are often overlooked in stem cell biology, tissue engineering and preclinical screening. The cardiovascular system, in particular, shows considerable sex-related differences, which need to be considered in cardiac tissue engineering. In this Review, we analyse sex-related properties of the heart muscle in the context of health and disease, and discuss a framework for including sex-based differences in human cardiac tissue engineering. We highlight how sex-based features can be implemented at the cellular and tissue levels, and how sex-specific cardiac models could advance the study of cardiovascular diseases. Finally, we define design criteria for sex-specific cardiac tissue engineering and provide an outlook to future research possibilities beyond the cardiovascular system.
... V našich pracích jsme testovali hypotézu, zda je úloha MPTP v patogenezi I/R poškození srdečního svalu závislá na pohlaví. 36,88,89 Zjistili jsme, že srdeční mitochondrie samic jsou významně odolnější k bobtnání, vyvolanému vyšší koncentrací Ca 2+ , což svědčí pro jejich větší odolnost k otevření MPTP (obr.7). Vzhledem k tomu, že otevření póru na vnitřní mitochondriální membráně je úzce spojeno se vznikem I/R poškození, je vyšší odolnost této struktury k Ca 2+ jedním z možných vysvětlení vyšší tolerance samičího srdce. ...
Experimental and clinical studies have clearly demonstrated significant sex differences in myocardial structure and function under normal and pathological conditions. The best examples are significant sex differences in cardiac tolerance to ischemia-reperfusion injury: adult male hearts are more susceptible as compared to pre-menopausal female heart. The importance of these findings is documented by the increasing number of publications on this topic during the last years. Detailed cellular and molecular mechanisms, responsible for sex differences are, unfortunately, still not known; it has been stressed that estrogens are not the only factor involved. Recently, a new hypothesis has been developed, suggesting an important role of cardiac mitochondria. One is clear already today: sex differences are so important that they should be taken into consideration in the clinical practice for the selection of the optimal diagnostic and therapeutic strategy.
