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Variation of the calcium retention capacity of cardiac mitochondria over the day. (A) Representative traces for calcium pulsing assay that is used to assess calcium retention capacity (CRC) of freshly isolated cardiac mitochondria from hearts of mice sacrificed at ZG 0 (Wake) and ZG 4 (Sleep) with arrows indicating successive infusions of 20-µM calcium pulses every 60 s in the presence of the low-affinity Calcium Green 5 N dye as detailed in the Methods' Section. (B) Chronogram displaying time of the daydependent variations in CRC of cardiac mitochondria (µM Ca 2+ /µg protein). n=7, 9, 6, 6, 5, 6 animals time
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Introduction
Incidents of myocardial infarction and sudden cardiac arrest vary with time of the day, but the mechanism for this effect is not clear. We hypothesized that diurnal changes in the ability of cardiac mitochondria to control calcium homeostasis dictate vulnerability to cardiovascular events.
Objectives
Here we investigate mitochondrial...
Contexts in source publication
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... traces for Ca 2+ pulsing of cardiac mitochondria at ZG 0 (wake) and ZG 4 (sleep) are given in Fig. 1A. It is clear from Fig. 1A that cardiac mitochondria isolated during sleep period exhibit greater tolerance to calcium pulsing relative to those isolated from animals sacrificed during their wake periods. and ZG 20, p<0.01, by ANOVA followed by Tukey test, N=5-9 animals per time point as specified in the figure's legend). Overall, when ...
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... traces for Ca 2+ pulsing of cardiac mitochondria at ZG 0 (wake) and ZG 4 (sleep) are given in Fig. 1A. It is clear from Fig. 1A that cardiac mitochondria isolated during sleep period exhibit greater tolerance to calcium pulsing relative to those isolated from animals sacrificed during their wake periods. and ZG 20, p<0.01, by ANOVA followed by Tukey test, N=5-9 animals per time point as specified in the figure's legend). Overall, when time points were combined ...
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... 0.57 respectively; p0.01), suggesting delayed mPTP opening of cardiac mitochondria under Ca 2+ overload during sleep (Fig. ...
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... shed light on the inherent ability of mitochondria to handle calcium stress we analyzed the average rates of mitochondrial Ca 2+ uptake ( Supplementary Fig. S1) by calculating the slope of the initial phase of fluorescence decay as shown in Fig. 2A. Traces with clear pulses characterized by fluorescence rise followed by fluorescence decay (Ca 2+ uptake), plateau (equilibrium), or even rise (release) prior to mPTP openings were considered in this analysis which is reflected in positive, zero, or negative rate values. ...
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... with clear pulses characterized by fluorescence rise followed by fluorescence decay (Ca 2+ uptake), plateau (equilibrium), or even rise (release) prior to mPTP openings were considered in this analysis which is reflected in positive, zero, or negative rate values. We show in Supplementary Fig. S1.A the chronogram of the normalized rates of calcium uptake at various time points. Only ZG 4 showed statistically higher rates relative to ZG 8 and ZG 12 (p<0.05). ...
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... statistically higher rates relative to ZG 8 and ZG 12 (p<0.05). Yet, the rates of Ca 2+ uptake calculated from the initial uptake phase for each of the first 4 pulses of Ca 2+ during sleep and wake periods were not significantly different (1.10 ± 0.16 M.min -1 .g -1 protein during wake vs. 1.25 ± 0.20 M.min -1 .g -1 protein during sleep, Fig. S1.B). To evaluate the overall rate of calcium uptake for each pulse we followed the time after which the signal amplitude drops to half of its initial value [31]. Mean half-amplitude time determined at ZG 16 was significantly greater than all other time points including ZG 4 (Fig. 2D). When combined data from wake period was compared ...
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Calcium homeostasis plays a vital role in protecting against Alzheimer’s disease (AD). In this study, amyloid-β (Aβ)-induced C. elegans models of AD were used to elucidate the mechanisms underlying calcium homeostasis in AD. Calcium acetate increased the intracellular calcium content, exacerbated Aβ1–42 aggregation, which is closely associated with...
Citations
... Compared with the vegetative stage (VC), 40 proteins are up-regulated more than 2-fold in the EXC stage (Table S3 in Supporting Information). The first-ranked protein (MSTRG.14207.1_fr2) is up-regulated 11.25-fold ( Figure S3A in Supporting Information), containing a domain of K +dependent Na + /Ca 2+ exchanger, which indicates that it may be related to functions such as transport and binding proteins (Abdel-Rahman et al., 2021). The second to fifth-ranked proteins (MSTRG.15482.1_fr3, ...
Sexual reproduction first appeared in unicellular protists and has continued to be an essential biological process in almost all eukaryotes. Ciliated protists, which contain both germline and somatic genomes within a single cell, have evolved a special form of sexual reproduction called conjugation that involves mitosis, meiosis, fertilization, nuclear differentiation, genome rearrangement, and the development of unique cellular structures. The molecular basis and mechanisms of conjugation vary dramatically among ciliates, and many details of the process and its regulation are still largely unknown. In order to better comprehend these processes and mechanisms from an evolutionary perspective, this study provides the first comprehensive overview of the transcriptome and proteome profiles during the entire life cycle of the newly-established marine model ciliate Euplotes vannus. Transcriptome analyses from 14 life cycle stages (three vegetative stages and 11 sexual stages) revealed over 26,000 genes that are specifically expressed at different stages, many of which are related to DNA replication, transcription, translation, mitosis, meiosis, nuclear differentiation, and/or genome rearrangement. Quantitative proteomic analyses identified 338 proteins with homologs associated with conjugation and/or somatic nuclear development in other ciliates, including dicer-like proteins, Hsp90 proteins, RNA polymerase II and transcription elongation factors, ribosomal-associated proteins, and ubiquitin-related proteins. Four of these homologs belong to the PIWI family, each with different expression patterns identified and confirmed by RT-qPCR, which may function in small RNA-mediated genome rearrangement. Proteins involved in the nonhomologous end-joining pathway are induced early during meiosis and accumulate in the developing new somatic nucleus, where more than 80% of the germline sequences are eliminated from the somatic genome. A number of new candidate genes and proteins likely to play roles in conjugation and its related genome rearrangements have also been revealed. The gene expression profiles reported here will be valuable resources for further studies of the origin and evolution of sexual reproduction in this new model species.
... Alterations of metabolic enzyme activity and ATP production eventually trigger heart failure (HF) as cardiomyocytes lack the ATP necessary to survive (Parihar and Parihar, 2017;Avula et al., 2021;Bulló et al., 2021). Thus, as a regulator of cellular mitochondrial homeostasis, mitophagy is a crucial factor in cardiomyocyte function and cardiac health (Morales et al., 2020;Abdel-Rahman et al., 2021;Ning et al., 2023). ...
Although highly active antiretroviral therapy (HAART) has changed infection with human immunodeficiency virus (HIV) from a diagnosis with imminent mortality to a chronic illness, HIV positive patients who do not develop acquired immunodeficiency syndrome (AIDs) still suffer from a high rate of cardiac dysfunction and fibrosis. Regardless of viral load and CD count, HIV-associated cardiomyopathy (HIVAC) still causes a high rate of mortality and morbidity amongst HIV patients. While this is a well characterized clinical phenomena, the molecular mechanism of HIVAC is not well understood. In this review, we consolidate, analyze, and discuss current research on the intersection between autophagy and HIVAC. Multiple studies have linked dysregulation in various regulators and functional components of autophagy to HIV infection regardless of mode of viral entry, i.e., coronary, cardiac chamber, or pericardial space. HIV proteins, including negative regulatory factor (Nef), glycoprotein 120 (gp120), and transactivator (Tat), have been shown to interact with type II microtubule-associated protein-1 β light chain (LC3-II), Rubiquitin, SQSTM1/p62, Rab7, autophagy-specific gene 7 (ATG7), and lysosomal-associated membrane protein 1 (LAMP1), all molecules critical to normal autophagy. HIV infection can also induce dysregulation of mitochondrial bioenergetics by altering production and equilibrium of adenosine triphosphate (ATP), mitochondrial reactive oxygen species (ROS), and calcium. These changes alter mitochondrial mass and morphology, which normally trigger autophagy to clear away dysfunctional organelles. However, with HIV infection also triggering autophagy dysfunction, these abnormal mitochondria accumulate and contribute to myocardial dysfunction. Likewise, use of HAART, azidothymidine and Abacavir, have been shown to induce cardiac dysfunction and fibrosis by inducing abnormal autophagy during antiretroviral therapy. Conversely, studies have shown that increasing autophagy can reduce the accumulation of dysfunctional mitochondria and restore cardiomyocyte function. Interestingly, Rapamycin, a mammalian target of rapamycin (mTOR) inhibitor, has also been shown to reduce HIV-induced cytotoxicity by regulating autophagy-related proteins, making it a non-antiviral agent with the potential to treat HIVAC. In this review, we synthesize these findings to provide a better understanding of the role autophagy plays in HIVAC and discuss the potential pharmacologic targets unveiled by this research.
... The alteration of stress vulnerability could be another mechanism to explain our observations. Animal studies show that during sleep, retaining mitochondrial calcium in the heart increases vulnerability to cardiac stress during the sleep-wake transition by dissipating membrane potential, slowing respiratory activities, and increasing ROS levels, and the change in stress vulnerability in the mitochondrial functions may explain the diurnal prevalence of cardiac pathologies [27]. ...
Background
Currently, it is still largely unknown whether the proportion of calcium intake at breakfast and dinner is associated with cardiovascular disease (CVD) in the general population.
Objectives
The aim of this study was to evaluate the association of dietary calcium intake at dinner versus breakfast with CVD in a nationally representative sample of US adults.
Methods
The study population consisted of 36,164 US adults (including 4,040 CVD cases) from the NHANES 2003 to 2018. According to the ratio of dietary calcium intake at dinner and breakfast (Δ = dinner/breakfast), 36,164 participants were divided into five groups. After adjustment for a series of confounder factors, logistic regression analyses were performed to examine the association between Δ and CVD. Dietary substitution models were used to explore the changes in CVD risk when a 5% dietary calcium intake at dinner was substituted with dietary calcium intake at breakfast.
Results
Compared with participants in the lowest quintile, participants in the highest quintile were more likely to have CVD, with an adjusted OR of CVD of 1.16 (95% CI, 1.03 to 1.31). When the total calcium intake remained constant, replacing a 5% dietary calcium intake at dinner with dietary calcium intake at breakfast was associated with a 6% lower risk of CVD.
Conclusions
Compared to the lowest quintile of Δ, participants in the highest quintile of Δ were likely to experience CVD in the general population. It is necessary to scientifically allocate dietary calcium intake at breakfast and dinner.
... Data from the 2007-2008 National Health and Nutrition Examination Survey (NHANES) showed lower alpha carotene was associated with greater difficulty maintaining sleep patterns [40]. In addition, previous studies have identified diurnal fluctuations in mitochondrial calcium dynamics that contribute to mROS [41]. This evidence suggests that maintaining mitochondrial health via carotenoids may have potential benefit in sleep. ...
Oxidative stress, an imbalance between pro-oxidant and antioxidant status, favouring the pro-oxidant state is a result of increased production of reactive oxygen species (ROS) or inadequate antioxidant protection. ROS are produced through several mechanisms in cells including during mitochondrial oxidative phosphorylation. Increased mitochondrial-derived ROS are associated with mitochondrial dysfunction, an early event in age-related diseases such as Alzheimer's diseases (ADs) and in metabolic disorders including diabetes. AD post-mortem investigations of affected brain regions have shown the accumulation of oxidative damage to macromolecules, and oxidative stress has been considered an important contributor to disease pathology. An increase in oxidative stress, which leads to increased levels of superoxide, hydrogen peroxide and other ROS in a potentially vicious cycle is both causative and a consequence of mitochondrial dysfunction. Mitochondrial dysfunction may be ameliorated by molecules with antioxidant capacities that accumulate in mitochondria such as carotenoids. However, the role of carotenoids in mitigating mitochondrial dysfunction is not fully understood. A better understanding of the role of antioxidants in mitochondrial function is a promising lead towards the development of novel and effective treatment strategies for age-related diseases. This review evaluates and summarises some of the latest developments and insights into the effects of carotenoids on mitochondrial dysfunction with a focus on the antioxidant properties of carotenoids. The mitochondria-protective role of carotenoids may be key in therapeutic strategies and targeting the mitochondria ROS is emerging in drug development for age-related diseases.
... Assessment of mitochondrial respiratory rates and hydrogen peroxide production rates was performed at 37 • C using the highresolution respirometry O2k system (Oroboros Oxygraph, Innsbruck, Austria) as described previously [97]. Prior to the experiment, oxygen calibration was carried out by permitting the respiration medium, MiR05 (110 mM sucrose, 0.5 mM EGTA, 3.0 mM MgCl 2 , 80 mM KCl, 60 mM K-lactobionate, 10 mM KH 2 PO 4 , 20 mM Taurine, 20 mM Hepes, 1.0 g/L BSA, pH 7.1) to equilibrate with air in a 2 mL oxygraph chamber while stirred at 540-560 rpm for 30-40 min, up till a stable signal was obtained. ...
... Furthermore, Hsp27 significantly inhibits ROS generation [40,41]. Mitochondria are the primary source of ROS production in cardiomyocytes [42]. Mitochondrial membrane potential is commonly used to assess mitochondrial function, and a decrease in the mitochondrial membrane potential suggests mitochondrial dysfunction. ...
Research suggests that ischemic glycolysis improves myocardial tolerance to anoxia and low-flow ischemia. The rate of glycolysis during ischemia reflects the severity of the injury caused by ischemia and subsequent functional recovery following reperfusion. Histone H2AK119 ubiquitination ( H2Aub ) is a common modification that is primarily associated with gene silencing. Recent studies have demonstrated that H2Aub contributes to the development of cardiovascular diseases. However, the underlying mechanism remains unclear. This study identified Hsp27 (heat shock protein 27) as a H2Aub binding protein and explored its involvement in mediating glycolysis and mitochondrial function. Functional studies revealed that inhibition of PRC1 (polycomb repressive complex 1) decreased H2Aub occupancy and promoted Hsp27 expression through inhibiting ubiquitination. Additionally, it increased glycolysis by activating the NF-κB / PFKFB3 signaling pathway during myocardial ischemia. Furthermore, Hsp27 reduced mitochondrial ROS production by chaperoning COQ9 , and suppressed ferroptosis during reperfusion. A delivery system was developed based on PCL-PEG-MAL (PPM)-PCM-SH (CWLSEAGPVVTVRALRGTGSW) to deliver PRT4165 (PRT), a potent inhibitor of PRC1 , to damaged myocardium, resulting in decreased H2Aub . These findings revealed a novel epigenetic mechanism connecting glycolysis and ferroptosis in protecting the myocardium against ischemia/reperfusion injury.
... For example, nuclear factor-erythroid 2-related factor 2 (NRF2) serves as a redox-responsive factor and mediates ROS elimination, 256 while downregulation of NRF2 is observed in elderly individuals. As expected, reduced ROS production or the oxidized form of glutathione (GSSG) disposition ameliorates cardiac aging, 257,258 supporting the concept that ROS derived by mitochondria are harmful to aging hearts. Recently, the correlation between ROS with cardiac aging is reported in some preclinical studies. ...
Cardiac aging is evident by a reduction in function which subsequently contributes to heart failure. The metabolic microenvironment has been identified as a hallmark of malignancy, but recent studies have shed light on its role in cardiovascular diseases (CVDs). Various metabolic pathways in cardiomyocytes and noncardiomyocytes determine cellular senescence in the aging heart. Metabolic alteration is a common process throughout cardiac degeneration. Importantly, the involvement of cellular senescence in cardiac injuries, including heart failure and myocardial ischemia and infarction, has been reported. However, metabolic complexity among human aging hearts hinders the development of strategies that targets metabolic susceptibility. Advances over the past decade have linked cellular senescence and function with their metabolic reprogramming pathway in cardiac aging, including autophagy, oxidative stress, epigenetic modifications, chronic inflammation, and myocyte systolic phenotype regulation. In addition, metabolic status is involved in crucial aspects of myocardial biology, from fibrosis to hypertrophy and chronic inflammation. However, further elucidation of the metabolism involvement in cardiac degeneration is still needed. Thus, deciphering the mechanisms underlying how metabolic reprogramming impacts cardiac aging is thought to contribute to the novel interventions to protect or even restore cardiac function in aging hearts. Here, we summarize emerging concepts about metabolic landscapes of cardiac aging, with specific focuses on why metabolic profile alters during cardiac degeneration and how we could utilize the current knowledge to improve the management of cardiac aging.
... organelles for reactive oxygen species (ROS) production in cardiomyocytes [7]. Cardiac aging is accompanied by a decline in mitochondrial function, accumulation of dysfunctional mitochondria, increased ROS production, and dysregulated mitochondrial quality control [8,9]. Damaged mitochondria cannot be easily cleared away via cell division, given their insufficient ability to proliferate and dilute damaged mitochondria through cell division. ...
Compromised mitophagy and mitochondrial homeostasis are major contributors for the etiology of cardiac aging, although the precise underlying mechanisms remains elusive. Shank3, a heart-enriched protein, has recently been reported to regulate aging-related neurodegenerative diseases. This study aimed to examine the role of Shank3 in the pathogenesis of cardiac senescence and the possible mechanisms involved. Cardiac-specific conditional Shank3 knockout (Shank3CKO) mice were subjected to natural aging. Mitochondrial function and mitophagy activity were determined in vivo, in mouse hearts and in vitro, in cardiomyocytes. Here, we showed that cardiac Shank3 expression exhibited a gradual increase during the natural progression of the aging, accompanied by overtly decreased mitophagy activity and a decline in cardiac function. Ablation of Shank3 promoted mitophagy, reduced mitochondria-derived superoxide (H2O2 and O2•⁻) production and apoptosis, and protected against cardiac dysfunction in the aged heart. In an in vitro study, senescent cardiomyocytes treated with D-gal exhibited reduced mitophagy and significantly elevated Shank3 expression. Shank3 knock-down restored mitophagy, leading to increased mitochondrial membrane potential, decreased mitochondrial oxidative stress, and reduced apoptosis in senescent cardiomyocytes, whereas Shank3 overexpression mimicked D-gal-induced mitophagy inhibition and mitochondrial dysfunction in normally cultured cardiomyocytes. Mechanistically, the IP assay revealed that Shank3 directly binds to CaMKII, and this interaction was further increased in the aged heart. Enhanced Shank3/CaMKII binding impedes mitochondrial translocation of CaMKII, resulting in the inhibition of parkin-mediated mitophagy, which ultimately leads to mitochondrial dysfunction and cardiac damage in the aged heart. Our study identified Shank3 as a novel contributor to aging-related cardiac damage. Manipulating Shank3/CaMKII-induced mitophagy inhibition could thus be an optional strategy for therapeutic intervention in clinical aging-related cardiac dysfunctions.
... This observation raises the question of whether internal clocks also set the pace of mitochondrial solute carriers and H + -cation exchangers, as these are critical for chemiosmotic processes. In this context, a correlative study between diurnal fluctuation of cardiac OXPHOS and Ca 2+ dynamics has shown increased activity of the mitochondrial Na + / Ca 2+ exchanger and Ca 2+ transporters, as well as a higher mitochondrial Ca 2+ retention capacity at night than in the day, and attributed the increased cardiac daytime vulnerability to reduced daytime mitochondrial Ca 2+ dynamics (Abdel-Rahman et al, 2021). ...
... More recent evidence indicates that many cation channels can be regulated over daily time (Abdel-Rahman et al, 2021). We thus wondered whether the protein levels of Letm1 might change across the day. ...
Mitochondria are fundamental for life and require balanced ion exchange to maintain proper functioning. The mitochondrial cation exchanger LETM1 sparks interest because of its pathophysiological role in seizures in the Wolf Hirschhorn Syndrome (WHS). Despite observation of sleep disorganization in epileptic WHS patients, and growing studies linking mitochondria and epilepsy to circadian rhythms, LETM1 has not been studied from the chronobiological perspective. Here we established a viable letm1 knock-out, using the diurnal vertebrate Danio rerio to study the metabolic and chronobiological consequences of letm1 deficiency. We report diurnal rhythms of Letm1 protein levels in wild-type fish. We show that mitochondrial nucleotide metabolism is deregulated in letm1−/− mutant fish, the rate-limiting enzyme of NAD ⁺ production is up-regulated, while NAD ⁺ and NADH pools are reduced. These changes were associated with increased expression amplitude of circadian core clock genes in letm1−/− compared with wild-type under light/dark conditions, suggesting decreased NAD(H) levels as a possible mechanism for circadian system perturbation in Letm1 deficiency. Replenishing NAD pool may ameliorate WHS-associated sleep and neurological disorders.
