bims-midhyp Biomed News
on Mitochondrial dysfunction and hypoxia
Issue of 2023‒07‒16
nineteen papers selected by
Alia Ablieh, Universität Heidelberg
  1. Mitochondria as intracellular signalling organelles. An update.
  2. Targeting AMPK/eNOS pathway and mitochondria by sonlicromanol protects myocardial cells against ischemia-reperfusion injury.
  3. Mitochondrial respiratory complex I deficiency inhibits brown adipogenesis by limiting heme regulation of histone demethylation.
  4. Aerobic Glycolysis in Photoreceptors Supports Energy Demand in the Absence of Mitochondrial Coupling.
  5. Aging Triggers Mitochondrial Dysfunction in Mice.
  6. MYC overrides HIF-1α to regulate proliferating primary cell metabolism in hypoxia.
  7. Mitochondria Deregulations in Cancer Offer Several Potential Targets of Therapeutic Interventions.
  8. Postictal hypoxia involves reactive oxygen species and is ameliorated by chronic mitochondrial uncoupling.
  9. Fluorescence microscopy imaging of mitochondrial metabolism in cancer cells.
  10. Mitochondria in cell senescence: A Friend or Foe?
  11. The impact of hypoxia-inducible factors in the pathogenesis of kidney diseases: a link through cell metabolism.
  12. Hypoxia-reprogramed megamitochondrion contacts and engulfs lysosome to mediate mitochondrial self-digestion.
  13. Mitochondrial Integrity Is Critical in Right Heart Failure Development.
  14. The Complex Relationship between Hypoxia Signaling, Mitochondrial Dysfunction and Inflammation in Calcific Aortic Valve Disease: Insights from the Molecular Mechanisms to Therapeutic Approaches.
  15. Neferine protected cardiomyocytes against hypoxia/oxygenation injury through SIRT1/Nrf2/HO-1 signaling.
  16. The Transcription Factor RUNX1 Aggravates Hypoxia-Induced Human Retinal Microvascular Endothelial Cell Dysfunction by Negatively Regulating TFF1 Promoter.
  17. Cytochrome c lysine acetylation regulates cellular respiration and cell death in ischemic skeletal muscle.
  18. Mechanisms of BCL-2 family proteins in mitochondrial apoptosis.
  19. Functional decomposition of metabolism allows a system-level quantification of fluxes and protein allocation towards specific metabolic functions.
  1. Cell Signal. 2023 Jul 06. pii: S0898-6568(23)00208-5. [Epub ahead of print]109 110794
    Mitochondria as intracellular signalling organelles. An update.
    Lucia-Doina Popov.
      Traditionally, mitochondria are known as "the powerhouse of the cell," responsible for energy (ATP) generation (by the electron transport chain, oxidative phosphorylation, the tricarboxylic acid cycle, and fatty acid ß-oxidation), and for the regulation of several metabolic processes, including redox homeostasis, calcium signalling, and cellular apoptosis. The extensive studies conducted in the last decades portray mitochondria as multifaceted signalling organelles that ultimately command cells' survival or death. Based on current knowledge, we'll outline the mitochondrial signalling to other intracellular compartments in homeostasis and pathology-related mitochondrial stress conditions here. The following topics are discussed: (i) oxidative stress and mtROS signalling in mitohormesis, (ii) mitochondrial Ca2+ signalling; (iii) the anterograde (nucleus-to-mitochondria) and retrograde (mitochondria-to-nucleus) signal transduction, (iv) the mtDNA role in immunity and inflammation, (v) the induction of mitophagy- and apoptosis - signalling cascades, (vi) the mitochondrial dysfunctions (mitochondriopathies) in cardiovascular, neurodegenerative, and malignant diseases. The novel insights into molecular mechanisms of mitochondria-mediated signalling can explain mitochondria adaptation to metabolic and environmental stresses to achieve cell survival.
    Keywords:  Mitochondriopathies; Mitophagy; Oxidative stress; Signal transduction; mtDNA
    DOI:  https://doi.org/10.1016/j.cellsig.2023.110794
  2. Gen Physiol Biophys. 2023 Jul;42(4): 373-382
    Targeting AMPK/eNOS pathway and mitochondria by sonlicromanol protects myocardial cells against ischemia-reperfusion injury.
    Kun Liao, Fangfei Huang, Xing Xie, Linhui Li.
      This work evaluated the cardioprotective effects of sonlicromanol, a new mitochondrial-directed drug, on cardiac ischemia/reperfusion (I/R) injury and explored the involvement of inflammatory and oxidative responses via activation of AMPK-eNOS-mitochondrial pathway. Male Sprague-Dawley rats underwent regional I/R injury through in vivo left anterior descending (LAD) coronary artery ligation for 40 minutes followed by 24 hours of reperfusion. Pretreatment of rats with sonlicromanol considerably reduced cardiac I/R injury in a dose-dependent manner, as indicated by lower infarct size and serum creatine-kinase levels, and improved cardiac function after reperfusion. Sonlicromanol (50 mg/kg) significantly reduced TNF-α, interleukin-1β, NF-κB-p65, and 8-isoprostane levels while increased manganese-superoxide dismutase and nitric-oxide levels and expression of eNOS and AMPK protein. It significantly reduced mitochondrial membrane depolarization and reactive oxygen species (ROS) levels. However, AMPK inhibition significantly reduced sonlicromanol protective actions. Cardioprotection by sonlicromanol was achieved by moderating inflammatory and oxidative responses, and AMPK/eNOS/mitochondrial signaling is a crucial regulator of these actions.
    DOI:  https://doi.org/10.4149/gpb_2023003
  3. Mitochondrion. 2023 Jul 12. pii: S1567-7249(23)00067-3. [Epub ahead of print]
    Mitochondrial respiratory complex I deficiency inhibits brown adipogenesis by limiting heme regulation of histone demethylation.
    Jingjing Liu, Wen Lu, Dongyue Yan, Junyuan Guo, Li Zhou, Bimin Shi, Xiong Su.
      Mitochondrial functions play a crucial role in determining the metabolic and thermogenic status of brown adipocytes. Increasing evidence reveals that the mitochondrial oxidative phosphorylation (OXPHOS) system plays an important role in brown adipogenesis, but the mechanistic insights are limited. Herein, we explored the potential metabolic mechanisms leading to OXPHOS regulation of brown adipogenesis in pharmacological and genetic models of mitochondrial respiratory complex I deficiency. OXPHOS deficiency inhibits brown adipogenesis through disruption of the brown adipogenic transcription circuit without affecting ATP levels. Neither blockage of calcium signaling nor antioxidant treatment can rescue the suppressed brown adipogenesis. Metabolomics analysis revealed a decrease in levels of tricarboxylic acid cycle intermediates and heme. Heme supplementation specifically enhances respiratory complex I activity without affecting complex II and partially reverses the inhibited brown adipogenesis by OXPHOS deficiency. Moreover, the regulation of brown adipogenesis by the OXPHOS-heme axis may be due to the suppressed histone methylation status by increasing histone demethylation. In summary, our findings identified a heme-sensing retrograde signaling pathway that connects mitochondrial OXPHOS to the regulation of brown adipocyte differentiation and metabolic functions.
    Keywords:  brown adipocytes; differentiation; heme; histone methylation; oxidative phosphorylation
    DOI:  https://doi.org/10.1016/j.mito.2023.07.004
  4. Adv Exp Med Biol. 2023 ;1415 435-441
    Aerobic Glycolysis in Photoreceptors Supports Energy Demand in the Absence of Mitochondrial Coupling.
    Daniel T Hass, Celia M Bisbach, Martin Sadilek, Ian R Sweet, James B Hurley.
      Metabolism is adapted to meet energetic needs. Based on the amount of ATP required to maintain plasma membrane potential, photoreceptor energy demands must be high. The available evidence suggests that photoreceptors primarily generate metabolic energy through aerobic glycolysis, though this evidence is based primarily on protein expression and not measurement of metabolic flux. Aerobic glycolysis can be validated by measuring flux of glucose to lactate. Aerobic glycolysis is also inefficient and thus an unexpected adaptation for photoreceptors to make. We measured metabolic rates to determine the energy-generating pathways that support photoreceptor metabolism. We found that photoreceptors indeed perform aerobic glycolysis and this is associated with mitochondrial uncoupling.
    Keywords:  Aerobic glycolysis; Metabolic flux; Mitochondria; Photoreceptors; Retina; Uncoupling
    DOI:  https://doi.org/10.1007/978-3-031-27681-1_64
  5. Int J Mol Sci. 2023 Jun 24. pii: 10591. [Epub ahead of print]24(13):
    Aging Triggers Mitochondrial Dysfunction in Mice.
    Frederico Luis Lima Rosa, Itanna Isis Araujo de Souza, Gustavo Monnerat, Antonio Carlos Campos de Carvalho, Leonardo Maciel.
      Direct analysis of isolated mitochondria from old mice enables a better understanding of heart senescence dysfunction. Despite a well-defined senescent phenotype in cardiomyocytes, the mitochondrial state in aged cardiomyocytes is still unclear. Here, we report data about mitochondrial function in old mice. Isolated cardiomyocytes' mitochondria were obtained by differential centrifugation from old and young mice hearts to perform functional analyses of mitochondrial O2 consumption, transmembrane potential, ROS formation, ATP production, and swelling. Our results show that mitochondria from old mouse hearts have reduced oxygen consumption during the phosphorylative states of complexes I and II. Additionally, these mitochondria produced more ROS and less ATP than those of young hearts. Mitochondria from old hearts also showed a depolarized membrane potential than mitochondria from young hearts and, as expected, a greater electron leak. Our results indicate that mitochondria from senescent cardiomyocytes are less efficient in O2 consumption, generating more ROS and producing less ATP. Furthermore, the phosphorylative state of complexes I and II presents a functional defect, contributing to greater leakage of protons and ROS production that can be harmful to the cell.
    Keywords:  aging; heart; mitochondrial dysfunction
    DOI:  https://doi.org/10.3390/ijms241310591
  6. Elife. 2023 07 10. pii: e82597. [Epub ahead of print]12
    MYC overrides HIF-1α to regulate proliferating primary cell metabolism in hypoxia.
    Courtney A Copeland, Benjamin A Olenchock, David Ziehr, Sarah McGarrity, Kevin Leahy, Jamey D Young, Joseph Loscalzo, William M Oldham.
      Hypoxia requires metabolic adaptations to sustain energetically demanding cellular activities. While the metabolic consequences of hypoxia have been studied extensively in cancer cell models, comparatively little is known about how primary cell metabolism responds to hypoxia. Thus, we developed metabolic flux models for human lung fibroblast and pulmonary artery smooth muscle cells proliferating in hypoxia. Unexpectedly, we found that hypoxia decreased glycolysis despite activation of hypoxia-inducible factor 1α (HIF-1α) and increased glycolytic enzyme expression. While HIF-1α activation in normoxia by prolyl hydroxylase (PHD) inhibition did increase glycolysis, hypoxia blocked this effect. Multi-omic profiling revealed distinct molecular responses to hypoxia and PHD inhibition, and suggested a critical role for MYC in modulating HIF-1α responses to hypoxia. Consistent with this hypothesis, MYC knockdown in hypoxia increased glycolysis and MYC over-expression in normoxia decreased glycolysis stimulated by PHD inhibition. These data suggest that MYC signaling in hypoxia uncouples an increase in HIF-dependent glycolytic gene transcription from glycolytic flux.
    Keywords:  MYC; biochemistry; cell biology; chemical biology; human; hypoxia; hypoxia-inducible factor; metabolic flux analysis; prolyl hydroxylase
    DOI:  https://doi.org/10.7554/eLife.82597
  7. Int J Mol Sci. 2023 Jun 21. pii: 10420. [Epub ahead of print]24(13):
    Mitochondria Deregulations in Cancer Offer Several Potential Targets of Therapeutic Interventions.
    Clara Musicco, Anna Signorile, Vito Pesce, Paola Loguercio Polosa, Antonella Cormio.
      Mitochondria play a key role in cancer and their involvement is not limited to the production of ATP only. Mitochondria also produce reactive oxygen species and building blocks to sustain rapid cell proliferation; thus, the deregulation of mitochondrial function is associated with cancer disease development and progression. In cancer cells, a metabolic reprogramming takes place through a different modulation of the mitochondrial metabolic pathways, including oxidative phosphorylation, fatty acid oxidation, the Krebs cycle, glutamine and heme metabolism. Alterations of mitochondrial homeostasis, in particular, of mitochondrial biogenesis, mitophagy, dynamics, redox balance, and protein homeostasis, were also observed in cancer cells. The use of drugs acting on mitochondrial destabilization may represent a promising therapeutic approach in tumors in which mitochondrial respiration is the predominant energy source. In this review, we summarize the main mitochondrial features and metabolic pathways altered in cancer cells, moreover, we present the best known drugs that, by acting on mitochondrial homeostasis and metabolic pathways, may induce mitochondrial alterations and cancer cell death. In addition, new strategies that induce mitochondrial damage, such as photodynamic, photothermal and chemodynamic therapies, and the development of nanoformulations that specifically target drugs in mitochondria are also described. Thus, mitochondria-targeted drugs may open new frontiers to a tailored and personalized cancer therapy.
    Keywords:  ROS; cancer therapy; mitochondrial drug delivery; mitochondrial inhibitors; targeting mitochondria
    DOI:  https://doi.org/10.3390/ijms241310420
  8. Neuropharmacology. 2023 Jul 06. pii: S0028-3908(23)00243-5. [Epub ahead of print]238 109653
    Postictal hypoxia involves reactive oxygen species and is ameliorated by chronic mitochondrial uncoupling.
    Bianca R Villa, Antis G George, Timothy E Shutt, Patrick G Sullivan, Jong M Rho, G Campbell Teskey.
      Prolonged severe hypoxia follows brief seizures and represents a mechanism underlying several negative postictal manifestations without interventions. Approximately 50% of the postictal hypoxia phenomenon can be accounted for by arteriole vasoconstriction. What accounts for the rest of the drop in unbound oxygen is unclear. Here, we determined the effect of pharmacological modulation of mitochondrial function on tissue oxygenation in the hippocampus of rats after repeatedly evoked seizures. Rats were treated with mitochondrial uncoupler 2,4 dinitrophenol (DNP) or antioxidants. Oxygen profiles were recorded using a chronically implanted oxygen-sensing probe, before, during, and after seizure induction. Mitochondrial function and redox tone were measured using in vitro mitochondrial assays and immunohistochemistry. Postictal cognitive impairment was assessed using the novel object recognition task. Mild mitochondrial uncoupling by DNP raised hippocampal oxygen tension and ameliorated postictal hypoxia. Chronic DNP also lowered mitochondrial oxygen-derived reactive species and oxidative stress in the hippocampus during postictal hypoxia. Uncoupling the mitochondria exerts therapeutic benefits on postictal cognitive dysfunction. Finally, antioxidants do not affect postictal hypoxia, but protect the brain from associated cognitive deficits. We provided evidence for a metabolic component of the prolonged oxygen deprivation that follow seizures and its pathological sequelae. Furthermore, we identified a molecular underpinning of this metabolic component, which involves excessive oxygen conversion into reactive species. Mild mitochondrial uncoupling may be a potential therapeutic strategy to treat the postictal state where seizure control is absent or poor.
    Keywords:  2,4-Dinitrophenol (DNP); Epilepsy; Mitochondria; Oxidative stress; Postictal period
    DOI:  https://doi.org/10.1016/j.neuropharm.2023.109653
  9. Front Oncol. 2023 ;13 1152553
    Fluorescence microscopy imaging of mitochondrial metabolism in cancer cells.
    Monika Gooz, Eduardo N Maldonado.
      Mitochondrial metabolism is an important contributor to cancer cell survival and proliferation that coexists with enhanced glycolytic activity. Measuring mitochondrial activity is useful to characterize cancer metabolism patterns, to identify metabolic vulnerabilities and to identify new drug targets. Optical imaging, especially fluorescent microscopy, is one of the most valuable tools for studying mitochondrial bioenergetics because it provides semiquantitative and quantitative readouts as well as spatiotemporal resolution of mitochondrial metabolism. This review aims to acquaint the reader with microscopy imaging techniques currently used to determine mitochondrial membrane potential (ΔΨm), nicotinamide adenine dinucleotide (NADH), ATP and reactive oxygen species (ROS) that are major readouts of mitochondrial metabolism. We describe features, advantages, and limitations of the most used fluorescence imaging modalities: widefield, confocal and multiphoton microscopy, and fluorescent lifetime imaging (FLIM). We also discus relevant aspects of image processing. We briefly describe the role and production of NADH, NADHP, flavins and various ROS including superoxide and hydrogen peroxide and discuss how these parameters can be analyzed by fluorescent microscopy. We also explain the importance, value, and limitations of label-free autofluorescence imaging of NAD(P)H and FAD. Practical hints for the use of fluorescent probes and newly developed sensors for imaging ΔΨm, ATP and ROS are described. Overall, we provide updated information about the use of microscopy to study cancer metabolism that will be of interest to all investigators regardless of their level of expertise in the field.
    Keywords:  FAD; NAD(P)H; ROS; fluorescence microscopy; mitochondrial membrane potential; mitochondrial metabolism
    DOI:  https://doi.org/10.3389/fonc.2023.1152553
  10. Adv Protein Chem Struct Biol. 2023 ;pii: S1876-1623(23)00040-8. [Epub ahead of print]136 35-91
    Mitochondria in cell senescence: A Friend or Foe?
    Qian Chen, Lindon Young, Robert Barsotti.
      Cell senescence denotes cell growth arrest in response to continuous replication or stresses damaging DNA or mitochondria. Mounting research suggests that cell senescence attributes to aging-associated failing organ function and diseases. Conversely, it participates in embryonic tissue maturation, wound healing, tissue regeneration, and tumor suppression. The acute or chronic properties and microenvironment may explain the double faces of senescence. Senescent cells display unique characteristics. In particular, its mitochondria become elongated with altered metabolomes and dynamics. Accordingly, mitochondria reform their function to produce more reactive oxygen species at the cost of low ATP production. Meanwhile, destructed mitochondrial unfolded protein responses further break the delicate proteostasis fostering mitochondrial dysfunction. Additionally, the release of mitochondrial damage-associated molecular patterns, mitochondrial Ca2+ overload, and altered NAD+ level intertwine other cellular organelle strengthening senescence. These findings further intrigue researchers to develop anti-senescence interventions. Applying mitochondrial-targeted antioxidants reduces cell senescence and mitigates aging by restoring mitochondrial function and attenuating oxidative stress. Metformin and caloric restriction also manifest senescent rescuing effects by increasing mitochondria efficiency and alleviating oxidative damage. On the other hand, Bcl2 family protein inhibitors eradicate senescent cells by inducing apoptosis to facilitate cancer chemotherapy. This review describes the different aspects of mitochondrial changes in senescence and highlights the recent progress of some anti-senescence strategies.
    Keywords:  Bcl2 family protein inhibitors; Caloric restriction; Cell senescence; Metabolic reprograming; Metformin; Mitochondria-targeted antioxidants; Mitochondrial damage-associated molecular patterns; Mitochondrial unfolded protein responses; NAD(+); Reactive oxygen species
    DOI:  https://doi.org/10.1016/bs.apcsb.2023.02.019
  11. Kidney Res Clin Pract. 2023 Jun 15.
    The impact of hypoxia-inducible factors in the pathogenesis of kidney diseases: a link through cell metabolism.
    Orestes Foresto-Neto, Ana Ruth Paolinetti Alves da Silva, Marcella Cipelli, Fernanda Paula Roncon Santana-Novelli, Niels Olsen Saraiva Camara.
      Kidneys are sensitive to disturbances in oxygen homeostasis. Hypoxia and activation of the hypoxia-inducible factor (HIF) pathway alter the expression of genes involved in the metabolism of renal and immune cells, interfering with their functioning. Whether the transcriptional activity of HIF protects the kidneys or participates in the pathogenesis of renal diseases is unclear. Several studies have indicated that HIF signaling promotes fibrosis in experimental models of kidney disease. Other reports showed a protective effect of HIF activation on kidney inflammation and injury. In addition to the direct effect of HIF on the kidneys, experimental evidence indicates that HIF-mediated metabolic shift activates inflammatory cells, supporting the HIF cascade as a link between lung or gut damage and worsening of renal disease. Although hypoxia and HIF activation are present in several scenarios of renal diseases, further investigations are needed to clarify whether interfering with the HIF pathway is beneficial in different pathological contexts.
    Keywords:  Cell metabolism; Gut-kidney axis; Hypoxia; Hypoxia-inducible factor 1; Immune cells; Kidney diseases; Lung-kidney axis
    DOI:  https://doi.org/10.23876/j.krcp.23.012
  12. Nat Commun. 2023 07 11. 14(1): 4105
    Hypoxia-reprogramed megamitochondrion contacts and engulfs lysosome to mediate mitochondrial self-digestion.
    Tianshu Hao, Jianglong Yu, Zhida Wu, Jie Jiang, Longlong Gong, Bingjun Wang, Hanze Guo, Huabin Zhao, Bin Lu, Simone Engelender, He He, Zhiyin Song.
      Mitochondria are the key organelles for sensing oxygen, which is consumed by oxidative phosphorylation to generate ATP. Lysosomes contain hydrolytic enzymes that degrade misfolded proteins and damaged organelles to maintain cellular homeostasis. Mitochondria physically and functionally interact with lysosomes to regulate cellular metabolism. However, the mode and biological functions of mitochondria-lysosome communication remain largely unknown. Here, we show that hypoxia remodels normal tubular mitochondria into megamitochondria by inducing broad inter-mitochondria contacts and subsequent fusion. Importantly, under hypoxia, mitochondria-lysosome contacts are promoted, and certain lysosomes are engulfed by megamitochondria, in a process we term megamitochondria engulfing lysosome (MMEL). Both megamitochondria and mature lysosomes are required for MMEL. Moreover, the STX17-SNAP29-VAMP7 complex contributes to mitochondria-lysosome contacts and MMEL under hypoxia. Intriguingly, MMEL mediates a mode of mitochondrial degradation, which we termed mitochondrial self-digestion (MSD). Moreover, MSD increases mitochondrial ROS production. Our results reveal a mode of crosstalk between mitochondria and lysosomes and uncover an additional pathway for mitochondrial degradation.
    DOI:  https://doi.org/10.1038/s41467-023-39811-9
  13. Int J Mol Sci. 2023 Jul 05. pii: 11108. [Epub ahead of print]24(13):
    Mitochondrial Integrity Is Critical in Right Heart Failure Development.
    Marion Müller, Elfi Donhauser, Tibor Maske, Cornelius Bischof, Daniel Dumitrescu, Volker Rudolph, Anna Klinke.
      Molecular processes underlying right ventricular (RV) dysfunction (RVD) and right heart failure (RHF) need to be understood to develop tailored therapies for the abatement of mortality of a growing patient population. Today, the armament to combat RHF is poor, despite the advancing identification of pathomechanistic processes. Mitochondrial dysfunction implying diminished energy yield, the enhanced release of reactive oxygen species, and inefficient substrate metabolism emerges as a potentially significant cardiomyocyte subcellular protagonist in RHF development. Dependent on the course of the disease, mitochondrial biogenesis, substrate utilization, redox balance, and oxidative phosphorylation are affected. The objective of this review is to comprehensively analyze the current knowledge on mitochondrial dysregulation in preclinical and clinical RVD and RHF and to decipher the relationship between mitochondrial processes and the functional aspects of the right ventricle (RV).
    Keywords:  mitochondria; oxidative stress; pulmonary hypertension; right heart failure
    DOI:  https://doi.org/10.3390/ijms241311108
  14. Int J Mol Sci. 2023 Jul 05. pii: 11105. [Epub ahead of print]24(13):
    The Complex Relationship between Hypoxia Signaling, Mitochondrial Dysfunction and Inflammation in Calcific Aortic Valve Disease: Insights from the Molecular Mechanisms to Therapeutic Approaches.
    Esmaa Bouhamida, Giampaolo Morciano, Gaia Pedriali, Daniela Ramaccini, Elena Tremoli, Carlotta Giorgi, Paolo Pinton, Simone Patergnani.
      Calcific aortic valve stenosis (CAVS) is among the most common causes of cardiovascular mortality in an aging population worldwide. The pathomechanisms of CAVS are such a complex and multifactorial process that researchers are still making progress to understand its physiopathology as well as the complex players involved in CAVS pathogenesis. Currently, there is no successful and effective treatment to prevent or slow down the disease. Surgical and transcatheter valve replacement represents the only option available for treating CAVS. Insufficient oxygen availability (hypoxia) has a critical role in the pathogenesis of almost all CVDs. This process is orchestrated by the hallmark transcription factor, hypoxia-inducible factor 1 alpha subunit (HIF-1α), which plays a pivotal role in regulating various target hypoxic genes and metabolic adaptations. Recent studies have shown a great deal of interest in understanding the contribution of HIF-1α in the pathogenesis of CAVS. However, it is deeply intertwined with other major contributors, including sustained inflammation and mitochondrial impairments, which are attributed primarily to CAVS. The present review aims to cover the latest understanding of the complex interplay effect of hypoxia signaling pathways, mitochondrial dysfunction, and inflammation in CAVS. We propose further hypotheses and interconnections on the complexity of these impacts in a perspective of better understanding the pathophysiology. These interplays will be examined considering recent studies that shall help us better dissect the molecular mechanism to enable the design and development of potential future therapeutic approaches that can prevent or slow down CAVS processes.
    Keywords:  HIF-1α; calcific aortic valve stenosis; hypoxia; inflammation; mitochondria; oxidative stress; therapeutic target
    DOI:  https://doi.org/10.3390/ijms241311105
  15. J Biochem Mol Toxicol. 2023 Jul 08. e23398
    Neferine protected cardiomyocytes against hypoxia/oxygenation injury through SIRT1/Nrf2/HO-1 signaling.
    Cheng Lu, Bing Jiang, Jie Xu, Xuan Zhang, Nianxin Jiang.
      Acute myocardial infarction is regarded as myocardial necrosis resulting from myocardial ischemia/reperfusion (I/R) damage and retains a major cause of mortality. Neferine, which was extracted from the green embryos of mature seeds of Nelumbo nucifera Gaertn., has been reported to possess a broad range of biological activities. However, its underlying mechanism on the protective effect of I/R has not been fully clarified. A hypoxia/reoxygenation (H/R) model with H9c2 cells closely simulating myocardial I/R injury was used as a cellular model. This study intended to research the effects and mechanism underlying neferine on H9c2 cells in response to H/R stimulation. Cell Counting Kit-8 and lactate dehydrogenase (LDH) release assays were employed to measure cell viability and LDH, respectively. Apoptosis and reactive oxygen species (ROS) were determined by flow cytometry analysis. Oxidative stress was evaluated by detecting malondialdehyde, superoxide dismutase, and catalase. Mitochondrial function was assessed by mitochondrial membrane potential, ATP content, and mitochondrial ROS. Western blot analysis was performed to examine the expression of related proteins. The results showed that hypoxia/reoxygenation (H/R)-induced cell damage, all of which were distinctly reversed by neferine. Moreover, we observed that neferine inhibited oxidative stress and mitochondrial dysfunction induced by H/R in H9c2 that were concomitant with increased sirtuin-1 (SITR1), nuclear factor erythroid 2-related factor 2 (Nrf2), and heme oxygenase-1 expression. On the contrary, silencing the SIRT1 gene with its small interferingRNA eliminated the beneficial effects of neferine. It is concluded that neferine preconditioning attenuated H/R-induced cardiac damage via suppressing apoptosis, oxidative stress, and mitochondrial dysfunction, which may be partially ascribed to the activation of SIRT1/Nrf2 signaling pathway.
    Keywords:  SIRT1/Nrf2; hypoxia/reoxygenation; ischemia/reperfusion; mitochondrial dysfunction; neferine; oxidative stress
    DOI:  https://doi.org/10.1002/jbt.23398
  16. Ann Clin Lab Sci. 2023 May;53(3): 427-437
    The Transcription Factor RUNX1 Aggravates Hypoxia-Induced Human Retinal Microvascular Endothelial Cell Dysfunction by Negatively Regulating TFF1 Promoter.
    Yanli Zhang, Shuang Qiu, Lingyan Liu, Lifen Qiu.
      OBJECTIVE: As a retinal vaso-proliferative disorder, retinopathy of prematurity (ROP) is characterized by neovascularization and angiogenesis, causing irreversible retinal damage and even visual loss among premature infants. Trefoil factor 1 (TFF1) has been identified as a key regulator in mediating retinal angiogenesis in diabetic retinopathy. However, whether TFF1 can mediate the angiogenic process in ROP remains unknown. Here, we aimed to investigate the regulatory function of TFF1 and its underlying mechanisms in hypoxia-exposed human retinal vascular endothelial cells (HRVECs) in vitro.METHODS: HRVECs were exposed to hypoxia condition to establish the in vitro ROP models. HRVEC viability was validated using CCK-8 assay. The migratory and angiogenic capacities of HRVECs were assessed by wound healing and tube formation assays, respectively. RT-qPCR was performed to detect gene levels. Western blotting was used to measure the protein levels of TFF1 and Runt-related transcription factor 1 (RUNX1). The binding relationship between RUNX1 to TFF1 promoter was confirmed by chromatin immunoprecipitation and luciferase reporter assays.
    RESULTS: Hypoxia downregulated TFF1 expression and elevated RUNX1 expression in HRVECs. Moreover, hypoxic condition increased HRVEC viability and accelerated HRVEC migration and angiogenesis, which were antagonized by TFF1 elevation or RUNX1 knockdown. RUNX1 as a transcription factor bound to TFF1 promoter and transcriptionally repressed TFF1 expression in HRVECs. In rescue assays, overexpression of TFF1 counteracted the promotive effect of RUNX1 overexpression on the viability, migratory and angiogenic abilities of HRVECs under hypoxia.
    CONCLUSIONS: RUNX1 transcriptionally suppresses TFF1 expression to aggravate hypoxia-induced HRVEC dysfunction.
    Keywords:  RUNX1; TFF1; retinal angiogenesis; retinopathy of prematurity
  17. Nat Commun. 2023 Jul 13. 14(1): 4166
    Cytochrome c lysine acetylation regulates cellular respiration and cell death in ischemic skeletal muscle.
    Paul T Morse, Gonzalo Pérez-Mejías, Junmei Wan, Alice A Turner, Inmaculada Márquez, Hasini A Kalpage, Asmita Vaishnav, Matthew P Zurek, Philipp P Huettemann, Katherine Kim, Tasnim Arroum, Miguel A De la Rosa, Dipanwita Dutta Chowdhury, Icksoo Lee, Joseph S Brunzelle, Thomas H Sanderson, Moh H Malek, David Meierhofer, Brian F P Edwards, Irene Díaz-Moreno, Maik Hüttemann.
      Skeletal muscle is more resilient to ischemia-reperfusion injury than other organs. Tissue specific post-translational modifications of cytochrome c (Cytc) are involved in ischemia-reperfusion injury by regulating mitochondrial respiration and apoptosis. Here, we describe an acetylation site of Cytc, lysine 39 (K39), which was mapped in ischemic porcine skeletal muscle and removed by sirtuin5 in vitro. Using purified protein and cellular double knockout models, we show that K39 acetylation and acetylmimetic K39Q replacement increases cytochrome c oxidase (COX) activity and ROS scavenging while inhibiting apoptosis via decreased binding to Apaf-1, caspase cleavage and activity, and cardiolipin peroxidase activity. These results are discussed with X-ray crystallography structures of K39 acetylated (1.50 Å) and acetylmimetic K39Q Cytc (1.36 Å) and NMR dynamics. We propose that K39 acetylation is an adaptive response that controls electron transport chain flux, allowing skeletal muscle to meet heightened energy demand while simultaneously providing the tissue with robust resilience to ischemia-reperfusion injury.
    DOI:  https://doi.org/10.1038/s41467-023-39820-8
  18. Nat Rev Mol Cell Biol. 2023 Jul 12.
    Mechanisms of BCL-2 family proteins in mitochondrial apoptosis.
    Peter E Czabotar, Ana J Garcia-Saez.
      The proteins of the BCL-2 family are key regulators of mitochondrial apoptosis, acting as either promoters or inhibitors of cell death. The functional interplay and balance between the opposing BCL-2 family members control permeabilization of the outer mitochondrial membrane, leading to the release of activators of the caspase cascade into the cytosol and ultimately resulting in cell death. Despite considerable research, our knowledge about the mechanisms of the BCL-2 family of proteins remains insufficient, which complicates cell fate predictions and does not allow us to fully exploit these proteins as targets for drug discovery. Detailed understanding of the formation and molecular architecture of the apoptotic pore in the outer mitochondrial membrane remains a holy grail in the field, but new studies allow us to begin constructing a structural model of its arrangement. Recent literature has also revealed unexpected activities for several BCL-2 family members that challenge established concepts of how they regulate mitochondrial permeabilization. In this Review, we revisit the most important advances in the field and integrate them into a new structure-function-based classification of the BCL-2 family members that intends to provide a comprehensive model for BCL-2 action in apoptosis. We close this Review by discussing the potential of drugging the BCL-2 family in diseases characterized by aberrant apoptosis.
    DOI:  https://doi.org/10.1038/s41580-023-00629-4
  19. Nat Commun. 2023 Jul 13. 14(1): 4161
    Functional decomposition of metabolism allows a system-level quantification of fluxes and protein allocation towards specific metabolic functions.
    Matteo Mori, Chuankai Cheng, Brian R Taylor, Hiroyuki Okano, Terence Hwa.
      Quantifying the contribution of individual molecular components to complex cellular processes is a grand challenge in systems biology. Here we establish a general theoretical framework (Functional Decomposition of Metabolism, FDM) to quantify the contribution of every metabolic reaction to metabolic functions, e.g. the synthesis of biomass building blocks. FDM allowed for a detailed quantification of the energy and biosynthesis budget for growing Escherichia coli cells. Surprisingly, the ATP generated during the biosynthesis of building blocks from glucose almost balances the demand from protein synthesis, the largest energy expenditure known for growing cells. This leaves the bulk of the energy generated by fermentation and respiration unaccounted for, thus challenging the common notion that energy is a key growth-limiting resource. Moreover, FDM together with proteomics enables the quantification of enzymes contributing towards each metabolic function, allowing for a first-principle formulation of a coarse-grained model of global protein allocation based on the structure of the metabolic network.
    DOI:  https://doi.org/10.1038/s41467-023-39724-7
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