bims-midhyp Biomed News
on Mitochondrial dysfunction and hypoxia
Issue of 2023–07–23
seventeen papers selected by
Alia Ablieh, Universität Heidelberg
  1. Liver mitochondrial cristae organizing protein MIC19 promotes energy expenditure and pedestrian locomotion by altering nucleotide metabolism.
  2. Mitochondrial dysfunction following repeated mild blast traumatic brain injury is attenuated by a mild mitochondrial uncoupling prodrug.
  3. DUSP1 interacts with and dephosphorylates VCP to improve mitochondrial quality control against endotoxemia-induced myocardial dysfunction.
  4. Hypoxia-induced mitochondrial stress granules.
  5. Fatty acid oxidation organizes mitochondrial supercomplexes to sustain astrocytic ROS and cognition.
  6. Identity, structure, and function of the mitochondrial permeability transition pore: controversies, consensus, recent advances, and future directions.
  7. The Role of Hypoxia-inducible Factor-1 in Bladder Cancer.
  8. Molecular mechanisms of endothelial dysfunction in coronary microcirculation dysfunction.
  9. Body mass dependence of oxidative phosphorylation efficiency in liver mitochondria from mammals.
  10. Got Oxygen? Studies on Mesenchymal Cell HIF-1α in Lung Development.
  11. Acetate attenuates kidney fibrosis in an oxidative stress-dependent manner.
  12. Brown Adipose Tissue and BMP3b Decrease Injury in Cardiac Ischemia-Reperfusion.
  13. Structures of p53/BCL-2 complex suggest a mechanism for p53 to antagonize BCL-2 activity.
  14. Mitochondrial genome-encoded long noncoding RNA Cytochrome B and mitochondrial dysfunction in diabetic retinopathy.
  15. Unravelling the role of NFE2L1 in stress responses and related diseases.
  16. MitoQ as an antenatal antioxidant treatment improves markers of lung maturation in healthy and hypoxic pregnancy.
  17. ROS-responsive exogenous functional mitochondria can rescue neural cells post-ischemic stroke.
  1. Cell Metab. 2023 Jul 14. pii: S1550-4131(23)00225-5. [Epub ahead of print]
    Liver mitochondrial cristae organizing protein MIC19 promotes energy expenditure and pedestrian locomotion by altering nucleotide metabolism.
    Jee Hyung Sohn, Beste Mutlu, Pedro Latorre-Muro, Jiaxin Liang, Christopher F Bennett, Kfir Sharabi, Noa Kantorovich, Mark Jedrychowski, Steven P Gygi, Alexander S Banks, Pere Puigserver.
      Liver mitochondria undergo architectural remodeling that maintains energy homeostasis in response to feeding and fasting. However, the specific components and molecular mechanisms driving these changes and their impact on energy metabolism remain unclear. Through comparative mouse proteomics, we found that fasting induces strain-specific mitochondrial cristae formation in the liver by upregulating MIC19, a subunit of the MICOS complex. Enforced MIC19 expression in the liver promotes cristae formation, mitochondrial respiration, and fatty acid oxidation while suppressing gluconeogenesis. Mice overexpressing hepatic MIC19 show resistance to diet-induced obesity and improved glucose homeostasis. Interestingly, MIC19 overexpressing mice exhibit elevated energy expenditure and increased pedestrian locomotion. Metabolite profiling revealed that uracil accumulates in the livers of these mice due to increased uridine phosphorylase UPP2 activity. Furthermore, uracil-supplemented diet increases locomotion in wild-type mice. Thus, MIC19-induced mitochondrial cristae formation in the liver increases uracil as a signal to promote locomotion, with protective effects against diet-induced obesity.
    Keywords:  brisk walking; diabetes; fatty liver; mitochondrial cristae; obesity; uracil
    DOI:  https://doi.org/10.1016/j.cmet.2023.06.015
  2. J Neurotrauma. 2023 Jul 21.
    Mitochondrial dysfunction following repeated mild blast traumatic brain injury is attenuated by a mild mitochondrial uncoupling prodrug.
    William Brad Hubbard, Hemendra Vekaria, Gopal Velmurugan, Olivia Kalimon, Paresh Prajapati, Emily Brown, John Geisler, Patrick G Sulllivan.
      Mild traumatic brain injury (mTBI) results in impairment of brain metabolism, which is propagated by mitochondrial dysfunction in the brain. Mitochondrial dysfunction has been identified as a pathobiological therapeutic target to quell cellular dyshomeostasis. Further, therapeutic approaches targeting mitochondrial impairments, such as mild mitochondrial uncoupling, have been shown to alleviate behavioral alterations after TBI. To examine how mild mitochondrial uncoupling modulates acute mitochondrial outcomes in a military-relevant model of mTBI, we utilized repeated blast overpressure of 11psi peak overpressure to model repeated mild blast traumatic brain injury (rmbTBI) in rats followed by assessment of mitochondrial respiration and mitochondrial-related oxidative damage at 2d post-rmbTBI. Treatment groups were administered 8 or 80 mg/kg MP201, a prodrug of 2,4 dinitrophenol (DNP) that displays improved pharmacokinetics compared to its metabolized form. Synaptic and glia-enriched mitochondria were isolated using fractionated mitochondrial magnetic separation technique. There was a consistent physiological response, decreased heart rate, following mbTBI among experimental groups. While there was a lack of injury effect in mitochondrial respiration of glia-enriched mitochondria, there were impairments in mitochondrial respiration in synaptic mitochondria isolated from the prefrontal cortex (PFC) and the amygdala/entorhinal/piriform cortex (AEP) region. Impairments in synaptic mitochondrial respiration were rescued by oral 80 mg/kg MP201 treatment after rmbTBI, which may be facilitated by increases in complex II and complex IV activity. Mitochondrial oxidative damage in glia-enriched mitochondria was increased in the PFC and hippocampus after rmbTBI. MP201 treatment alleviated elevated glia-enriched mitochondrial oxidative damage following rmbTBI. However, there was a lack of injury-associated differences in oxidative damage in synaptic mitochondria. Overall, our report demonstrates that rmbTBI results in mitochondrial impairment diffusely throughout the brain and mild mitochondrial uncoupling can restore mitochondrial bioenergetics and oxidative balance.
    Keywords:  METABOLISM; MILITARY INJURY; MITOCHONDRIA; OXIDATIVE STRESS; TRAUMATIC BRAIN INJURY
    DOI:  https://doi.org/10.1089/neu.2023.0102
  3. Cell Mol Life Sci. 2023 Jul 18. 80(8): 213
    DUSP1 interacts with and dephosphorylates VCP to improve mitochondrial quality control against endotoxemia-induced myocardial dysfunction.
    Hang Zhu, Jin Wang, Ting Xin, Shanshan Chen, Ruiying Hu, Yukun Li, Mingming Zhang, Hao Zhou.
      Dual specificity phosphatase 1 (DUSP1) and valosin-containing protein (VCP) have both been reported to regulate mitochondrial homeostasis. However, their impact on mitochondrial quality control (MQC) and myocardial function during LPS-induced endotoxemia remains unclear. We addressed this issue by modeling LPS-induced endotoxemia in DUSP1 transgenic (DUSP1TG) mice and in cultured DUSP1-overexpressing HL-1 cardiomyocytes. Accompanying characteristic structural and functional deficits, cardiac DUSP1 expression was significantly downregulated following endotoxemia induction in wild type mice. In contrast, markedly reduced myocardial inflammation, cardiomyocyte apoptosis, cardiac structural disorder, cardiac injury marker levels, and normalized systolic/diastolic function were observed in DUSP1TG mice. Furthermore, DUSP1 overexpression in HL-1 cells significantly attenuated LPS-mediated mitochondrial dysfunction by preserving MQC, as indicated by normalized mitochondrial dynamics, improved mitophagy, enhanced biogenesis, and attenuated mitochondrial unfolded protein response. Molecular assays showed that VCP was a substrate of DUSP1 and the interaction between DUSP1 and VCP primarily occurred on the mitochondria. Mechanistically, DUSP1 phosphatase domain promoted the physiological DUSP1/VCP interaction which prevented LPS-mediated VCP Ser784 phosphorylation. Accordingly, transfection with a phosphomimetic VCP mutant abolished the protective actions of DUSP1 on MQC and aggravated inflammation, apoptosis, and contractility/relaxation capacity in HL-1 cardiomyocytes. These findings support the involvement of the novel DUSP1/VCP/MQC pathway in the pathogenesis of endotoxemia-caused myocardial dysfunction.
    Keywords:  Apoptosis; DUSP1; Endotoxemia-caused myocardial dysfunction; Mitochondria; Mitochondrial quality control; Myocardial inflammation; Oxidative stress; VCP
    DOI:  https://doi.org/10.1007/s00018-023-04863-z
  4. Cell Death Dis. 2023 Jul 19. 14(7): 448
    Hypoxia-induced mitochondrial stress granules.
    Chun-Ling Sun, Marc Van Gilst, C Michael Crowder.
      Perturbations of mitochondrial proteostasis have been associated with aging, neurodegenerative diseases, and recently with hypoxic injury. While examining hypoxia-induced mitochondrial protein aggregation in C. elegans, we found that sublethal hypoxia, sodium azide, or heat shock-induced abundant ethidium bromide staining mitochondrial granules that preceded evidence of protein aggregation. Genetic manipulations that reduce cellular and organismal hypoxic death block the formation of these mitochondrial stress granules (mitoSG). Knockdown of mitochondrial nucleoid proteins also blocked the formation of mitoSG by a mechanism distinct from the mitochondrial unfolded protein response. Lack of the major mitochondrial matrix protease LONP-1 resulted in the constitutive formation of mitoSG without external stress. Ethidium bromide-staining RNA-containing mitochondrial granules were also observed in rat cardiomyocytes treated with sodium azide, a hypoxia mimetic. Mitochondrial stress granules are an early mitochondrial pathology controlled by LONP and the nucleoid, preceding hypoxia-induced protein aggregation.
    DOI:  https://doi.org/10.1038/s41419-023-05988-6
  5. Nat Metab. 2023 Jul 17.
    Fatty acid oxidation organizes mitochondrial supercomplexes to sustain astrocytic ROS and cognition.
    Brenda Morant-Ferrando, Daniel Jimenez-Blasco, Paula Alonso-Batan, Jesús Agulla, Rebeca Lapresa, Dario Garcia-Rodriguez, Sara Yunta-Sanchez, Irene Lopez-Fabuel, Emilio Fernandez, Peter Carmeliet, Angeles Almeida, Marina Garcia-Macia, Juan P Bolaños.
      Having direct access to brain vasculature, astrocytes can take up available blood nutrients and metabolize them to fulfil their own energy needs and deliver metabolic intermediates to local synapses1,2. These glial cells should be, therefore, metabolically adaptable to swap different substrates. However, in vitro and in vivo studies consistently show that astrocytes are primarily glycolytic3-7, suggesting glucose is their main metabolic precursor. Notably, transcriptomic data8,9 and in vitro10 studies reveal that mouse astrocytes are capable of mitochondrially oxidizing fatty acids and that they can detoxify excess neuronal-derived fatty acids in disease models11,12. Still, the factual metabolic advantage of fatty acid use by astrocytes and its physiological impact on higher-order cerebral functions remain unknown. Here, we show that knockout of carnitine-palmitoyl transferase-1A (CPT1A)-a key enzyme of mitochondrial fatty acid oxidation-in adult mouse astrocytes causes cognitive impairment. Mechanistically, decreased fatty acid oxidation rewired astrocytic pyruvate metabolism to facilitate electron flux through a super-assembled mitochondrial respiratory chain, resulting in attenuation of reactive oxygen species formation. Thus, astrocytes naturally metabolize fatty acids to preserve the mitochondrial respiratory chain in an energetically inefficient disassembled conformation that secures signalling reactive oxygen species and sustains cognitive performance.
    DOI:  https://doi.org/10.1038/s42255-023-00835-6
  6. Cell Death Differ. 2023 Jul 17.
    Identity, structure, and function of the mitochondrial permeability transition pore: controversies, consensus, recent advances, and future directions.
    Paolo Bernardi, Christoph Gerle, Andrew P Halestrap, Elizabeth A Jonas, Jason Karch, Nelli Mnatsakanyan, Evgeny Pavlov, Shey-Shing Sheu, Alexander A Soukas.
      The mitochondrial permeability transition (mPT) describes a Ca2+-dependent and cyclophilin D (CypD)-facilitated increase of inner mitochondrial membrane permeability that allows diffusion of molecules up to 1.5 kDa in size. It is mediated by a non-selective channel, the mitochondrial permeability transition pore (mPTP). Sustained mPTP opening causes mitochondrial swelling, which ruptures the outer mitochondrial membrane leading to subsequent apoptotic and necrotic cell death, and is implicated in a range of pathologies. However, transient mPTP opening at various sub-conductance states may contribute several physiological roles such as alterations in mitochondrial bioenergetics and rapid Ca2+ efflux. Since its discovery decades ago, intensive efforts have been made to identify the exact pore-forming structure of the mPT. Both the adenine nucleotide translocase (ANT) and, more recently, the mitochondrial F1FO (F)-ATP synthase dimers, monomers or c-subunit ring alone have been implicated. Here we share the insights of several key investigators with different perspectives who have pioneered mPT research. We critically assess proposed models for the molecular identity of the mPTP and the mechanisms underlying its opposing roles in the life and death of cells. We provide in-depth insights into current controversies, seeking to achieve a degree of consensus that will stimulate future innovative research into the nature and role of the mPTP.
    DOI:  https://doi.org/10.1038/s41418-023-01187-0
  7. Curr Mol Med. 2023 Jul 20.
    The Role of Hypoxia-inducible Factor-1 in Bladder Cancer.
    Jiagui Chai, Sifan Yin, Wenbo Feng, Tao Zhang, Changxing Ke.
      Bladder cancer (BC) is one of the most common malignant tumors worldwide and poses a significant hazard to human health. During the development of BC, hypoxia plays a crucial role. Hypoxia-inducible factor (HIF) is a key transcription factor for hypoxic adaptation, which regulates the transcription of various genes, including inflammation, angiogenesis, and glycolytic metabolism. Recent studies have shown the precise role of HIF in various biological behaviors of BC. More importantly, a new antitumor medication targeting HIF-2 has been used to treat renal cancer. However, therapies targeting HIF-1 in BC have not yet been developed. In this review, we discussed how HIF-1 is expressed and affects the growth, metastasis, and angiogenesis of BC. At the same time, we investigated several HIF-1 inhibitors that provide new perspectives for targeting HIF-1.
    Keywords:  Angiogenesis; Bladder cancer; Drug resistance; Glucose metabolism; HIF-1; Metastasis; Proliferation; Treatment.
    DOI:  https://doi.org/10.2174/1566524023666230720163448
  8. J Thromb Thrombolysis. 2023 Jul 19.
    Molecular mechanisms of endothelial dysfunction in coronary microcirculation dysfunction.
    Zhiyu Zhang, Xiangjun Li, Jiahuan He, Shipeng Wang, Jingyue Wang, Junqian Liu, Yushi Wang.
      Coronary microvascular endothelial cells (CMECs) react to changes in coronary blood flow and myocardial metabolites and regulate coronary blood flow by balancing vasoconstrictors-such as endothelin-1-and the vessel dilators prostaglandin, nitric oxide, and endothelium-dependent hyperpolarizing factor. Coronary microvascular endothelial cell dysfunction is caused by several cardiovascular risk factors and chronic rheumatic diseases that impact CMEC blood flow regulation, resulting in coronary microcirculation dysfunction (CMD). The mechanisms of CMEC dysfunction are not fully understood. However, the following could be important mechanisms: the overexpression and activation of nicotinamide adenine dinucleotide phosphate oxidase (Nox), and mineralocorticoid receptors; the involvement of reactive oxygen species (ROS) caused by a decreased expression of sirtuins (SIRT3/SIRT1); forkhead box O3; and a decreased SKCA/IKCA expression in the endothelium-dependent hyperpolarizing factor electrical signal pathway. In addition, p66Shc is an adapter protein that promotes oxidative stress; although there are no studies on its involvement with cardiac microvessels, it is possible it plays an important role in CMD.
    Keywords:  Coronary blood flow regulation; Coronary microcirculation dysfunction; Coronary microvascular endothelial cells; Molecular mechanism
    DOI:  https://doi.org/10.1007/s11239-023-02862-2
  9. Comp Biochem Physiol A Mol Integr Physiol. 2023 Jul 19. pii: S1095-6433(23)00123-X. [Epub ahead of print] 111490
    Body mass dependence of oxidative phosphorylation efficiency in liver mitochondria from mammals.
    Boël Mélanie, Voituron Yann, Roussel Damien.
      In eukaryotes, the performances of an organism are dependent on body mass and chemically supported by the mitochondrial production of ATP. Although the relationship between body mass and mitochondrial oxygen consumption is well described, the allometry of the transduction efficiency from oxygen to ATP production (ATP/O) is still poorly understood. Using a comparative approach, we investigated the oxygen consumption and ATP production of liver mitochondria from twelve species of mammals ranging from 5 g to 600 kg. We found that both oxygen consumption and ATP production are mass dependent but not the ATP/O at the maximal phosphorylating state. The results also showed that for sub-maximal phosphorylating states the ATP/O value positively correlated with body mass, irrespective of the metabolic intensity. This result contrasts with previous data obtained in mammalian muscles, suggesting a tissue-dependence of the body mass effect on mitochondrial efficiency.
    Keywords:  Bioenergetics; Liver; Mitochondria; Oxidative phosphorylation
    DOI:  https://doi.org/10.1016/j.cbpa.2023.111490
  10. Am J Respir Cell Mol Biol. 2023 Jul 21.
    Got Oxygen? Studies on Mesenchymal Cell HIF-1α in Lung Development.
    Reece P Stevens, Ji Young Lee, Natalie Bauer, Troy Stevens.
      
    Keywords:  Angiopoietin-2; Bronchopulmonary dysplasia; Hypoxia inducible factor-1; Mesenchymal cells; Oxygen
    DOI:  https://doi.org/10.1165/rcmb.2023-0247ED
  11. Physiol Rep. 2023 07;11(14): e15774
    Acetate attenuates kidney fibrosis in an oxidative stress-dependent manner.
    Chiaki Kawabata, Yosuke Hirakawa, Reiko Inagi, Masaomi Nangaku.
      Short-chain fatty acids (SCFAs) are the end products of the fermentation of dietary fibers by the intestinal microbiota and reported to exert positive effects on host physiology. Acetate is the most abundant SCFA in humans and is shown to improve acute kidney injury in a mouse model of ischemia-reperfusion injury. However, how SCFAs protect the kidney and whether SCFAs have a renoprotective effect in chronic kidney disease (CKD) models remain to be elucidated. We investigated whether acetate and other SCFAs could attenuate the kidney damage. In in vitro experiments, cell viability of acetate-treated human kidney 2 (HK-2) cells was significantly higher than that of vehicle-treated in an oxidative stress model, and acetate reduced cellular reactive oxygen species (ROS) production. In mitochondrial analysis, the MitoSOX-positive cell proportion decreased, and transcription of dynamin-1-like protein gene, a fission gene, was decreased by acetate treatment. In in vivo experiments in mice, acetate treatment significantly ameliorated fibrosis induced by unilateral ureteral obstruction, and the oxidative stress marker phosphorylated histone H2AX (γH2AX) was also reduced. Further, acetate treatment ameliorated dysmorphic mitochondria in the proximal tubules, and ROS and mitochondrial analyses suggested that acetate improved mitochondrial damage. Our findings indicate a renoprotective effect of acetate in CKD.
    Keywords:  acetate; chronic kidney disease; mitochondria; reactive oxygen species; short-chain fatty acid
    DOI:  https://doi.org/10.14814/phy2.15774
  12. Circ Res. 2023 Jul 18.
    Brown Adipose Tissue and BMP3b Decrease Injury in Cardiac Ischemia-Reperfusion.
    Íngrid Martí-Pàmies, Robrecht Thoonen, Michael Morley, Lauren Graves, Jesus Tamez, Alex Caplan, Kendra McDaid, Vincent Yao, Allyson Hindle, Robert E Gerszten, Laurie A Farrell, Li Li, Yu-Hua Tseng, Gerson Profeta, Emmanuel S Buys, Donald B Bloch, Marielle Scherrer-Crosbie.
       BACKGROUND: Despite advances in treatment, myocardial infarction (MI) is a leading cause of heart failure and death worldwide, with both ischemia and reperfusion (I/R) causing cardiac injury. A previous study using a mouse model of nonreperfused MI showed activation of brown adipose tissue (BAT). Recent studies showed that molecules secreted by BAT target the heart. We investigated whether BAT attenuates cardiac injury in I/R and sought to identify potential cardioprotective proteins secreted by BAT.
    METHODS: Myocardial I/R surgery with or without BAT transplantation was performed in wild-type (WT) mice and in mice with impaired BAT function (uncoupling protein 1 [Ucp1]-deficient mice). To identify potential cardioprotective factors produced by BAT, RNA-seq was performed in BAT from WT and Ucp1-/- mice. Subsequently, myocardial I/R surgery with or without BAT transplantation was performed in Bmp3b (bone morphogenetic protein 3b)-deficient mice, and WT mice subjected to myocardial I/R were treated using BMP3b.
    RESULTS: Dysfunction of BAT in mice was associated with larger MI size after I/R; conversely, augmenting BAT by transplantation decreased MI size. We identified Bmp3b as a protein secreted by BAT after I/R. Compared with WT mice, Bmp3b-deficient mice developed larger MIs. Increasing functional BAT by transplanting BAT from WT mice to Bmp3b-deficient mice reduced I/R injury whereas transplanting BAT from Bmp3b-deficient mice did not. Treatment of WT mice with BMP3b before reperfusion decreased MI size. The cardioprotective effect of BMP3b was mediated through SMAD1/5/8. In humans, the plasma level of BMP3b increased after MI and was positively correlated with the extent of cardiac injury.
    CONCLUSIONS: The results of this study suggest a cardioprotective role of BAT and BMP3b, a protein secreted by BAT, in a model of I/R injury. Interventions increasing BMP3b levels or targeting Smad 1/5 may represent novel therapeutic approaches to decrease myocardial damage in I/R injury.
    Keywords:  heart failure; mice; myocardium; reperfusion; uncoupling protein 1
    DOI:  https://doi.org/10.1161/CIRCRESAHA.122.322337
  13. Nat Commun. 2023 07 18. 14(1): 4300
    Structures of p53/BCL-2 complex suggest a mechanism for p53 to antagonize BCL-2 activity.
    Hudie Wei, Haolan Wang, Genxin Wang, Lingzhi Qu, Longying Jiang, Shuyan Dai, Xiaojuan Chen, Ye Zhang, Zhuchu Chen, Youjun Li, Ming Guo, Yongheng Chen.
      Mitochondrial apoptosis is strictly controlled by BCL-2 family proteins through a subtle network of protein interactions. The tumor suppressor protein p53 triggers transcription-independent apoptosis through direct interactions with BCL-2 family proteins, but the molecular mechanism is not well understood. In this study, we present three crystal structures of p53-DBD in complex with the anti-apoptotic protein BCL-2 at resolutions of 2.3-2.7 Å. The structures show that two loops of p53-DBD penetrate directly into the BH3-binding pocket of BCL-2. Structure-based mutations at the interface impair the p53/BCL-2 interaction. Specifically, the binding sites for p53 and the pro-apoptotic protein Bax in the BCL-2 pocket are mostly identical. In addition, formation of the p53/BCL-2 complex is negatively correlated with the formation of BCL-2 complexes with pro-apoptotic BCL-2 family members. Defects in the p53/BCL-2 interaction attenuate p53-mediated cell apoptosis. Overall, our study provides a structural basis for the interaction between p53 and BCL-2, and suggests a molecular mechanism by which p53 regulates transcription-independent apoptosis by antagonizing the interaction of BCL-2 with pro-apoptotic BCL-2 family members.
    DOI:  https://doi.org/10.1038/s41467-023-40087-2
  14. Antioxid Redox Signal. 2023 Jul 18.
    Mitochondrial genome-encoded long noncoding RNA Cytochrome B and mitochondrial dysfunction in diabetic retinopathy.
    Ghulam Mohammad, Jay S Kumar, Renu Kowluru.
      Aim Mitochondrial dysfunction is closely associated with the development of diabetic complications. In diabetic retinopathy, electron transport chain is compromised and mtDNA is damaged, downregulating transcription of mtDNA-encoded cytochrome B (CYTB) and its antisense long noncoding RNA, LncCytB. Our goal was to investigate the role of LncCytB in the regulation of CYTB and mitochondrial function in diabetic retinopathy. Methods Using human retinal endothelial cells (HRECs), genetically manipulated for LncCytB (overexpression or silencing), the effect of high glucose (20mM D-glucose) on LncCytB-CYTB interactions (by Chromatin isolation by RNA Purification), CYTB gene expression (by qRT-PCR), complex III activity, mitochondrial free radicals and oxygen consumption rate (OCR, by Seahorse XF analyzer) was investigated. Key results were confirmed in the retinal microvessels from streptozotocin-induced diabetic mice. Results High glucose decreased LncCytB-CYTB interactions, and while LncCytB overexpression ameliorated glucose-induced decrease in CYTB gene transcripts, complex III activity and OCR and increase in mitochondrial ROS, LncCytB-siRNA further attenuated CYTB gene transcription, complex III activity and OCR. Similar decrease in LncCytB-CYTB interactions and CYTB transcription was observed in diabetic mice. Furthermore, protection of mitochondrial homeostasis by overexpressing superoxide dismutase or Sirtuin 1 in mice, ameliorated diabetes-induced decrease in LncCytB-CYTB interactions and CYTB gene transcripts, and also improved complex III activity and mitochondrial respiration. Innovation and Conclusion LncCytB downregulation in hyperglycemic milieu downregulates CYTB transcription, which inhibits complex III activity and compromises mitochondrial stability and oxygen consumption rate. Thus, preventing LncCytB downregulation in diabetes has potential of inhibiting the development of diabetic retinopathy, possibly via maintaining mitochondrial respiration.
    DOI:  https://doi.org/10.1089/ars.2023.0303
  15. Redox Biol. 2023 Jul 14. pii: S2213-2317(23)00220-3. [Epub ahead of print]65 102819
    Unravelling the role of NFE2L1 in stress responses and related diseases.
    Xingzhu Liu, Chang Xu, Wanglong Xiao, Nianlong Yan.
      The nuclear factor erythroid 2 (NF-E2)-related factor 1 (NFE2L1, also known as Nrf1) is a highly conserved transcription factor that belongs to the CNC-bZIP subfamily. Its significance lies in its control over redox balance, proteasome activity, and organ integrity. Stress responses encompass a series of compensatory adaptations utilized by cells and organisms to cope with extracellular or intracellular stress initiated by stressful stimuli. Recently, extensive evidence has demonstrated that NFE2L1 plays a crucial role in cellular stress adaptation by 1) responding to oxidative stress through the induction of antioxidative responses, and 2) addressing proteotoxic stress or endoplasmic reticulum (ER) stress by regulating the ubiquitin-proteasome system (UPS), unfolded protein response (UPR), and ER-associated degradation (ERAD). It is worth noting that NFE2L1 serves as a core factor in proteotoxic stress adaptation, which has been extensively studied in cancer and neurodegeneration associated with enhanced proteasomal stress. In these contexts, utilization of NFE2L1 inhibitors to attenuate proteasome "bounce-back" response holds tremendous potential for enhancing the efficacy of proteasome inhibitors. Additionally, abnormal stress adaptations of NFE2L1 and disturbances in redox and protein homeostasis contribute to the pathophysiological complications of cardiovascular diseases, inflammatory diseases, and autoimmune diseases. Therefore, a comprehensive exploration of the molecular basis of NFE2L1 and NFE2L1-mediated diseases related to stress responses would not only facilitate the identification of novel diagnostic and prognostic indicators but also enable the identification of specific therapeutic targets for NFE2L1-related diseases.
    Keywords:  Adaptive responses; Cancer; NFE2L1; Neurodegeneration; Oxidative stress; Proteasome
    DOI:  https://doi.org/10.1016/j.redox.2023.102819
  16. J Physiol. 2023 Jul 19.
    MitoQ as an antenatal antioxidant treatment improves markers of lung maturation in healthy and hypoxic pregnancy.
    Mitchell C Lock, Kimberley J Botting, Beth J Allison, Youguo Niu, Sage G Ford, Michael P Murphy, Sandra Orgeig, Dino A Giussani, Janna L Morrison.
      Chronic fetal hypoxaemia is a common pregnancy complication that increases the risk of infants experiencing respiratory complications at birth. In turn, chronic fetal hypoxaemia promotes oxidative stress, and maternal antioxidant therapy in animal models of hypoxic pregnancy has proven to be protective with regards to fetal growth and cardiovascular development. However, whether antenatal antioxidant therapy confers any benefit on lung development in complicated pregnancies has not yet been investigated. Here, we tested the hypothesis that maternal antenatal treatment with MitoQ will protect the developing lung in hypoxic pregnancy in sheep, a species with similar fetal lung developmental milestones as humans. Maternal treatment with MitoQ during late gestation promoted fetal pulmonary surfactant maturation and an increase in the expression of lung mitochondrial complexes III and V independent of oxygenation. Maternal treatment with MitoQ in hypoxic pregnancy also increased the expression of genes regulating liquid reabsorption in the fetal lung. These data support the hypothesis tested and suggest that MitoQ as an antenatal targeted antioxidant treatment may improve lung maturation in the late gestation fetus. KEY POINTS: Chronic fetal hypoxaemia promotes oxidative stress, and maternal antioxidant therapy in hypoxic pregnancy has proven to be protective with regards to fetal growth and cardiovascular development. MitoQ is a targeted antioxidant that uses the cell and the mitochondrial membrane potential to accumulate within the mitochondria. Treatment of healthy or hypoxic pregnancy with MitoQ, increases the expression of key molecules involved in surfactant maturation, lung liquid reabsorption and in mitochondrial proteins driving ATP synthesis in the fetal sheep lung. There were no detrimental effects of MitoQ treatment alone on the molecular components measured in the present study, suggesting that maternal antioxidant treatment has no effect on other components of normal maturation of the surfactant system.
    Keywords:  antioxidant; fetal growth restriction; fetus; hypoxia; lung development; surfactant
    DOI:  https://doi.org/10.1113/JP284786
  17. Front Cell Dev Biol. 2023 ;11 1207748
    ROS-responsive exogenous functional mitochondria can rescue neural cells post-ischemic stroke.
    Yanjiao Li, Yachao Wang, Weiqi Yang, Zhen Wu, Daiping Ma, Jianxiu Sun, Huixian Tao, Qinlian Ye, Jingnan Liu, Zhaoxia Ma, Lihua Qiu, Weiping Li, Liyan Li, Min Hu.
      Background: The transfer of mitochondria from healthy mesenchymal stem cells (MSCs) to injured MSCs has been shown to have potential therapeutic benefits for neural cell post-ischemic stroke. Specifically, functional mitochondria can perform their normal functions after being internalized by stressed cells, leading to host cell survival. However, while this approach shows promise, there is still a lack of understanding regarding which neural cells can internalize functional mitochondria and the regulatory mechanisms involved. To address this gap, we investigated the ability of different neural cells to internalize exogenous functional mitochondria extracted from MSCs. Methods: Functional mitochondria (F-Mito) isolated from umbilical cord derived-MSCs (UCMSCs) were labeled with lentivirus of HBLV-mito-dsred-Null-PURO vector. The ability of stressed cells to internalize F-Mito was analyzed using a mouse (C57BL/6 J) middle cerebral artery occlusion (MCAO) model and an oxygen-glucose deprivation/reoxygenation (OGD/R) cell model. The cell viability was measured by CCK-8 kit. Time-course of intracellular ROS levels in stressed cells were analyzed by DCFH-DA staining after OGD/R and F-Mito treatment. MitoSOX, Mitotracker and WGA labeling were used to assess the relationship between ROS levels and the uptake of F-Mito at the single-cell level. Pharmacological modulation of ROS was performed using acetylcysteine (ROS inhibitor). Results: Our findings demonstrate that neurons and endothelial cells are more effective at internalizing mitochondria than astrocytes, both in vitro and in vivo, using an ischemia-reperfusion model. Additionally, internalized F-Mito decreases host cell reactive oxygen species (ROS) levels and rescues survival. Importantly, we found that the ROS response in stressed cells after ischemia is a crucial determinant in positively mediating the internalization of F-Mito by host cells, and inhibiting the generation of ROS chemicals in host cells may decrease the internalization of F-Mito. These results offer insight into how exogenous mitochondria rescue neural cells via ROS response in an ischemic stroke model. Overall, our study provides solid evidence for the translational application of MSC-derived mitochondria as a promising treatment for ischemic stroke.
    Keywords:  ROS; exogenous functional mitochondria; ischemic stroke; mitochondria internalization; mitochondria transplantation; neuroprotection
    DOI:  https://doi.org/10.3389/fcell.2023.1207748
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