bims-midhyp Biomed News
on Mitochondrial dysfunction and hypoxia
Issue of 2023–09–17
twenty-one papers selected by
Alia Ablieh, Universität Heidelberg
  1. Early steps in the biogenesis of mitochondrially encoded oxidative phosphorylation subunits.
  2. Mitochondria Derived Vesicle Packaging as a Novel Therapeutic Mechanism in Pulmonary Hypertension.
  3. Dznep, a histone modification inhibitor, inhibits HIF1α binding to TIMP2 gene and suppresses TIMP2 expression under hypoxia.
  4. Prefoldin 2 contributes to mitochondrial morphology and function.
  5. Impact of hypoxia and reoxygenation on the extra/intracellular metabolome and on transporter expression in a human kidney proximal tubular cell line.
  6. Mitochondrial degradation: Mitophagy and beyond.
  7. Integration of Chemo-mechanical signaling in response to fluid shear stress by the endothelium.
  8. Altered Smooth Muscle Cell Histone Acetylome by the SPHK2/S1P Axis Promotes Pulmonary Hypertension.
  9. The heat shock protein Hsp27 controls mitochondrial function by modulating ceramide generation.
  10. Obesity Blunts the Effect of Mesenchymal Stem Cell-Derived Extracellular Vesicles.
  11. Left ventricular hypertrophy and metabolic resetting in the Notch3-deficient adult mouse heart.
  12. Dermomyotome-derived endothelial cells migrate to the dorsal aorta to support hematopoietic stem cell emergence.
  13. Metabolic targeting of platelets to combat thrombosis: dawn of a new paradigm?
  14. Multi-omic analyses and network biology in cardiovascular disease.
  15. Understanding mechanisms of antioxidant action in health and disease.
  16. Gene expression flux analysis reveals specific regulatory modalities of gene expression.
  17. A STAT3 protein complex required for mitochondrial mRNA stability and cancer.
  18. The cell-specific roles of Nrf2 in acute and chronic phases of ischemic stroke.
  19. Different stimuli induce endothelial dysfunction and promote atherosclerosis through the Piezo1/YAP signaling axis.
  20. Down-regulation of the mitochondrial fusion protein Opa1/Mfn2 promotes cardiomyocyte hypertrophy in Su5416/hypoxia-induced pulmonary hypertension rats.
  21. A new era of understanding in vivo metabolic flux in thermogenic adipocytes.
  1. IUBMB Life. 2023 Sep 15.
    Early steps in the biogenesis of mitochondrially encoded oxidative phosphorylation subunits.
    Sung-Jun Jung, Sagar Sridhara, Martin Ott.
      The complexes mediating oxidative phosphorylation (OXPHOS) in the inner mitochondrial membrane consist of proteins encoded in the nuclear or the mitochondrial DNA. The mitochondrially encoded membrane proteins (mito-MPs) represent the catalytic core of these complexes and follow complicated pathways for biogenesis. Owing to their overall hydrophobicity, mito-MPs are co-translationally inserted into the inner membrane by the Oxa1 insertase. After insertion, OXPHOS biogenesis factors mediate the assembly of mito-MPs into complexes and participate in the regulation of mitochondrial translation, while protein quality control factors recognize and degrade faulty or excess proteins. This review summarizes the current understanding of these early steps occurring during the assembly of mito-MPs by concentrating on results obtained in the model organism baker's yeast.
    Keywords:  eukaryotic gene expression; mitochondria; protein folding; protein synthesis
    DOI:  https://doi.org/10.1002/iub.2784
  2. Am J Respir Cell Mol Biol. 2023 Sep 15.
    Mitochondria Derived Vesicle Packaging as a Novel Therapeutic Mechanism in Pulmonary Hypertension.
    Qiang Zhao, Zhixue Liu, Ping Song, Zuyi Yuan, Ming-Hui Zou.
      Increasing evidence suggests that mitochondrial dysfunction in pulmonary endothelial cells (ECs) plays a causative role in the initiation and progression of pulmonary hypertension (PH); how mitochondria become dysfunctional in PH remains elusive. Mitochondria-derived vesicles (MDVs) are small subcellular vesicles that excise from mitochondria. Whether or not MDVs deregulation causes mitochondrial dysfunction in PH is unknown. This aim of this study was to determine MDVs regulation in ECs and to elucidate how MDVs deregulation in ECs leads to PH. MDVs formation and mitochondrial morphology/dynamics were examined in ECs of the EC-specific-Liver kinase B1 (LKB1) knock out mice (LKB1ec-/-), in monocrotaline (MCT)-induced PH rats, and in lungs of patients with PH. Pulmonary ECs of PH patients and hypoxia-treated pulmonary ECs exhibited increased mitochondrial fragmentation and disorganized mitochondrial ultrastructure characterized by electron lucent-swelling matrix compartments and concentric layering of cristae network, along with defective MDVs shedding. MDVs actively regulated mitochondrial membrane dynamics and mitochondrial ultrastructure via its removing mitofission-related cargoes. The shedding of MDVs from parental mitochondria required LKB1-mediated mitochondrial recruitment of Rab9 GTPase. LKB1ec-/- mice spontaneously developed PH with decreased mitochondrial pools of Rab9 GTPase, defective MDVs shedding, and disequilibrium of mitochondrial fusion-fission cycle in pulmonary ECs. Aerosol intra-tracheal delivery of adeno-associated virus LKB1 reversed PH, along with improved MDVs shedding and mitochondrial functions in rats in vivo. We conclude that LKB1 regulates MDVs shedding and mitochondrial dynamics in pulmonary ECs by enhancing mitochondrial recruitment of Rab9 GTPase. Defect of LKB1-mediated MDVs shedding from parental mitochondria instigates ECs dysfunction and PH.
    Keywords:  Pulmonary hypertension , Endothelial dysfunction , Mitochondria derived vesicles , Liver kinase B1
    DOI:  https://doi.org/10.1165/rcmb.2023-0010OC
  3. Physiol Rep. 2023 Sep;11(17): e15810
    Dznep, a histone modification inhibitor, inhibits HIF1α binding to TIMP2 gene and suppresses TIMP2 expression under hypoxia.
    Tomotaka Yamazaki, Imari Mimura, Yu Kurata, Tetsuhiro Tanaka, Masaomi Nangaku.
      Epidemiological studies have shown that patients who recovered from acute kidney injury (AKI) may subsequently develop chronic kidney disease (CKD). AKI is primarily caused by renal hypoxia, and it causes epigenetic alterations, known as hypoxic memory. 3-Deazaneplanocin A (Dznep), an inhibitor of histone modification, suppresses renal fibrosis and the expression of tissue inhibitor of metalloproteinases-2 (TIMP2), a profibrotic factor, in mouse ischemia-reperfusion models. The current study investigated the epigenetic regulation of TIMP2 in human kidney 2 (HK-2) cells. The expression of TIMP2 was upregulated in HK-2 cells under hypoxic conditions and was suppressed by Dznep. ChIP-qPCR showed that Dznep reduced the amount of H3K4me3 at the promoter region of the TIMP2 gene under hypoxic condition. Formaldehyde-assisted isolation of regulatory elements-qPCR of the TIMP2 gene showed that Dznep reduced open chromatin area. In addition, based on ChIP-qPCR of hypoxia-inducible factor 1 alpha (HIF1α), Dznep inhibited the binding of HIF1α to the TIMP2 gene under hypoxic conditions. The reporter assays for the binding region of HIF1α showed enhanced transcriptional activity by hypoxia. Dznep suppresses the expression of TIMP2 under hypoxic conditions by inhibiting the binding of HIF1α to the TIMP2 gene.
    Keywords:  Dznep; hypoxia-inducible factor; open chromatin
    DOI:  https://doi.org/10.14814/phy2.15810
  4. BMC Biol. 2023 09 12. 21(1): 193
    Prefoldin 2 contributes to mitochondrial morphology and function.
    Ismail Tahmaz, Somayeh Shahmoradi Ghahe, Monika Stasiak, Kamila P Liput, Katarzyna Jonak, Ulrike Topf.
       BACKGROUND: Prefoldin is an evolutionarily conserved co-chaperone of the tailless complex polypeptide 1 ring complex (TRiC)/chaperonin containing tailless complex 1 (CCT). The prefoldin complex consists of six subunits that are known to transfer newly produced cytoskeletal proteins to TRiC/CCT for folding polypeptides. Prefoldin function was recently linked to the maintenance of protein homeostasis, suggesting a more general function of the co-chaperone during cellular stress conditions. Prefoldin acts in an adenosine triphosphate (ATP)-independent manner, making it a suitable candidate to operate during stress conditions, such as mitochondrial dysfunction. Mitochondrial function depends on the production of mitochondrial proteins in the cytosol. Mechanisms that sustain cytosolic protein homeostasis are vital for the quality control of proteins destined for the organelle and such mechanisms among others include chaperones.
    RESULTS: We analyzed consequences of the loss of prefoldin subunits on the cell proliferation and survival of Saccharomyces cerevisiae upon exposure to various cellular stress conditions. We found that prefoldin subunits support cell growth under heat stress. Moreover, prefoldin facilitates the growth of cells under respiratory growth conditions. We showed that mitochondrial morphology and abundance of some respiratory chain complexes was supported by the prefoldin 2 (Pfd2/Gim4) subunit. We also found that Pfd2 interacts with Tom70, a receptor of mitochondrial precursor proteins that are targeted into mitochondria.
    CONCLUSIONS: Our findings link the cytosolic prefoldin complex to mitochondrial function. Loss of the prefoldin complex subunit Pfd2 results in adaptive cellular responses on the proteome level under physiological conditions suggesting a continuous need of Pfd2 for maintenance of cellular homeostasis. Within this framework, Pfd2 might support mitochondrial function directly as part of the cytosolic quality control system of mitochondrial proteins or indirectly as a component of the protein homeostasis network.
    Keywords:  Chaperone; Mitochondria; Pfd2/Gim4; Prefoldin; Proteostasis; Tom70
    DOI:  https://doi.org/10.1186/s12915-023-01695-y
  5. Metabolomics. 2023 Sep 13. 19(9): 83
    Impact of hypoxia and reoxygenation on the extra/intracellular metabolome and on transporter expression in a human kidney proximal tubular cell line.
    Quentin Faucher, Stéphanie Chadet, Antoine Humeau, François-Ludovic Sauvage, Hélène Arnion, Philippe Gatault, Matthias Buchler, Sébastien Roger, Roland Lawson, Pierre Marquet, Chantal Barin-Le Guellec.
       INTRODUCTION: Ischemia-reperfusion injury (IRI) induces several perturbations that alter immediate kidney graft function after transplantation and may affect long-term graft outcomes. Given the IRI-dependent metabolic disturbances previously reported, we hypothesized that proximal transporters handling endo/exogenous substrates may be victims of such lesions.
    OBJECTIVES: This study aimed to determine the impact of hypoxia/reoxygenation on the human proximal transport system through two semi-targeted omics analyses.
    METHODS: Human proximal tubular cells were cultured in hypoxia (6 or 24 h), each followed by 2, 24 or 48-h reoxygenation. We investigated the transcriptomic modulation of transporters. Using semi-targeted LC-MS/MS profiling, we characterized the extra/intracellular metabolome. Statistical modelling was used to identify significant metabolic variations.
    RESULTS: The expression profile of transporters was impacted during hypoxia (y + LAT1 and OCTN2), reoxygenation (MRP2, PEPT1/2, rBAT, and OATP4C1), or in both conditions (P-gp and GLUT1). The P-gp and GLUT1 transcripts increased (FC (fold change) = 2.93 and 4.11, respectively) after 2-h reoxygenation preceded by 24-h hypoxia. We observed a downregulation (FC = 0.42) of y+LAT1 after 24-h hypoxia, and of PEPT2 after 24-h hypoxia followed by 2-h reoxygenation (FC = 0.40). Metabolomics showed that hypoxia altered the energetic pathways. However, intracellular metabolic homeostasis and cellular exchanges were promptly restored after reoxygenation.
    CONCLUSION: This study provides insight into the transcriptomic response of the tubular transporters to hypoxia/reoxygenation. No correlation was found between the expression of transporters and the metabolic variations observed. Given the complexity of studying the global tubular transport systems, we propose that further studies focus on targeted transporters.
    Keywords:  Ischemia-reperfusion injury; Membrane transporters; Metabolomics; Proximal tubular cells; Statistical modeling
    DOI:  https://doi.org/10.1007/s11306-023-02044-4
  6. Mol Cell. 2023 Sep 07. pii: S1097-2765(23)00656-1. [Epub ahead of print]
    Mitochondrial degradation: Mitophagy and beyond.
    Louise Uoselis, Thanh Ngoc Nguyen, Michael Lazarou.
      Mitochondria are central hubs of cellular metabolism that also play key roles in signaling and disease. It is therefore fundamentally important that mitochondrial quality and activity are tightly regulated. Mitochondrial degradation pathways contribute to quality control of mitochondrial networks and can also regulate the metabolic profile of mitochondria to ensure cellular homeostasis. Here, we cover the many and varied ways in which cells degrade or remove their unwanted mitochondria, ranging from mitophagy to mitochondrial extrusion. The molecular signals driving these varied pathways are discussed, including the cellular and physiological contexts under which the different degradation pathways are engaged.
    Keywords:  MDV; PINK1; Parkin; degradation; mitochondria; mitochondrial quality control; mitophagy; proteasome; selective autophagy; ubiquitin
    DOI:  https://doi.org/10.1016/j.molcel.2023.08.021
  7. Curr Opin Cell Biol. 2023 Sep 11. pii: S0955-0674(23)00081-9. [Epub ahead of print]85 102232
    Integration of Chemo-mechanical signaling in response to fluid shear stress by the endothelium.
    Annmarie Dominguez, M Luisa Iruela-Arispe.
      Physical forces exert profound effects on cells affecting fate, function, and response to stressors. In the case of the endothelium, the layer that resides in the inner surface of blood vessels, the collective effect of hemodynamic forces influences the onset and severity of vascular pathologies. Justifiably, much emphasis has been placed in understanding how endothelial cells sense and respond to mechanical challenges, particularly hemodynamic shear stress. In this review, we highlight recent developments that have expanded our understanding of the molecular mechanisms underlying mechanotransduction. We describe examples of protein compartmentalization in response to shear stress, consider the contribution of the glycocalyx, and discuss the specific role ion channels in response to flow. We also highlight the recently recognized contribution of the receptor ALK5 in sensing turbulent flow. Research in the last three years has enriched our understanding of the molecular landscape responsible for recognizing and transducing shear stress responses, including novel transcriptional-dependent and transcriptional-independent mechanisms.
    DOI:  https://doi.org/10.1016/j.ceb.2023.102232
  8. Circ Res. 2023 Sep 12.
    Altered Smooth Muscle Cell Histone Acetylome by the SPHK2/S1P Axis Promotes Pulmonary Hypertension.
    A Dushani C U Ranasinghe, Maggie Holohan, Kalyn M Borger, Deborah L Donahue, Rafael D Kuc, Martin Gerig, Andrew Kim, Victoria A Ploplis, Francis J Castellino, Margaret A Schwarz.
       BACKGROUND: Epigenetic regulation of vascular remodeling in pulmonary hypertension (PH) is poorly understood. Transcription regulating, histone acetylation code alters chromatin accessibility to promote transcriptional activation. Our goal was to identify upstream mechanisms that disrupt epigenetic equilibrium in PH.
    METHODS: Human pulmonary artery smooth muscle cells (PASMCs), human idiopathic pulmonary arterial hypertension (iPAH):human PASMCs, iPAH lung tissue, failed donor lung tissue, human pulmonary microvascular endothelial cells, iPAH:PASMC and non-iPAH:PASMC RNA-seq databases, NanoString nCounter, and cleavage under targets and release using nuclease were utilized to investigate histone acetylation, hyperacetylation targets, protein and gene expression, sphingolipid activation, cell proliferation, and gene target identification. SPHK2 (sphingosine kinase 2) knockout was compared with control C57BL/6NJ mice after 3 weeks of hypoxia and assessed for indices of PH.
    RESULTS: We identified that Human PASMCs are vulnerable to the transcription-promoting epigenetic mediator histone acetylation resulting in alterations in transcription machinery and confirmed its pathological existence in PH:PASMC cells. We report that SPHK2 is elevated as much as 20-fold in iPAH lung tissue and is elevated in iPAH:PASMC cells. During PH pathogenesis, nuclear SPHK2 activates nuclear bioactive lipid S1P (sphingosine 1-phosphate) catalyzing enzyme and mediates transcription regulating histone H3K9 acetylation (acetyl histone H3 lysine 9 [Ac-H3K9]) through EMAP (endothelial monocyte activating polypeptide) II. In iPAH lungs, we identified a 4-fold elevation of the reversible epigenetic transcription modulator Ac-H3K9:H3 ratio. Loss of SPHK2 inhibited hypoxic-induced PH and Ac-H3K9 in mice. We discovered that pulmonary vascular endothelial cells are a priming factor of the EMAP II/SPHK2/S1P axis that alters the acetylome with a specificity for PASMC, through hyperacetylation of histone H3K9. Using cleavage under targets and release using nuclease, we further show that EMAP II-mediated SPHK2 has the potential to modify the local transcription machinery of pluripotency factor KLF4 (Krüppel-like factor 4) by hyperacetylating KLF4 Cis-regulatory elements while deletion and targeted inhibition of SPHK2 rescues transcription altering Ac-H3K9.
    CONCLUSIONS: SPHK2 expression and its activation of the reversible histone H3K9 acetylation in human pulmonary artery smooth muscle cell represent new therapeutic targets that could mitigate PH vascular remodeling.
    Keywords:  chromatin; endothelial cell; goal; mice; pulmonary artery
    DOI:  https://doi.org/10.1161/CIRCRESAHA.123.322740
  9. Cell Rep. 2023 Sep 06. pii: S2211-1247(23)01092-6. [Epub ahead of print] 113081
    The heat shock protein Hsp27 controls mitochondrial function by modulating ceramide generation.
    Rowan A Boyd, Saurav Majumder, Johnny Stiban, Grace Mavodza, Alexandra J Straus, Sachin K Kempelingaiah, Varun Reddy, Yusuf A Hannun, Lina M Obeid, Can E Senkal.
      Sphingolipids have key functions in membrane structure and cellular signaling. Ceramide is the central molecule of the sphingolipid metabolism and is generated by ceramide synthases (CerS) in the de novo pathway. Despite their critical function, mechanisms regulating CerS remain largely unknown. Using an unbiased proteomics approach, we find that the small heat shock protein 27 (Hsp27) interacts specifically with CerS1 but not other CerS. Functionally, our data show that Hsp27 acts as an endogenous inhibitor of CerS1. Wild-type Hsp27, but not a mutant deficient in CerS1 binding, inhibits CerS1 activity. Additionally, silencing of Hsp27 enhances CerS1-generated ceramide accumulation in cells. Moreover, phosphorylation of Hsp27 modulates Hsp27-CerS1 interaction and CerS1 activity in acute stress-response conditions. Biologically, we show that Hsp27 knockdown impedes mitochondrial function and induces lethal mitophagy in a CerS1-dependent manner. Overall, we identify an important mode of CerS1 regulation and CerS1-mediated mitophagy through protein-protein interaction with Hsp27.
    Keywords:  C18-ceramide; CP: Molecular biology; CerS1; Hsp27; ceramide; ceramide synthase; mitophagy; sphingolipids
    DOI:  https://doi.org/10.1016/j.celrep.2023.113081
  10. Kidney Int Rep. 2023 Sep;8(9): 1841-1851
    Obesity Blunts the Effect of Mesenchymal Stem Cell-Derived Extracellular Vesicles.
    Weijun Huang, Siting Hong, Xiangyang Zhu, Mina H Alsaeedi, Hui Tang, James D Krier, Deep Gandhi, Kyra L Jordan, Ishran M Saadiq, Yamei Jiang, Alfonso Eirin, Lilach O Lerman.
       Introduction: Mesenchymal stem/stromal cell-derived extracellular vesicles (MSC-EVs) are paracrine vectors with therapeutic functions comparable to their parent cells. However, it remains unclear if donor obesity affects their therapeutic functions. We tested the hypothesis that the curative effect of human adipose tissue-derived MSC-EVs (A-MSC-EVs) is blunted by obesity.
    Methods: MSC-EVs were isolated by ultracentrifugation from mesenchymal stem/stromal cells (MSCs) collected from abdominal subcutaneous fat of obese and lean human subjects (obese and lean-MSC-EVs, respectively) and injected into the aorta of mice 2 weeks after renal artery stenosis (RAS) induction. Magnetic resonance imaging studies were conducted 2 weeks after MSC-EVs delivery to determine renal function. The effect of MSC-EVs on tissue injury was assessed by histology and gene expression of inflammatory factors, including interleukin (IL)-1β, IL-6, monocyte chemotactic protein-1 (MCP-1), and tumor necrosis factor alpha (TNF-α). Oxidative damage, macrophage infiltration, plasma renin, and hypoxia inducible factor-1α (HIF-1α) were also assessed.
    Results: Tracking showed that MSC-EVs localized in the kidney tissue, including glomeruli and tubules. All MSC-EVs decreased systolic blood pressure (SBP) and plasma renin and improved the poststenotic kidney (STK) volume, but obese-MSC-EVs were less effective than lean-MSC-EVs in improving medullary hypoxia, fibrosis, and tubular injury. Lean-MSC-EVs decreased inflammation, whereas obesity attenuated this effect. Only lean-MSC-EVs decreased STK cortical HIF-1α expression.
    Conclusion: Obesity attenuates the antihypoxia, antifibrosis, antiinflammation, and tubular repair functions of human MSC-EVs in chronic ischemic kidney disease. These observations may have implications for the self-repair potency of obese subjects and for the use of autologous MSC-EVs in regenerative medicine.
    Keywords:  chronic kidney disease; extracellular vesicle; mesenchymal stem cell; obesity; regenerative medicine; stenotic kidney
    DOI:  https://doi.org/10.1016/j.ekir.2023.06.009
  11. Sci Rep. 2023 Sep 12. 13(1): 15022
    Left ventricular hypertrophy and metabolic resetting in the Notch3-deficient adult mouse heart.
    Francesca Del Gaudio, Dongli Liu, Maarja Andaloussi Mäe, Eike-Benjamin Braune, Emil M Hansson, Qing-Dong Wang, Christer Betsholtz, Urban Lendahl.
      The heart depends on a functional vasculature for oxygenation and transport of nutrients, and it is of interest to learn how primary impairment of the vasculature can indirectly affect cardiac function and heart morphology. Notch3-deficiency causes vascular smooth muscle cell (VSMC) loss in the vasculature but the consequences for the heart remain largely elusive. Here, we demonstrate that Notch3-/- mice have enlarged hearts with left ventricular hypertrophy and mild fibrosis. Cardiomyocytes were hypertrophic but not hyperproliferative, and the expression of several cardiomyocyte markers, including Tnt2, Myh6, Myh7 and Actn2, was altered. Furthermore, expression of genes regulating the metabolic status of the heart was affected: both Pdk4 and Cd36 were downregulated, indicating a metabolic switch from fatty acid oxidation to glucose consumption. Notch3-/- mice furthermore showed lower liver lipid content. Notch3 was expressed in heart VSMC and pericytes but not in cardiomyocytes, suggesting that a perturbation of Notch signalling in VSMC and pericytes indirectly impairs the cardiomyocytes. In keeping with this, Pdgfbret/ret mice, characterized by reduced numbers of VSMC and pericytes, showed left ventricular and cardiomyocyte hypertrophy. In conclusion, we demonstrate that reduced Notch3 or PDGFB signalling in vascular mural cells leads to cardiomyocyte dysfunction.
    DOI:  https://doi.org/10.1038/s41598-023-42010-7
  12. Elife. 2023 Sep 11. pii: e58300. [Epub ahead of print]12
    Dermomyotome-derived endothelial cells migrate to the dorsal aorta to support hematopoietic stem cell emergence.
    Pankaj Sahai-Hernandez, Claire Pouget, Shai Eyal, Ondrej Svoboda, Jose Chacon, Lin Grimm, Tor Gjøen, David Traver.
      Development of the dorsal aorta is a key step in the establishment of the adult blood-forming system, since hematopoietic stem and progenitor cells (HSPCs) arise from ventral aortic endothelium in all vertebrate animals studied. Work in zebrafish has demonstrated that arterial and venous endothelial precursors arise from distinct subsets of lateral plate mesoderm. Here, we profile the transcriptome of the earliest detectable endothelial cells (ECs) during zebrafish embryogenesis to demonstrate that tissue-specific EC programs initiate much earlier than previously appreciated, by the end of gastrulation. Classic studies in the chick embryo showed that paraxial mesoderm generates a subset of somite-derived endothelial cells (SDECs) that incorporate into the dorsal aorta to replace HSPCs as they exit the aorta and enter circulation. We describe a conserved program in the zebrafish, where a rare population of endothelial precursors delaminates from the dermomyotome to incorporate exclusively into the developing dorsal aorta. Although SDECs lack hematopoietic potential, they act as a local niche to support the emergence of HSPCs from neighboring hemogenic endothelium. Thus, at least three subsets of ECs contribute to the developing dorsal aorta: vascular ECs, hemogenic ECs, and SDECs. Taken together, our findings indicate that the distinct spatial origins of endothelial precursors dictate different cellular potentials within the developing dorsal aorta.
    Keywords:  bipotent muscle progenitor; developmental biology; dorsal aorta; endothelial cells; hemogenic endothelium; paraxial mesoderm; somite derived endothelium; zebrafish
    DOI:  https://doi.org/10.7554/eLife.58300
  13. Cardiovasc Res. 2023 Sep 14. pii: cvad149. [Epub ahead of print]
    Metabolic targeting of platelets to combat thrombosis: dawn of a new paradigm?
    Gagan D Flora, Manasa K Nayak, Madankumar Ghatge, Anil K Chauhan.
      Current antithrombotic therapies used in clinical settings either target the coagulation pathways or platelet activation receptors (P2Y12 or GPIIb/IIIa), as well as the cyclooxygenase (COX) enzyme through aspirin. However, they are associated with bleeding risk and are not suitable for long-term use. Thus, novel strategies which provide broad protection against platelet activation with minimal bleeding risks are required. Regardless of the nature of agonist stimulation, platelet activation is an energy-intensive and ATP-driven process characterized by metabolic switching towards a high rate of aerobic glycolysis, relative to oxidative phosphorylation (OXPHOS). Consequently, there has been considerable interest in recent years in investigating whether targeting metabolic pathways in platelets, especially aerobic glycolysis and OXPHOS, can modulate their activation, thereby preventing thrombosis. This review briefly discusses the choices of metabolic substrates available to platelets that drive their metabolic flexibility. We have comprehensively elucidated the relevance of aerobic glycolysis in facilitating platelet activation and the underlying molecular mechanisms that trigger this switch from OXPHOS. We have provided a detailed account of the antiplatelet effects of targeting vital metabolic checkpoints such as pyruvate dehydrogenase kinases (PDKs) and pyruvate kinase M2 (PKM2) that preferentially drive the pyruvate flux to aerobic glycolysis. Furthermore, we discuss the role of fatty acids, and glutamine oxidation in mitochondria and their subsequent role in driving OXPHOS and platelet activation. While the approach of targeting metabolic regulatory mechanisms in platelets to prevent their activation is still in a nascent stage, accumulating evidence highlights its beneficial effects as a potentially novel antithrombotic strategy.
    Keywords:  Aerobic glycolysis; OXPHOS; Platelets; Thrombosis
    DOI:  https://doi.org/10.1093/cvr/cvad149
  14. Proteomics. 2023 Sep 10. e2200289
    Multi-omic analyses and network biology in cardiovascular disease.
    Cristine J Reitz, Uros Kuzmanov, Anthony O Gramolini.
      Heart disease remains a leading cause of death in North America and worldwide. Despite advances in therapies, the chronic nature of cardiovascular diseases ultimately results in frequent hospitalizations and steady rates of mortality. Systems biology approaches have provided a new frontier toward unraveling the underlying mechanisms of cell, tissue, and organ dysfunction in disease. Mapping the complex networks of molecular functions across the genome, transcriptome, proteome, and metabolome has enormous potential to advance our understanding of cardiovascular disease, discover new disease biomarkers, and develop novel therapies. Computational workflows to interpret these data-intensive analyses as well as integration between different levels of interrogation remain important challenges in the advancement and application of systems biology-based analyses in cardiovascular research. This review will focus on summarizing the recent developments in network biology-level profiling in the heart, with particular emphasis on modeling of human heart failure. We will provide new perspectives on integration between different levels of large "omics" datasets, including integration of gene regulatory networks, protein-protein interactions, signaling networks, and metabolic networks in the heart.
    Keywords:  cardiovascular; heart failure; integration; multi-omics; systems biology
    DOI:  https://doi.org/10.1002/pmic.202200289
  15. Nat Rev Mol Cell Biol. 2023 Sep 15.
    Understanding mechanisms of antioxidant action in health and disease.
    Barry Halliwell.
      Several different reactive oxygen species (ROS) are generated in vivo. They have roles in the development of certain human diseases whilst also performing physiological functions. ROS are counterbalanced by an antioxidant defence network, which functions to modulate ROS levels to allow their physiological roles whilst minimizing the oxidative damage they cause that can contribute to disease development. This Review describes the mechanisms of action of antioxidants synthesized in vivo, antioxidants derived from the human diet and synthetic antioxidants developed as therapeutic agents, with a focus on the gaps in our current knowledge and the approaches needed to close them. The Review also explores the reasons behind the successes and failures of antioxidants in treating or preventing human disease. Antioxidants may have special roles in the gastrointestinal tract, and many lifestyle features known to promote health (especially diet, exercise and the control of blood glucose and cholesterol levels) may be acting, at least in part, by antioxidant mechanisms. Certain reactive sulfur species may be important antioxidants but more accurate determinations of their concentrations in vivo are needed to help assess their contributions.
    DOI:  https://doi.org/10.1038/s41580-023-00645-4
  16. iScience. 2023 Oct 20. 26(10): 107758
    Gene expression flux analysis reveals specific regulatory modalities of gene expression.
    Benjamin Martin, David M Suter.
      The level of a given protein is determined by the synthesis and degradation rates of its mRNA and protein. While several studies have quantified the contribution of different gene expression steps in regulating protein levels, these are limited by using equilibrium approximations in out-of-equilibrium biological systems. Here, we introduce gene expression flux analysis to quantitatively dissect the dynamics of the expression level for specific proteins and use it to analyze published transcriptomics and proteomics datasets. Our analysis reveals distinct regulatory modalities shared by sets of genes with clear functional signatures. We also find that protein degradation plays a stronger role than expected in the adaptation of protein levels. These findings suggest that shared regulatory strategies can lead to versatile responses at the protein level and highlight the importance of going beyond equilibrium approximations to dissect the quantitative contribution of different steps of gene expression to protein dynamics.
    Keywords:  Biological constraints; Complex system biology; Flux data; Molecular mechanism of gene regulation
    DOI:  https://doi.org/10.1016/j.isci.2023.107758
  17. Cell Rep. 2023 Sep 12. pii: S2211-1247(23)01044-6. [Epub ahead of print]42(9): 113033
    A STAT3 protein complex required for mitochondrial mRNA stability and cancer.
    C Dilanka Fernando, W Samantha N Jayasekara, Chaitanya Inampudi, Maija R J Kohonen-Corish, Wendy A Cooper, Traude H Beilharz, Tracy M Josephs, Daniel J Garama, Daniel J Gough.
      Signal transducer and activator of transcription 3 (STAT3) is a potent transcription factor necessary for life whose activity is corrupted in diverse diseases, including cancer. STAT3 biology was presumed to be entirely dependent on its activity as a transcription factor until the discovery of a mitochondrial pool of STAT3, which is necessary for normal tissue function and tumorigenesis. However, the mechanism of this mitochondrial activity remained elusive. This study uses immunoprecipitation and mass spectrometry to identify a complex containing STAT3, leucine-rich pentatricopeptide repeat containing (LRPPRC), and SRA stem-loop-interacting RNA-binding protein (SLIRP) that is required for the stability of mature mitochondrially encoded mRNAs and transport to the mitochondrial ribosome. Moreover, we show that this complex is enriched in patients with lung adenocarcinoma and that its deletion inhibits the growth of lung cancer in vivo, providing therapeutic opportunities through the specific targeting of the mitochondrial activity of STAT3.
    Keywords:  CP: Cancer; CP: Molecular biology; LRPPRC; SLIRP; STAT3; lung adenocarcinoma; mRNA stability; mitochondria
    DOI:  https://doi.org/10.1016/j.celrep.2023.113033
  18. CNS Neurosci Ther. 2023 Sep 16.
    The cell-specific roles of Nrf2 in acute and chronic phases of ischemic stroke.
    George Fadoul, Milos Ikonomovic, Feng Zhang, Tuo Yang.
      Ischemic stroke refers to the sudden loss of blood flow in a specific area of the brain. It is the fifth leading cause of mortality and the leading cause of permanent disability. The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) controls the production of several antioxidants and protective proteins and it has been investigated as a possible pharmaceutical target for reducing harmful oxidative events in brain ischemia. Each cell type exhibits different roles and behaviors in different phases post-stroke, which is comprehensive yet important to understand to optimize management strategies and goals for care for stroke patients. In this review, we comprehensively summarize the protective effects of Nrf2 in experimental ischemic stroke, emphasizing the role of Nrf2 in different cell types including neurons, astrocytes, oligodendrocytes, microglia, and endothelial cells during acute and chronic phases of stroke and providing insights on the neuroprotective role of Nrf2 on each cell type throughout the long term of stroke care. We also highlight the importance of targeting Nrf2 in clinical settings while considering a variety of important factors such as age, drug dosage, delivery route, and time of administration.
    Keywords:  MCAO; astrocytes; endothelial cells; ischemic preconditioning; microglia; neurons; neuroprotection; oligodendrocytes; oxidative stress
    DOI:  https://doi.org/10.1111/cns.14462
  19. Arch Biochem Biophys. 2023 Sep 13. pii: S0003-9861(23)00254-0. [Epub ahead of print] 109755
    Different stimuli induce endothelial dysfunction and promote atherosclerosis through the Piezo1/YAP signaling axis.
    Jingying Mao, Ronghao Yang, Ping Yuan, Fei Wu, Yan Wei, Yongmei Nie, Chunxiang Zhang, Xiangyu Zhou.
      Vascular endothelial dysfunction is the initial step in atherosclerosis (AS). AS tends to occur at vascular bifurcations and curves, and endothelial cells(ECs) are highly susceptible to injury due to mechanical forces induced by disturbed flow (DF) with inconsistent blood flow directions. However, the pathogenesis of endothelial cell dysfunction in AS remains unclear and needs further study. Here, we found that Piezo1 expression was significantly increased in DF- and oxidized low-density lipoprotein(ox-LDL)-treated HUVECs in vitro and a model of atherosclerotic plaque growth in ApoE-/- mice fed a Western diet. Furthermore, Piezo1 upregulated autophagy levels in the HUVECs model, which was reversed by Piezo1 knockdown with a lentivirus-mediated shRNA system. Mechanistically, the level of Yes-associated protein (YAP), a transcriptional coactivator in the Hippo pathway, was significantly elevated in the DF- and ox-LDL-induced HUVECs model, and this effect was further inhibited by Piezo1 knockdown. Moreover, the Piezo1 agonist Yoda1 inhibited the protein level of microtubule-associated protein 1 light chain 3-II(LC3-II) and increased the protein level of sequestosome1(p62/SQSTM1) in a dose-dependent manner, while significantly promoting the protein expression and nuclear translocation of YAP. The YAP inhibitor CA3 weakened Yoda1-mediated inhibition of autophagy. Our results suggest that Piezo1 may regulate endothelial autophagy by promoting YAP activation and nuclear translocation, thereby contributing to vascular endothelial dysfunction.
    Keywords:  Atherosclerosis; Autophagy; Piezo1; Shear stress; YAP
    DOI:  https://doi.org/10.1016/j.abb.2023.109755
  20. Arch Biochem Biophys. 2023 Sep 09. pii: S0003-9861(23)00242-4. [Epub ahead of print]747 109743
    Down-regulation of the mitochondrial fusion protein Opa1/Mfn2 promotes cardiomyocyte hypertrophy in Su5416/hypoxia-induced pulmonary hypertension rats.
    Fangmei Luo, Minyi Fu, Ting Wang, Yanan Qi, Xuefeng Zhong, Dai Li, Bin Liu.
       BACKGROUND: Maladaptive right ventricular (RV) remodeling is the most important pathological feature of pulmonary hypertension (PH), involving processes such as myocardial hypertrophy and fibrosis. A growing number of studies have shown that mitochondria-associated endoplasmic reticulum membranes (MAMs) are involved in various physiological and pathological processes, such as calcium homeostasis, lipid metabolism, inflammatory response, mitochondrial dynamics, and autophagy/mitophagy. The abnormal expression of MAMs-related factors is closely related to the occurrence and development of heart-related diseases. However, the role of MAM-related factors in the maladaptive RV remodeling of PH rats remains unclear.
    METHODS AND RESULTS: We first obtained the transcriptome data of RV tissues from PH rats induced by Su5416 combined with hypoxia treatment (SuHx) from the Gene Expression Omnibus (GEO) database. The results showed that two MAMs-related genes (Opa1 and Mfn2) were significantly down-regulated in RV tissues of SuHx rats, accompanied by significant up-regulation of cardiac hypertrophy-related genes (such as Nppb and Myh7). Subsequently, using the SuHx-induced PH rat model, we found that the downregulation of mitochondrial fusion proteins Opa1 and Mfn2 may be involved in maladaptive RV remodeling by accelerating mitochondrial dysfunction. Finally, at the cellular level, we found that overexpression of Opa1 and Mfn2 could inhibit hypoxia-induced mitochondrial fission and reduce ROS production in H9c2 cardiomyocytes, thereby retarded the progression of cardiomyocyte hypertrophy.
    CONCLUSIONS: The down-regulation of mitochondrial fusion protein Opa1/Mfn2 can accelerate cardiomyocyte hypertrophy and then participate in maladaptive RV remodeling in SuHx-induced PH rats, which may be potential targets for preventing maladaptive RV remodeling.
    Keywords:  Maladaptive right ventricular remodeling; Mitochondria-associated endoplasmic reticulum membranes; Mitochondrial dynamics; Mitofusin 2; Optic atrophy 1; Pulmonary hypertension
    DOI:  https://doi.org/10.1016/j.abb.2023.109743
  21. Curr Opin Genet Dev. 2023 Sep 11. pii: S0959-437X(23)00092-8. [Epub ahead of print]83 102112
    A new era of understanding in vivo metabolic flux in thermogenic adipocytes.
    John A Haley, Cholsoon Jang, David A Guertin.
      Nonshivering thermogenesis by brown adipose tissue (BAT) is an adaptive mechanism for maintaining body temperature in cold environments. BAT is critical in rodents and human infants and has substantial influence on adult human metabolism. Stimulating BAT therapeutically is also being investigated as a strategy against metabolic diseases because of its ability to function as a catabolic sink. Thus, understanding how brown adipocytes and the related brite/beige adipocytes use nutrients to fuel their demanding metabolism has both basic and translational implications. Recent advances in mass spectrometry and isotope tracing are improving the ability to study metabolic flux in vivo. Here, we review how such strategies are advancing our understanding of adipocyte thermogenesis and conclude with key future questions.
    DOI:  https://doi.org/10.1016/j.gde.2023.102112
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