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Chen B, Lyssiotis CA, Shah YM. Mitochondria-organelle crosstalk in establishing compartmentalized metabolic homeostasis. Mol Cell 2025; 85:1487-1508. [PMID: 40250411 DOI: 10.1016/j.molcel.2025.03.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2024] [Revised: 02/21/2025] [Accepted: 03/04/2025] [Indexed: 04/20/2025]
Abstract
Mitochondria serve as central hubs in cellular metabolism by sensing, integrating, and responding to metabolic demands. This integrative function is achieved through inter-organellar communication, involving the exchange of metabolites, lipids, and signaling molecules. The functional diversity of metabolite exchange and pathway interactions is enabled by compartmentalization within organelle membranes. Membrane contact sites (MCSs) are critical for facilitating mitochondria-organelle communication, creating specialized microdomains that enhance the efficiency of metabolite and lipid exchange. MCS dynamics, regulated by tethering proteins, adapt to changing cellular conditions. Dysregulation of mitochondrial-organelle interactions at MCSs is increasingly recognized as a contributing factor in the pathogenesis of multiple diseases. Emerging technologies, such as advanced microscopy, biosensors, chemical-biology tools, and functional genomics, are revolutionizing our understanding of inter-organellar communication. These approaches provide novel insights into the role of these interactions in both normal cellular physiology and disease states. This review will highlight the roles of metabolite transporters, lipid-transfer proteins, and mitochondria-organelle interfaces in the coordination of metabolism and transport.
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Affiliation(s)
- Brandon Chen
- Cellular and Molecular Biology Program, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Costas A Lyssiotis
- Cellular and Molecular Biology Program, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Internal Medicine, Division of Gastroenterology and Hepatology, Michigan Medicine at the University of Michigan, Ann Arbor, MI 48109, USA; Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA.
| | - Yatrik M Shah
- Cellular and Molecular Biology Program, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Internal Medicine, Division of Gastroenterology and Hepatology, Michigan Medicine at the University of Michigan, Ann Arbor, MI 48109, USA; Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA.
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Westerberg NS, Atneosen-Åsegg M, Melheim M, Chollet ME, Harrison SP, Siller R, Sullivan GJ, Almaas R. Effect of hypoxia on aquaporins and hepatobiliary transport systems in human hepatic cells. Pediatr Res 2025; 97:195-201. [PMID: 38951656 DOI: 10.1038/s41390-024-03368-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2024] [Revised: 06/03/2024] [Accepted: 06/13/2024] [Indexed: 07/03/2024]
Abstract
OBJECTIVES Hepatic ischemia and hypoxia are accompanied by reduced bile flow, biliary sludge and cholestasis. Hepatobiliary transport systems, nuclear receptors and aquaporins were studied after hypoxia and reoxygenation in human hepatic cells. METHODS Expression of Aquaporin 8 (AQP8), Aquaporin 9 (AQP9), Pregnane X receptor (PXR), Farnesoid X receptor (FXR), Organic anion transporting polypeptide 1 (OATP1), and the Multidrug resistance-associated protein 4 (MRP4) were investigated in induced pluripotent stem cells (iPSCs) derived hepatic cells and the immortalized hepatic line HepG2. HepG2 was subjected to combined oxygen and glucose deprivation for 4 h followed by reoxygenation. RESULTS Expression of AQP8 and AQP9 increased during differentiation in iPSC-derived hepatic cells. Hypoxia did not alter mRNA levels of AQP8, but reoxygenation caused a marked increase in AQP8 mRNA expression. While expression of OATP1 had a transient increase during reoxygenation, MRP4 showed a delayed downregulation. Knock-down of FXR did not alter the expression of AQP8, AQP9, MRP4, or OATP1. Post-hypoxic protein levels of AQP8 were reduced after 68 h of reoxygenation compared to normoxic controls. CONCLUSIONS Post-transcriptional mechanisms rather than reduced transcription cause reduction in AQP8 protein concentration after hypoxia-reoxygenation in hepatic cells. Expression patterns differed between hepatobiliary transport systems during hypoxia and reoxygenation. IMPACT Expression of AQP8 and AQP9 increased during differentiation in induced pluripotent stem cells. Expression of hepatobiliary transporters varies during hypoxia and reoxygenation. Post-hypoxic protein levels of AQP8 were reduced after 68 h of reoxygenation. Post-transcriptional mechanisms rather than reduced transcription cause reduction in AQP8 protein concentration after hypoxia-reoxygenation in hepatic cells. Hypoxia and reoxygenation may affect aquaporins in hepatic cells and potentially affect bile composition.
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Affiliation(s)
- Niklas Starck Westerberg
- Department of Pediatric Research, Oslo University Hospital, Oslo, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | | | - Maria Melheim
- Department of Pediatric Research, Oslo University Hospital, Oslo, Norway
| | - Maria Eugenia Chollet
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Department of Haematology, Oslo University Hospital, Oslo, Norway
- Research Institute of Internal Medicine, Oslo University Hospital, Oslo, Norway
| | - Sean P Harrison
- Department of Pediatric Research, Oslo University Hospital, Oslo, Norway
| | - Richard Siller
- Department of Molecular Medicine, University of Oslo, Oslo, Norway
| | - Gareth J Sullivan
- Department of Pediatric Research, Oslo University Hospital, Oslo, Norway
- School of Medicine, University of St Andrews, St Andrews, UK
| | - Runar Almaas
- Department of Pediatric Research, Oslo University Hospital, Oslo, Norway.
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
- European Reference Network-Rare Liver, Hamburg, Germany.
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Orrico F, Lopez AC, Silva N, Franco M, Mouro-Chanteloup I, Denicola A, Ostuni MA, Thomson L, Möller MN. Hydrogen peroxide diffusion across the red blood cell membrane occurs mainly by simple diffusion through the lipid fraction. Free Radic Biol Med 2025; 226:389-396. [PMID: 39551450 DOI: 10.1016/j.freeradbiomed.2024.11.031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2024] [Revised: 11/11/2024] [Accepted: 11/14/2024] [Indexed: 11/19/2024]
Abstract
Hydrogen peroxide (H2O2) is an oxidant produced endogenously by several enzymatic pathways. While it can cause molecular damage, H2O2 also plays a role in regulating cell proliferation and survival through redox signaling pathways. In the vascular system, red blood cells (RBCs) are notably efficient at metabolizing H2O2. In addition to a robust antioxidant defense, we recently determined that human RBCs also have a high membrane permeability to H2O2 that is independent of aquaporin 1 or aquaporin 3. In this work, we sought to further investigate the permeation mechanism of H2O2 through the membrane of human RBCs. First, we explored the role of other erythrocytic membrane proteins in H2O2 transport, including urea transporter B and ammonia transporter Rh proteins. However, no differences were found in H2O2 permeability in RBCs lacking these proteins compared to control RBCs. We then focused on the hypothesis that H2O2 diffuses through the lipid bilayer. To test this, we studied H2O2 permeability in RBCs from patients with Gaucher disease (GD), which accumulate sphingolipids in the membrane, affecting RBC morphology and deformability. We found that RBCs from GD patients exhibited lower H₂O₂ membrane permeability. In another approach, we treated normal RBCs with hexanol, which fluidizes the lipid fraction of the RBC membrane, and observed an increase in the permeability to H2O2. In contrast, hexanol had no effect on the rate of water efflux by aquaporin 1. Together, these results support the hypothesis that H2O2 diffusion through the RBC membrane occurs primarily through the lipid fraction.
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Affiliation(s)
- Florencia Orrico
- Laboratorio de Fisicoquímica Biológica, Instituto de Química Biológica, Facultad de Ciencias, Universidad de la República, Montevideo, 11400, Uruguay; Laboratorio de Enzimología, Instituto de Química Biológica, Facultad de Ciencias, Universidad de la República, Montevideo, 11400, Uruguay; Centro de Investigaciones Biomédicas (CEINBIO), Universidad de la República, Montevideo, 11800, Uruguay.
| | - Ana C Lopez
- Laboratorio de Fisicoquímica Biológica, Instituto de Química Biológica, Facultad de Ciencias, Universidad de la República, Montevideo, 11400, Uruguay; Laboratorio de Enzimología, Instituto de Química Biológica, Facultad de Ciencias, Universidad de la República, Montevideo, 11400, Uruguay; Centro de Investigaciones Biomédicas (CEINBIO), Universidad de la República, Montevideo, 11800, Uruguay.
| | - Nicolás Silva
- Laboratorio de Fisicoquímica Biológica, Instituto de Química Biológica, Facultad de Ciencias, Universidad de la República, Montevideo, 11400, Uruguay; Laboratorio de Enzimología, Instituto de Química Biológica, Facultad de Ciencias, Universidad de la República, Montevideo, 11400, Uruguay; Centro de Investigaciones Biomédicas (CEINBIO), Universidad de la República, Montevideo, 11800, Uruguay.
| | - Mélanie Franco
- Université Paris Cité and Université des Antilles, INSERM, BIGR, F-75015, Paris, France.
| | | | - Ana Denicola
- Laboratorio de Fisicoquímica Biológica, Instituto de Química Biológica, Facultad de Ciencias, Universidad de la República, Montevideo, 11400, Uruguay; Centro de Investigaciones Biomédicas (CEINBIO), Universidad de la República, Montevideo, 11800, Uruguay.
| | - Mariano A Ostuni
- Université Paris Cité and Université des Antilles, INSERM, BIGR, F-75015, Paris, France.
| | - Leonor Thomson
- Laboratorio de Enzimología, Instituto de Química Biológica, Facultad de Ciencias, Universidad de la República, Montevideo, 11400, Uruguay; Centro de Investigaciones Biomédicas (CEINBIO), Universidad de la República, Montevideo, 11800, Uruguay.
| | - Matias N Möller
- Laboratorio de Fisicoquímica Biológica, Instituto de Química Biológica, Facultad de Ciencias, Universidad de la República, Montevideo, 11400, Uruguay; Centro de Investigaciones Biomédicas (CEINBIO), Universidad de la República, Montevideo, 11800, Uruguay.
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Yadav DK, Singh DD, Shin D. Distinctive roles of aquaporins and novel therapeutic opportunities against cancer. RSC Med Chem 2024:d4md00786g. [PMID: 39697243 PMCID: PMC11650210 DOI: 10.1039/d4md00786g] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2024] [Accepted: 11/11/2024] [Indexed: 12/20/2024] Open
Abstract
Aquaporins (AQPs) are integral membrane proteins responsible for facilitating the transmembrane transport of water and small solutes. Their involvement in diverse physiological functions extends to pathological conditions, including cancer, positioning them as promising targets for anticancer therapy. Tumor cells, particularly those with high metastatic potential, exhibit elevated AQP expression, reinforcing their critical role in tumor biology. Emerging evidence highlights AQPs' involvement in key oncogenic processes such as cell migration, proliferation, and tumor-associated edema, suggesting their potential as novel therapeutic targets. Despite this, the development of selective and potent AQP inhibitors has proven challenging. Efforts to produce small-molecule AQP inhibitors have largely been unsuccessful. However, recent advancements include monoclonal human IgG antibodies targeting extracellular domains of aquaporin-4, offering new therapeutic strategies, particularly in glioblastoma, where AQP-4 is overexpressed. However, recent advancements include monoclonal human IgG antibodies targeting extracellular domains of aquaporin-4, offering new therapeutic strategies, particularly in glioblastoma, where AQP-4 is over expressed. These antibodies hold promise for selectively targeting and eradicating AQP-4-expressing cells in malignant brain tumors. This review discusses the critical role AQPs play in cancer, including their contributions to tumor cell proliferation, migration, angiogenesis, and edema formation. Additionally, we explore innovative therapeutic approaches, such as antibody-based interventions, and outline potential future research directions in AQP-targeted cancer therapies.
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Affiliation(s)
- Dharmendra Kumar Yadav
- College of Pharmacy, Gachon University Hambakmoeiro 191, Yeonsu-gu Incheon 21924 Republic of Korea +82 32 820 4948 +82 32 820 4945
| | - Desh Deepak Singh
- Amity Institute of Biotechnology, Amity University Rajasthan Jaipur India
| | - Dongyun Shin
- College of Pharmacy, Gachon University Hambakmoeiro 191, Yeonsu-gu Incheon 21924 Republic of Korea +82 32 820 4948 +82 32 820 4945
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Khalil M, Gena P, Di Ciaula A, Portincasa P, Calamita G. Aquaporins in Biliary Function: Pathophysiological Implications and Therapeutic Targeting. Int J Mol Sci 2024; 25:12133. [PMID: 39596202 PMCID: PMC11593884 DOI: 10.3390/ijms252212133] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2024] [Revised: 11/04/2024] [Accepted: 11/07/2024] [Indexed: 11/28/2024] Open
Abstract
Aquaporins (AQPs) are transmembrane proteins permeable to water and a series of small solutes. AQPs play a key role in pathways of hepatobiliary secretion at the level of the liver, bile ducts, and gallbladder. AQP8 and -9 are pivotal in facilitating the osmotic water movement of hepatic bile, which is composed of 95% water. In the biliary tract, AQP1 and -4 are involved in the rearrangement of bile composition by mechanisms of reabsorption/secretion of water. In the gallbladder, AQP1 and -8 are also involved in trans-epithelial bidirectional water flow with the ultimate goal of bile concentration. Pathophysiologically, AQPs have been indicated as players in several hepatobiliary disorders, including cholestatic diseases and cholesterol cholelithiasis. Research on AQP function and the modulation of AQP expression is in progress, with the identification of potent and homolog-specific compounds modulating the expression or inhibiting these membrane channels with promising pharmacological developments. This review summarizes the contribution of AQPs in physiological and pathophysiological stages related to hepatobiliary function.
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Affiliation(s)
- Mohamad Khalil
- Clinica Medica “A. Murri”, Department of Precision and Regenerative Medicine and Ionian Area (DiMePre-J), University of Bari “Aldo Moro”, 70121 Bari, Italy; (M.K.); (A.D.C.)
| | - Patrizia Gena
- Department of Biosciences, Biotechnologies and Environment, University of Bari “Aldo Moro”, 70125 Bari, Italy;
| | - Agostino Di Ciaula
- Clinica Medica “A. Murri”, Department of Precision and Regenerative Medicine and Ionian Area (DiMePre-J), University of Bari “Aldo Moro”, 70121 Bari, Italy; (M.K.); (A.D.C.)
| | - Piero Portincasa
- Clinica Medica “A. Murri”, Department of Precision and Regenerative Medicine and Ionian Area (DiMePre-J), University of Bari “Aldo Moro”, 70121 Bari, Italy; (M.K.); (A.D.C.)
| | - Giuseppe Calamita
- Department of Biosciences, Biotechnologies and Environment, University of Bari “Aldo Moro”, 70125 Bari, Italy;
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Shen Z, Sheng H, Zhao J, Xu J, Cai Z, Zhang H, Guo Z, Liu J, Liang H, Tan L, Gan S, Huang J, Zhu S. AQP8 Modulates Mitochondrial H 2O 2 Transport to Influence Glioma Proliferation. Cancer Invest 2024; 42:345-356. [PMID: 38742677 DOI: 10.1080/07357907.2024.2352467] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2024] [Accepted: 05/03/2024] [Indexed: 05/16/2024]
Abstract
BACKGROUND Aquaporin-8 (AQP8) is involved in impacting glioma proliferation and can effect tumour growth by regulating Intracellular reactive oxygen species (ROS) signalling levels. In addition to transporting H2O2, AQP8 has been shown to affect ROS signaling, but evidence is lacking in gliomas. In this study, we aimed to investigate how AQP8 affects ROS signaling in gliomas. MATERIALS AND METHODS We constructed A172 and U251 cell lines with AQP8 knockdown and AQP8 rescue by CRISPR/Cas9 technology and overexpression of lentiviral vectors. We used CCK-8 and flow cytometry to test cell proliferation and cycle, immunofluorescence and Mito-Tracker CMXRos to observe the distribution of AQP8 expression in glioma cells, Amplex and DHE to study mitochondria release of H2O2, mitochondrial membrane potential (MMP) and NAD+/NADH ratio to assess mitochondrial function and protein blotting to detect p53 and p21 expression. RESULT We found that AQP8 co-localised with mitochondria and that knockdown of AQP8 inhibited the release of H2O2 from mitochondria and led to increased levels of ROS in mitochondria, thereby impairing mitochondrial function. We also discovered that AQP8 knockdown resulted in suppression of cell proliferation and was blocked at the G0/G1 phase with increased expression of mitochondrial ROS signalling-related p53/p21. CONCLUSIONS This finding provides further evidence for mechanistic studies of AQP8 as a prospective target for the treatment of gliomas.
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Affiliation(s)
- ZiHao Shen
- Department of Human Anatomy, College of Basic Medicine, Chongqing Medical University, Chongqing, PR China
- Neuroscience Research Center, Chongqing Medical University, Chongqing, PR China
| | - HuaJun Sheng
- Department of Human Anatomy, College of Basic Medicine, Chongqing Medical University, Chongqing, PR China
- Neuroscience Research Center, Chongqing Medical University, Chongqing, PR China
| | - Jing Zhao
- Xi'an Hospital of TCM, Xi'an, PR China
| | - Jin Xu
- Department of Human Anatomy, College of Basic Medicine, Chongqing Medical University, Chongqing, PR China
- Neuroscience Research Center, Chongqing Medical University, Chongqing, PR China
| | - ZiLing Cai
- Department of Human Anatomy, College of Basic Medicine, Chongqing Medical University, Chongqing, PR China
- Neuroscience Research Center, Chongqing Medical University, Chongqing, PR China
| | - Hao Zhang
- Department of Human Anatomy, College of Basic Medicine, Chongqing Medical University, Chongqing, PR China
- Neuroscience Research Center, Chongqing Medical University, Chongqing, PR China
| | - Zhen Guo
- Department of Human Anatomy, College of Basic Medicine, Chongqing Medical University, Chongqing, PR China
- Neuroscience Research Center, Chongqing Medical University, Chongqing, PR China
| | - JunNan Liu
- Department of Human Anatomy, College of Basic Medicine, Chongqing Medical University, Chongqing, PR China
- Neuroscience Research Center, Chongqing Medical University, Chongqing, PR China
| | - Hang Liang
- Department of Human Anatomy, College of Basic Medicine, Chongqing Medical University, Chongqing, PR China
- Neuroscience Research Center, Chongqing Medical University, Chongqing, PR China
| | - LiHao Tan
- Department of Human Anatomy, College of Basic Medicine, Chongqing Medical University, Chongqing, PR China
- Neuroscience Research Center, Chongqing Medical University, Chongqing, PR China
| | - ShengWei Gan
- Department of Human Anatomy, College of Basic Medicine, Chongqing Medical University, Chongqing, PR China
- Neuroscience Research Center, Chongqing Medical University, Chongqing, PR China
| | - Juan Huang
- Department of Human Anatomy, College of Basic Medicine, Chongqing Medical University, Chongqing, PR China
- Neuroscience Research Center, Chongqing Medical University, Chongqing, PR China
| | - ShuJuan Zhu
- Department of Human Anatomy, College of Basic Medicine, Chongqing Medical University, Chongqing, PR China
- Neuroscience Research Center, Chongqing Medical University, Chongqing, PR China
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Mu K, Kitts DD. Intestinal polyphenol antioxidant activity involves redox signaling mechanisms facilitated by aquaporin activity. Redox Biol 2023; 68:102948. [PMID: 37922763 PMCID: PMC10643476 DOI: 10.1016/j.redox.2023.102948] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2023] [Accepted: 10/26/2023] [Indexed: 11/07/2023] Open
Abstract
Ascertaining whether dietary polyphenols evoke an antioxidant or prooxidant activity, which translates to a functional role required to maintain intestinal cell homeostasis continues to be an active and controversial area of research for food chemists and biochemists alike. We have proposed that the paradoxical function of polyphenols to autoxidize to generate H2O2 is a required first step in the capacity of some plant phenolics to function as intracellular antioxidants. This is based on the fact that cell redox homeostasis is achieved by a balance between H2O2 formation and subsequent outcomes of antioxidant systems function. Maintaining optimal extracellular and intracellular H2O2 concentrations is required for cell survival, since low levels are important to upregulate endogenous antioxidant capacity; whereas, concentrations that go beyond homeostatic control typically result in an inflammatory response, growth arrest, or eventual cell death. Aquaporins (AQPs) are a family of water channel membrane proteins that facilitate cellular transportation of water and other small molecule-derived solutes, such as H2O2, in all organisms. In the intestine, AQPs act as gatekeepers to regulate intracellular uptake of H2O2, generated from extracellular polyphenol autoxidation, thus enabling an intracellular cell signaling responses to mitigate onset of oxidative stress and intestinal inflammation. In this review, we highlight the potential role of AQPs to control important underlying mechanisms that define downstream regulation of intestinal redox homeostasis, specifically. It has been established that polyphenols that undergo oxidation to the quinone form, resulting in subsequent adduction to a thiol group on Keap1-Nrf2 complex, trigger Nrf2 activation and a cascade of indirect intracellular antioxidant effects. Here, we propose a similar mechanism that involves H2O2 generated from specific dietary polyphenols with a predisposition to undergo autoxidation. The ultimate bioactivity is regulated and expressed by AQP membrane function and thus, by extension, represents expression of an intracellular antioxidant chemoprotection mechanism.
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Affiliation(s)
- Kaiwen Mu
- Food Science, Food Nutrition and Health Program. Faculty of Land and Food System, The University of British Columbia, 2205 East Mall, Vancouver, B.C, V6T 1Z4, Canada
| | - David D Kitts
- Food Science, Food Nutrition and Health Program. Faculty of Land and Food System, The University of British Columbia, 2205 East Mall, Vancouver, B.C, V6T 1Z4, Canada.
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Calamita G, Delporte C. Insights into the Function of Aquaporins in Gastrointestinal Fluid Absorption and Secretion in Health and Disease. Cells 2023; 12:2170. [PMID: 37681902 PMCID: PMC10486417 DOI: 10.3390/cells12172170] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2023] [Revised: 08/16/2023] [Accepted: 08/17/2023] [Indexed: 09/09/2023] Open
Abstract
Aquaporins (AQPs), transmembrane proteins permeable to water, are involved in gastrointestinal secretion. The secretory products of the glands are delivered either to some organ cavities for exocrine glands or to the bloodstream for endocrine glands. The main secretory glands being part of the gastrointestinal system are salivary glands, gastric glands, duodenal Brunner's gland, liver, bile ducts, gallbladder, intestinal goblet cells, exocrine and endocrine pancreas. Due to their expression in gastrointestinal exocrine and endocrine glands, AQPs fulfill important roles in the secretion of various fluids involved in food handling. This review summarizes the contribution of AQPs in physiological and pathophysiological stages related to gastrointestinal secretion.
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Affiliation(s)
- Giuseppe Calamita
- Department of Biosciences, Biotechnologies and Environment, University of Bari Aldo Moro, 70125 Bari, Italy;
| | - Christine Delporte
- Laboratory of Pathophysiological and Nutritional Biochemistry, Faculty of Medicine, Université Libre de Bruxelles, 1070 Brussels, Belgium
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Guo X, Zhang H, Wang H, He XX, Wang JX, Wei W, Liu M, Xu JM, Liu YN, Jiang RS. Identification of Key Modules and Hub Genes Involved in Regulating the Color of Chicken Breast Meat Using WGCNA. Animals (Basel) 2023; 13:2356. [PMID: 37508133 PMCID: PMC10376702 DOI: 10.3390/ani13142356] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Revised: 07/12/2023] [Accepted: 07/18/2023] [Indexed: 07/30/2023] Open
Abstract
Meat color is one of the most important economic traits in chickens. However, the gene network and regulatory mechanisms contributing to meat color traits in chickens remain largely unknown. In the present study, we performed weighted gene co-expression network analysis (WGCNA) based on RNA-Seq datasets of 16 pectoralis major muscle samples from two yellow-feather chicken breeds to identify the modules and hub genes related to meat color in chickens. A total of 18,821 genes were used to construct the weighted gene co-expression network, and 29 co-expression gene modules were identified. Among these modules, five modules including blue, brown, steel blue, paleturquoise and orange modules were found to be significantly correlated with meat color traits. Furthermore, several genes within the association module involved in the regulation of mitochondrial activity (e.g., ATP5L, UQCR10 and COX7C) and lipid oxidation (e.g., CAV3, RBP4A and APOH) were identified as hub genes that may play a crucial role in the regulation of meat color. These results provide valuable information to improve our understanding of gene expression and regulation in relation to meat color traits and contribute to future molecular breeding for improving meat color in chickens.
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Affiliation(s)
- Xing Guo
- College of Animal Science and Technology, Anhui Agricultural University, Hefei 230036, China
| | - Hong Zhang
- College of Animal Science and Technology, Anhui Agricultural University, Hefei 230036, China
| | - Hao Wang
- College of Animal Science and Technology, Anhui Agricultural University, Hefei 230036, China
| | - Xin-Xin He
- College of Animal Science and Technology, Anhui Agricultural University, Hefei 230036, China
| | - Jiang-Xian Wang
- College of Animal Science and Technology, Anhui Agricultural University, Hefei 230036, China
| | - Wei Wei
- College of Animal Science and Technology, Anhui Agricultural University, Hefei 230036, China
| | - Meng Liu
- College of Animal Science and Technology, Anhui Agricultural University, Hefei 230036, China
| | - Jin-Mei Xu
- College of Animal Science and Technology, Anhui Agricultural University, Hefei 230036, China
| | - Ya-Nan Liu
- College of Animal Science and Technology, Anhui Agricultural University, Hefei 230036, China
| | - Run-Shen Jiang
- College of Animal Science and Technology, Anhui Agricultural University, Hefei 230036, China
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Leischner C, Marongiu L, Piotrowsky A, Niessner H, Venturelli S, Burkard M, Renner O. Relevant Membrane Transport Proteins as Possible Gatekeepers for Effective Pharmacological Ascorbate Treatment in Cancer. Antioxidants (Basel) 2023; 12:antiox12040916. [PMID: 37107291 PMCID: PMC10135768 DOI: 10.3390/antiox12040916] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 03/23/2023] [Accepted: 04/06/2023] [Indexed: 04/29/2023] Open
Abstract
Despite the increasing number of newly diagnosed malignancies worldwide, therapeutic options for some tumor diseases are unfortunately still limited. Interestingly, preclinical but also some clinical data suggest that the administration of pharmacological ascorbate seems to respond well, especially in some aggressively growing tumor entities. The membrane transport and channel proteins are highly relevant for the use of pharmacological ascorbate in cancer therapy and are involved in the transfer of active substances such as ascorbate, hydrogen peroxide, and iron that predominantly must enter malignant cells to induce antiproliferative effects and especially ferroptosis. In this review, the relevant conveying proteins from cellular surfaces are presented as an integral part of the efficacy of pharmacological ascorbate, considering the already known genetic and functional features in tumor tissues. Accordingly, candidates for diagnostic markers and therapeutic targets are mentioned.
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Affiliation(s)
- Christian Leischner
- Institute of Nutritional Sciences, Department of Nutritional Biochemistry, University of Hohenheim, Garbenstraße 30, 70599 Stuttgart, Germany
| | - Luigi Marongiu
- Institute of Nutritional Sciences, Department of Nutritional Biochemistry, University of Hohenheim, Garbenstraße 30, 70599 Stuttgart, Germany
- Department of Internal Medicine VIII, University Hospital Tuebingen, Otfried-Mueller-Straße 10, 72076 Tuebingen, Germany
| | - Alban Piotrowsky
- Institute of Nutritional Sciences, Department of Nutritional Biochemistry, University of Hohenheim, Garbenstraße 30, 70599 Stuttgart, Germany
| | - Heike Niessner
- Department of Dermatology, Division of Dermatooncology, University of Tuebingen, Liebermeisterstraße 25, 72076 Tuebingen, Germany
- Cluster of Excellence iFIT (EXC 2180) "Image Guided and Functionally Instructed Tumor Therapies", 72076 Tuebingen, Germany
| | - Sascha Venturelli
- Institute of Nutritional Sciences, Department of Nutritional Biochemistry, University of Hohenheim, Garbenstraße 30, 70599 Stuttgart, Germany
- Institute of Physiology, Department of Vegetative and Clinical Physiology, University of Tuebingen, Wilhelmstraße 56, 72074 Tuebingen, Germany
| | - Markus Burkard
- Institute of Nutritional Sciences, Department of Nutritional Biochemistry, University of Hohenheim, Garbenstraße 30, 70599 Stuttgart, Germany
| | - Olga Renner
- Institute of Nutritional Sciences, Department of Nutritional Biochemistry, University of Hohenheim, Garbenstraße 30, 70599 Stuttgart, Germany
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11
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Calamita G, Delporte C. Aquaporins in Glandular Secretion. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2023; 1398:225-249. [PMID: 36717498 DOI: 10.1007/978-981-19-7415-1_16] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Exocrine and endocrine glands deliver their secretory product, respectively, at the surface of the target organs or within the bloodstream. The release of their products has been shown to rely on secretory mechanisms often involving aquaporins (AQPs). This chapter will provide insight into the role of AQPs in secretory glands located within the gastrointestinal tract, including salivary glands, gastric glands, duodenal Brunner's glands, liver, gallbladder, intestinal goblets cells, and pancreas, as well and in other parts of the body, including airway submucosal glands, lacrimal glands, mammary glands, and eccrine sweat glands. The involvement of AQPs in both physiological and pathophysiological conditions will also be highlighted.
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Affiliation(s)
- Giuseppe Calamita
- Department of Biosciences, Biotechnologies and Environment, University of Bari "Aldo Moro", Bari, Italy
| | - Christine Delporte
- Laboratory of Pathophysiological and Nutritional Biochemistry, Faculty of Medicine, Université Libre de Bruxelles, Brussels, Belgium.
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12
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Huang B, Jin L, Zhang L, Cui X, Zhang Z, Lu Y, Yu L, Ma T, Zhang H. Aquaporin-8 transports hydrogen peroxide to regulate granulosa cell autophagy. Front Cell Dev Biol 2022; 10:897666. [PMID: 36081911 PMCID: PMC9445271 DOI: 10.3389/fcell.2022.897666] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Accepted: 07/25/2022] [Indexed: 11/20/2022] Open
Abstract
Aquaporin-8 (AQP8), a member of the aquaporin family, is strongly expressed in follicular granulosa cells, which could affect the hormone secretion level in females. AQP8, as a membrane protein, could mediate H2O2 into cells, thereby triggering various biological events. The deficiency of Aqp8 increases female fertility, resulting from the decrease in follicular atresia. The low cell death rate is related to the apoptosis of granulosa cells. However, the mechanism by which AQP8 regulates the autophagy of granulosa cells remains unclear. Thus, this study aimed to explore the effect of AQP8 on autophagy in follicular atresia. We found that the expression of the autophagy marker light-chain protein 3 was significantly downregulated in the granulosa cells of Aqp8-knockout (Aqp8−/−) mice, compared with wild-type (Aqp8+/+) mice. Immunofluorescence staining and transmission electron microscopic examination indicated that the number of autophagosomes in the granulosa cells of Aqp8−/− mice decreased. Using a follicular granulosa cell autophagy model, namely a follicular atresia model, we verified that the concentration of H2O2 significantly increased during the autophagy of granulosa cells, consistent with the Aqp8 mRNA level. Intracellular H2O2 accumulation was modulated by endogenous AQP8 expression level, indicating that AQP8-mediated H2O2 was involved in the autophagy of granulosa cells. AQP8 deficiency impaired the elevation of H2O2 concentration through phosphorylated tyrosine activation. In addition, we carried out the analysis of transcriptome sequencing datasets in the ovary and found there were obvious differences in principal components, differentially expressed genes (DEGs) and KEGG pathways, which might be involved in AQP8-regulated follicular atresia. Taken together, these findings indicated that AQP8-mediated H2O2 transport could mediate the autophagy of granulosa cells. AQP8 might be a potential target for diseases related to ovarian insufficiency.
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Affiliation(s)
- Binbin Huang
- Department of Pathophysiology, College of Basic Medical Sciences, Dalian Medical University, Dalian, China
- Department of Maternal, Child and Adolescent Health, School of Public Health, Anhui Medical University, MOE Key Laboratory of Population Health Across Life Cycle, NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract, Anhui Provincial Key Laboratory of Population Health and Aristogenics, Hefei, Anhui, China
| | - Lingling Jin
- Department of Pathophysiology, College of Basic Medical Sciences, Dalian Medical University, Dalian, China
| | - Luodan Zhang
- Department of Nephrology, Anhui Provincial Children’s Hospital, Hefei, Anhui, China
| | - Xiaolin Cui
- Department of Pathophysiology, College of Basic Medical Sciences, Dalian Medical University, Dalian, China
| | - Zhen Zhang
- Department of Pathophysiology, College of Basic Medical Sciences, Dalian Medical University, Dalian, China
| | - Yongqi Lu
- Department of Maternal, Child and Adolescent Health, School of Public Health, Anhui Medical University, MOE Key Laboratory of Population Health Across Life Cycle, NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract, Anhui Provincial Key Laboratory of Population Health and Aristogenics, Hefei, Anhui, China
| | - Lujia Yu
- Department of Maternal, Child and Adolescent Health, School of Public Health, Anhui Medical University, MOE Key Laboratory of Population Health Across Life Cycle, NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract, Anhui Provincial Key Laboratory of Population Health and Aristogenics, Hefei, Anhui, China
| | - Tonghui Ma
- Department of Pathophysiology, College of Basic Medical Sciences, Dalian Medical University, Dalian, China
| | - He Zhang
- Department of Pathophysiology, College of Basic Medical Sciences, Dalian Medical University, Dalian, China
- *Correspondence: He Zhang,
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NADPH and Mitochondrial Quality Control as Targets for a Circadian-Based Fasting and Exercise Therapy for the Treatment of Parkinson's Disease. Cells 2022; 11:cells11152416. [PMID: 35954260 PMCID: PMC9367803 DOI: 10.3390/cells11152416] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Revised: 08/01/2022] [Accepted: 08/01/2022] [Indexed: 02/01/2023] Open
Abstract
Dysfunctional mitochondrial quality control (MQC) is implicated in the pathogenesis of Parkinson's disease (PD). The improper selection of mitochondria for mitophagy increases reactive oxygen species (ROS) levels and lowers ATP levels. The downstream effects include oxidative damage, failure to maintain proteostasis and ion gradients, and decreased NAD+ and NADPH levels, resulting in insufficient energy metabolism and neurotransmitter synthesis. A ketosis-based metabolic therapy that increases the levels of (R)-3-hydroxybutyrate (BHB) may reverse the dysfunctional MQC by partially replacing glucose as an energy source, by stimulating mitophagy, and by decreasing inflammation. Fasting can potentially raise cytoplasmic NADPH levels by increasing the mitochondrial export and cytoplasmic metabolism of ketone body-derived citrate that increases flux through isocitrate dehydrogenase 1 (IDH1). NADPH is an essential cofactor for nitric oxide synthase, and the nitric oxide synthesized can diffuse into the mitochondrial matrix and react with electron transport chain-synthesized superoxide to form peroxynitrite. Excessive superoxide and peroxynitrite production can cause the opening of the mitochondrial permeability transition pore (mPTP) to depolarize the mitochondria and activate PINK1-dependent mitophagy. Both fasting and exercise increase ketogenesis and increase the cellular NAD+/NADH ratio, both of which are beneficial for neuronal metabolism. In addition, both fasting and exercise engage the adaptive cellular stress response signaling pathways that protect neurons against the oxidative and proteotoxic stress implicated in PD. Here, we discuss how intermittent fasting from the evening meal through to the next-day lunch together with morning exercise, when circadian NAD+/NADH is most oxidized, circadian NADP+/NADPH is most reduced, and circadian mitophagy gene expression is high, may slow the progression of PD.
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Abstract
Aquaporins (AQPs) are a family of transmembrane water channel proteins, which were initially characterized as a novel protein family that plays a vital role in transcellular and transepithelial water movement. AQP1, AQP2, AQP4, AQP5, and AQP8 are primarily water selective, whereas AQP3, AQP7, AQP9, and AQP10 (called “aqua-glyceroporins”) also transport glycerol and other small solutes. Recently, multiple reports have suggested that AQPs have important roles in cancer cell growth, migration, invasion, and angiogenesis, each of which is important in human carcinogenesis. Here, we review recent data concerning the involvement of AQPs in tumor growth, angiogenesis, and metastasis and explore the expression profiles from various resected cancer samples to further dissect the underlying molecular mechanisms. Moreover, we discuss the potential role of AQPs during the development of genomic instability and performed modeling to describe the integration of binding between AQPs with various SH3 domain binning adaptor molecules. Throughout review and discussion of numerous reports, we have tried to provide key evidence that AQPs play key roles in tumor biology, which may provide a unique opportunity in designing a novel class of anti-tumor agents.
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Affiliation(s)
- Chul So Moon
- Department of Otolaryngology-Head and Neck Surgery, The Johns Hopkins Medical Institution, Baltimore, MD, United States.,HJM Cancer Research Foundation Corporation, Lutherville, MD, United States
| | - David Moon
- Department of Otolaryngology-Head and Neck Surgery, The Johns Hopkins Medical Institution, Baltimore, MD, United States.,HJM Cancer Research Foundation Corporation, Lutherville, MD, United States
| | - Sung Koo Kang
- Department of Otolaryngology-Head and Neck Surgery, The Johns Hopkins Medical Institution, Baltimore, MD, United States.,HJM Cancer Research Foundation Corporation, Lutherville, MD, United States
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15
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Gletten RB, Cantrell LS, Bhattacharya S, Schey KL. Lens Aquaporin-5 Inserts Into Bovine Fiber Cell Plasma Membranes Via Unconventional Protein Secretion. Invest Ophthalmol Vis Sci 2022; 63:5. [PMID: 35816045 PMCID: PMC9284464 DOI: 10.1167/iovs.63.8.5] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Purpose To spatially map aquaporin-5 (AQP5) expression in the bovine lens, molecularly characterize cytoplasmic AQP5-containing vesicles in the outer cortex, and elucidate AQP5 membrane trafficking mechanisms. Methods Immunofluorescence was performed on bovine lens cryosections using AQP5, TOMM20, COX IV, calnexin, LC3B, Sec22β, LIMP-2, and connexin 50 antibodies and the membrane dye CM-DiI. AQP5 plasma membrane insertion was defined via line expression profile analysis. Transmission electron microscopy (TEM) was performed on bovine lens sections to examine cytoplasmic organelle morphology and subcellular localization in cortical fiber cells. Bovine lenses were treated with 10-nM bafilomycin A1 or 0.1% dimethyl sulfoxide vehicle control for 24 hours in ex vivo culture to determine changes in AQP5 plasma membrane expression. Results Immunofluorescence analysis revealed cytoplasmic AQP5 expression in lens epithelial cells and differentiating fiber cells. In the lens cortex, complete AQP5 plasma membrane insertion occurs at r/a = 0.951 ± 0.005. AQP5-containing cytoplasmic vesicles are spheroidal in morphology with linear extensions, express TOMM20, and contain LC3B and LIMP-2, but not Sec22β, as fiber cells mature. TEM analysis revealed complex vesicular assemblies with congruent subcellular localization to AQP5-containing cytoplasmic vesicles. AQP5-containing cytoplasmic vesicles appear to dock with the plasma membrane. Bafilomycin A1 treatment reduced AQP5 plasma membrane expression by 27%. Conclusions AQP5 localizes to spheroidal, linear cytoplasmic vesicles in the differentiating bovine lens fiber cells. During fiber cell differentiation, these vesicles incorporate LC3B and presumably fuse with LIMP-2–positive lysosomes. Our data suggest that AQP5 to the plasma membrane through lysosome-associated unconventional protein secretion, a novel mechanism of AQP5 trafficking.
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Affiliation(s)
- Romell B Gletten
- Department of Biochemistry, Vanderbilt University, Nashville, Tennessee, United States
| | - Lee S Cantrell
- Department of Biochemistry, Vanderbilt University, Nashville, Tennessee, United States
| | - Sujoy Bhattacharya
- Department of Ophthalmology and Visual Sciences, Vanderbilt University, Nashville, Tennessee, United States
| | - Kevin L Schey
- Department of Biochemistry, Vanderbilt University, Nashville, Tennessee, United States
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16
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Hoehne MN, Jacobs LJHC, Lapacz KJ, Calabrese G, Murschall LM, Marker T, Kaul H, Trifunovic A, Morgan B, Fricker M, Belousov VV, Riemer J. Spatial and temporal control of mitochondrial H 2 O 2 release in intact human cells. EMBO J 2022; 41:e109169. [PMID: 35146782 PMCID: PMC8982624 DOI: 10.15252/embj.2021109169] [Citation(s) in RCA: 56] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Revised: 01/16/2022] [Accepted: 01/24/2022] [Indexed: 02/06/2023] Open
Abstract
Hydrogen peroxide (H2 O2 ) has key signaling roles at physiological levels, while causing molecular damage at elevated concentrations. H2 O2 production by mitochondria is implicated in regulating processes inside and outside these organelles. However, it remains unclear whether and how mitochondria in intact cells release H2 O2 . Here, we employed a genetically encoded high-affinity H2 O2 sensor, HyPer7, in mammalian tissue culture cells to investigate different modes of mitochondrial H2 O2 release. We found substantial heterogeneity of HyPer7 dynamics between individual cells. We further observed mitochondria-released H2 O2 directly at the surface of the organelle and in the bulk cytosol, but not in the nucleus or at the plasma membrane, pointing to steep gradients emanating from mitochondria. Gradient formation is controlled by cytosolic peroxiredoxins, which act redundantly and with a substantial reserve capacity. Dynamic adaptation of cytosolic thioredoxin reductase levels during metabolic changes results in improved H2 O2 handling and explains previously observed differences between cell types. Our data suggest that H2 O2 -mediated signaling is initiated only in close proximity to mitochondria and under specific metabolic conditions.
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Affiliation(s)
- Michaela Nicole Hoehne
- Department for ChemistryInstitute for BiochemistryRedox BiochemistryUniversity of CologneCologneGermany
| | - Lianne J H C Jacobs
- Department for ChemistryInstitute for BiochemistryRedox BiochemistryUniversity of CologneCologneGermany
| | - Kim Jasmin Lapacz
- Department for ChemistryInstitute for BiochemistryRedox BiochemistryUniversity of CologneCologneGermany
| | - Gaetano Calabrese
- Department for ChemistryInstitute for BiochemistryRedox BiochemistryUniversity of CologneCologneGermany
| | - Lena Maria Murschall
- Department for ChemistryInstitute for BiochemistryRedox BiochemistryUniversity of CologneCologneGermany
| | - Teresa Marker
- Department for ChemistryInstitute for BiochemistryRedox BiochemistryUniversity of CologneCologneGermany
| | - Harshita Kaul
- Cologne Excellence Cluster on Cellular Stress Responses in Aging‐Associated Diseases (CECAD)University of CologneCologneGermany
- Institute for Mitochondrial Diseases and AgingMedical FacultyUniversity of CologneCologneGermany
| | - Aleksandra Trifunovic
- Cologne Excellence Cluster on Cellular Stress Responses in Aging‐Associated Diseases (CECAD)University of CologneCologneGermany
- Institute for Mitochondrial Diseases and AgingMedical FacultyUniversity of CologneCologneGermany
- Center for Molecular MedicineUniversity of CologneCologneGermany
| | - Bruce Morgan
- Institute of BiochemistryCentre for Human and Molecular Biology (ZHMB)Saarland UniversitySaarbrueckenGermany
| | - Mark Fricker
- Department of Plant SciencesUniversity of OxfordOxfordUK
| | - Vsevolod V Belousov
- Department of Metabolism and Redox BiologyShemyakin‐Ovchinnikov Institute of Bioorganic ChemistryMoscowRussia
- Center for Precision Genome Editing and Genetic Technologies for BiomedicinePirogov Russian National Research Medical UniversityMoscowRussia
- Federal Center of Brain Research and NeurotechnologiesFMBAMoscowRussia
- Institute for Cardiovascular PhysiologyGeorg August University GöttingenGöttingenGermany
| | - Jan Riemer
- Department for ChemistryInstitute for BiochemistryRedox BiochemistryUniversity of CologneCologneGermany
- Cologne Excellence Cluster on Cellular Stress Responses in Aging‐Associated Diseases (CECAD)University of CologneCologneGermany
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17
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Zhang M, Shi H, Li N, Wei N, Tian Y, Peng J, Chen X, Zhang L, Zhang M, Dong H. Aquaporin OsPIP2;2 links the H2O2 signal and a membrane-anchored transcription factor to promote plant defense. PLANT PHYSIOLOGY 2022; 188:2325-2341. [PMID: 34958388 PMCID: PMC8968290 DOI: 10.1093/plphys/kiab604] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Accepted: 11/19/2021] [Indexed: 06/14/2023]
Abstract
To overcome pathogen infection, plants deploy a highly efficient innate immune system, which often uses hydrogen peroxide (H2O2), a versatile reactive oxygen species, to activate downstream defense responses. H2O2 is a potential substrate of aquaporins (AQPs), the membrane channels that facilitate the transport of small compounds across plasma membranes or organelle membranes. To date, however, the functional relationship between AQPs and H2O2 in plant immunity is largely undissected. Here, we report that the rice (Oryza sativa) AQP OsPIP2;2 transports pathogen-induced apoplastic H2O2 into the cytoplasm to intensify rice resistance against various pathogens. OsPIP2;2-transported H2O2 is required for microbial molecular pattern flg22 to activate the MAPK cascade and to induce the downstream defense responses. In response to flg22, OsPIP2;2 is phosphorylated at the serine residue S125, and therefore gains the ability to transport H2O2. Phosphorylated OsPIP2;2 also triggers the translocation of OsmaMYB, a membrane-anchored MYB transcription factor, into the plant cell nucleus to impart flg22-induced defense responses against pathogen infection. On the contrary, if OsPIP2;2 is not phosphorylated, OsmaMYB remains associated with the plasma membrane, and plant defense responses are no longer induced. These results suggest that OsPIP2;2 positively regulates plant innate immunity by mediating H2O2 transport into the plant cell and mediating the translocation of OsmaMYB from plasma membrane to nucleus.
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Affiliation(s)
- Mou Zhang
- Department of Plant Pathology, Nanjing Agricultural University, Nanjing, China
| | - Haotian Shi
- Department of Plant Pathology, Nanjing Agricultural University, Nanjing, China
| | - Ningning Li
- Department of Plant Pathology, Nanjing Agricultural University, Nanjing, China
| | - Nana Wei
- Department of Plant Pathology, Nanjing Agricultural University, Nanjing, China
| | - Yan Tian
- Department of Plant Pathology, Nanjing Agricultural University, Nanjing, China
| | - Jinfeng Peng
- Department of Plant Pathology, Nanjing Agricultural University, Nanjing, China
| | - Xiaochen Chen
- Department of Plant Pathology, Nanjing Agricultural University, Nanjing, China
| | - Liyuan Zhang
- National Key Laboratory of Crop Biology, Shandong Agricultural University, Taian, China
- Department of Plant Pathology, Shandong Agricultural University, Taian, China
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18
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Wagner K, Unger L, Salman MM, Kitchen P, Bill RM, Yool AJ. Signaling Mechanisms and Pharmacological Modulators Governing Diverse Aquaporin Functions in Human Health and Disease. Int J Mol Sci 2022; 23:1388. [PMID: 35163313 PMCID: PMC8836214 DOI: 10.3390/ijms23031388] [Citation(s) in RCA: 61] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Revised: 01/18/2022] [Accepted: 01/20/2022] [Indexed: 02/07/2023] Open
Abstract
The aquaporins (AQPs) are a family of small integral membrane proteins that facilitate the bidirectional transport of water across biological membranes in response to osmotic pressure gradients as well as enable the transmembrane diffusion of small neutral solutes (such as urea, glycerol, and hydrogen peroxide) and ions. AQPs are expressed throughout the human body. Here, we review their key roles in fluid homeostasis, glandular secretions, signal transduction and sensation, barrier function, immunity and inflammation, cell migration, and angiogenesis. Evidence from a wide variety of studies now supports a view of the functions of AQPs being much more complex than simply mediating the passive flow of water across biological membranes. The discovery and development of small-molecule AQP inhibitors for research use and therapeutic development will lead to new insights into the basic biology of and novel treatments for the wide range of AQP-associated disorders.
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Affiliation(s)
- Kim Wagner
- School of Biomedicine, University of Adelaide, Adelaide, SA 5005, Australia;
| | - Lucas Unger
- College of Health and Life Sciences, Aston University, Birmingham B4 7ET, UK; (L.U.); (P.K.)
| | - Mootaz M. Salman
- Department of Physiology Anatomy and Genetics, University of Oxford, Oxford OX1 3QX, UK;
- Oxford Parkinson’s Disease Centre, University of Oxford, South Parks Road, Oxford OX1 3QX, UK
| | - Philip Kitchen
- College of Health and Life Sciences, Aston University, Birmingham B4 7ET, UK; (L.U.); (P.K.)
| | - Roslyn M. Bill
- College of Health and Life Sciences, Aston University, Birmingham B4 7ET, UK; (L.U.); (P.K.)
| | - Andrea J. Yool
- School of Biomedicine, University of Adelaide, Adelaide, SA 5005, Australia;
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19
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Orrico F, Lopez AC, Saliwonczyk D, Acosta C, Rodriguez-Grecco I, Mouro-Chanteloup I, Ostuni MA, Denicola A, Thomson L, Möller MN. The permeability of human red blood cell membranes to hydrogen peroxide is independent of aquaporins. J Biol Chem 2021; 298:101503. [PMID: 34929164 PMCID: PMC8753180 DOI: 10.1016/j.jbc.2021.101503] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2021] [Revised: 12/10/2021] [Accepted: 12/13/2021] [Indexed: 11/28/2022] Open
Abstract
Hydrogen peroxide (H2O2) not only is an oxidant but also is an important signaling molecule in vascular biology, mediating several physiological functions. Red blood cells (RBCs) have been proposed to be the primary sink of H2O2 in the vasculature because they are the main cellular component of blood with a robust antioxidant defense and a high membrane permeability. However, the exact permeability of human RBC to H2O2 is neither known nor is it known if the mechanism of permeation involves the lipid fraction or protein channels. To gain insight into the permeability process, we measured the partition constant of H2O2 between water and octanol or hexadecane using a novel double-partition method. Our results indicated that there is a large thermodynamic barrier to H2O2 permeation. The permeability coefficient of H2O2 through phospholipid membranes containing cholesterol with saturated or unsaturated acyl chains was determined to be 4 × 10−4 and 5 × 10−3 cm s−1, respectively, at 37 °C. The permeability coefficient of human RBC membranes to H2O2 at 37 °C, on the other hand, was 1.6 × 10−3 cm s−1. Different aquaporin-1 and aquaporin-3 inhibitors proved to have no effect on the permeation of H2O2. Moreover, human RBCs devoid of either aquaporin-1 or aquaporin-3 were equally permeable to H2O2 as normal human RBCs. Therefore, these results indicate that H2O2 does not diffuse into RBCs through aquaporins but rather through the lipid fraction or a still unidentified membrane protein.
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Affiliation(s)
- Florencia Orrico
- Laboratorio de Fisicoquímica Biológica, Instituto de Química Biológica, Facultad de Ciencias, Universidad de la República, Montevideo 11400, Uruguay; Laboratorio de Enzimología, Instituto de Química Biológica, Facultad de Ciencias, Universidad de la República, Montevideo 11400, Uruguay; Centro de Investigaciones Biomédicas (CEINBIO), Universidad de la República, Montevideo 11800, Uruguay
| | - Ana C Lopez
- Laboratorio de Fisicoquímica Biológica, Instituto de Química Biológica, Facultad de Ciencias, Universidad de la República, Montevideo 11400, Uruguay; Laboratorio de Enzimología, Instituto de Química Biológica, Facultad de Ciencias, Universidad de la República, Montevideo 11400, Uruguay; Centro de Investigaciones Biomédicas (CEINBIO), Universidad de la República, Montevideo 11800, Uruguay
| | - Daniela Saliwonczyk
- Laboratorio de Enzimología, Instituto de Química Biológica, Facultad de Ciencias, Universidad de la República, Montevideo 11400, Uruguay; Departamento de Medicina Transfusional, Hospital de Clínicas, Facultad de Medicina, Universidad de la República
| | - Cecilia Acosta
- Laboratorio de Enzimología, Instituto de Química Biológica, Facultad de Ciencias, Universidad de la República, Montevideo 11400, Uruguay; Departamento de Medicina Transfusional, Hospital de Clínicas, Facultad de Medicina, Universidad de la República
| | - Ismael Rodriguez-Grecco
- Departamento de Medicina Transfusional, Hospital de Clínicas, Facultad de Medicina, Universidad de la República
| | - Isabelle Mouro-Chanteloup
- Université de Paris, UMR_S1134, BIGR, Inserm, F-75015 Paris, France; Laboratoire d'Excellence GR-Ex, Paris, France
| | - Mariano A Ostuni
- Université de Paris, UMR_S1134, BIGR, Inserm, F-75015 Paris, France; Laboratoire d'Excellence GR-Ex, Paris, France
| | - Ana Denicola
- Laboratorio de Fisicoquímica Biológica, Instituto de Química Biológica, Facultad de Ciencias, Universidad de la República, Montevideo 11400, Uruguay; Centro de Investigaciones Biomédicas (CEINBIO), Universidad de la República, Montevideo 11800, Uruguay
| | - Leonor Thomson
- Laboratorio de Enzimología, Instituto de Química Biológica, Facultad de Ciencias, Universidad de la República, Montevideo 11400, Uruguay; Centro de Investigaciones Biomédicas (CEINBIO), Universidad de la República, Montevideo 11800, Uruguay.
| | - Matias N Möller
- Laboratorio de Fisicoquímica Biológica, Instituto de Química Biológica, Facultad de Ciencias, Universidad de la República, Montevideo 11400, Uruguay; Centro de Investigaciones Biomédicas (CEINBIO), Universidad de la República, Montevideo 11800, Uruguay.
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20
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Estrogen alleviates hepatocyte necroptosis depending on GPER in hepatic ischemia reperfusion injury. J Physiol Biochem 2021; 78:125-137. [PMID: 34651286 DOI: 10.1007/s13105-021-00846-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2021] [Accepted: 09/09/2021] [Indexed: 01/28/2023]
Abstract
Hepatic ischemia reperfusion injury (IRI) occurs in liver transplantation, complex liver resection, and hemorrhagic shock, which causes donor organ shortage and hepatic damage. The burst of reactive oxygen species (ROS) during reperfusion leads to cell apoptosis and necroptosis. It has been reported that estrogen could attenuate hepatic IRI. G protein estrogen receptor (GPER) mediates estrogen effects via nonclassic receptor systems. Here, we investigate whether estrogen protecting liver from hepatic IRI depends on GPER and the influence of GPER activation on hepatocyte necroptosis. We proved that estrogen had a protective effect on both hepatocyte hypoxia re-oxygen (H/R) challenge and mouse hepatic ischemia reperfusion model. However, the application of GPER specific antagonist G15 before estrogen inhibited this beneficial effect. The results of mitochondria functional measurement revealed that estrogen improved hepatocyte mitochondria function by activating GPER, which might benefit from the increased expression of connexin 43 (Cx43) in mitochondria. To investigate the relationship between GPER activation and necroptosis, we used caspase-3/7 inhibitor benzyloxycarbonyl-Asp(OMe)-Glu(OMe)-Val-Asp(OMe)-chloromethylketone (Z-DEVD-FMK) to eliminate the interference of apoptosis. Estrogen showed a protective effect on hepatic IRI after using Z-DEVD-FMK, which could be suppressed by G15. GPER activation decreased the level of receptor interacting protein kinase (RIPK) 3, phosphorylated (p-) RIPK1, and p-mixed lineage kinase domain-like (MLKL). The co-immunoprecipitation result indicated that GPER could bind with RIPK3. GPER is indispensable in estrogen protecting liver from IRI. GPER activation attenuates hepatocyte necroptosis by decreasing the level of RIPK3, p-RIPK1, and p-MLKL.
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A multiplier peroxiporin signal transduction pathway powers piscine spermatozoa. Proc Natl Acad Sci U S A 2021; 118:2019346118. [PMID: 33674382 DOI: 10.1073/pnas.2019346118] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
The primary task of a spermatozoon is to deliver its nuclear payload to the egg to form the next-generation zygote. With polyandry repeatedly evolving in the animal kingdom, however, sperm competition has become widespread, with the highest known intensities occurring in fish. Yet, the molecular controls regulating spermatozoon swimming performance in these organisms are largely unknown. Here, we show that the kinematic properties of postactivated piscine spermatozoa are regulated through a conserved trafficking mechanism whereby a peroxiporin ortholog of mammalian aquaporin-8 (Aqp8bb) is inserted into the inner mitochondrial membrane to facilitate H2O2 efflux in order to maintain ATP production. In teleosts from more ancestral lineages, such as the zebrafish (Danio rerio) and the Atlantic salmon (Salmo salar), in which spermatozoa are activated in freshwater, an intracellular Ca2+-signaling directly regulates this mechanism through monophosphorylation of the Aqp8bb N terminus. In contrast, in more recently evolved marine teleosts, such the gilthead seabream (Sparus aurata), in which spermatozoa activation occurs in seawater, a cross-talk between Ca2+- and oxidative stress-activated pathways generate a multiplier regulation of channel trafficking via dual N-terminal phosphorylation. These findings reveal that teleost spermatozoa evolved increasingly sophisticated detoxification pathways to maintain swimming performance under a high osmotic stress, and provide insight into molecular traits that are advantageous for postcopulatory sexual selection.
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Di Ciaula A, Calamita G, Shanmugam H, Khalil M, Bonfrate L, Wang DQH, Baffy G, Portincasa P. Mitochondria Matter: Systemic Aspects of Nonalcoholic Fatty Liver Disease (NAFLD) and Diagnostic Assessment of Liver Function by Stable Isotope Dynamic Breath Tests. Int J Mol Sci 2021; 22:7702. [PMID: 34299321 PMCID: PMC8305940 DOI: 10.3390/ijms22147702] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2021] [Revised: 07/08/2021] [Accepted: 07/14/2021] [Indexed: 02/07/2023] Open
Abstract
The liver plays a key role in systemic metabolic processes, which include detoxification, synthesis, storage, and export of carbohydrates, lipids, and proteins. The raising trends of obesity and metabolic disorders worldwide is often associated with the nonalcoholic fatty liver disease (NAFLD), which has become the most frequent type of chronic liver disorder with risk of progression to cirrhosis and hepatocellular carcinoma. Liver mitochondria play a key role in degrading the pathways of carbohydrates, proteins, lipids, and xenobiotics, and to provide energy for the body cells. The morphological and functional integrity of mitochondria guarantee the proper functioning of β-oxidation of free fatty acids and of the tricarboxylic acid cycle. Evaluation of the liver in clinical medicine needs to be accurate in NAFLD patients and includes history, physical exam, imaging, and laboratory assays. Evaluation of mitochondrial function in chronic liver disease and NAFLD is now possible by novel diagnostic tools. "Dynamic" liver function tests include the breath test (BT) based on the use of substrates marked with the non-radioactive, naturally occurring stable isotope 13C. Hepatocellular metabolization of the substrate will generate 13CO2, which is excreted in breath and measured by mass spectrometry or infrared spectroscopy. Breath levels of 13CO2 are biomarkers of specific metabolic processes occurring in the hepatocyte cytosol, microsomes, and mitochondria. 13C-BTs explore distinct chronic liver diseases including simple liver steatosis, non-alcoholic steatohepatitis, liver fibrosis, cirrhosis, hepatocellular carcinoma, drug, and alcohol effects. In NAFLD, 13C-BT use substrates such as α-ketoisocaproic acid, methionine, and octanoic acid to assess mitochondrial oxidation capacity which can be impaired at an early stage of disease. 13C-BTs represent an indirect, cost-effective, and easy method to evaluate dynamic liver function. Further applications are expected in clinical medicine. In this review, we discuss the involvement of liver mitochondria in the progression of NAFLD, together with the role of 13C-BT in assessing mitochondrial function and its potential use in the prevention and management of NAFLD.
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Affiliation(s)
- Agostino Di Ciaula
- Clinica Medica “A. Murri”, Department of Biomedical Sciences & Human Oncology, University of Bari Medical School, 70124 Bari, Italy; (A.D.C.); (H.S.); (M.K.); (L.B.)
| | - Giuseppe Calamita
- Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari “Aldo Moro”, 70100 Bari, Italy;
| | - Harshitha Shanmugam
- Clinica Medica “A. Murri”, Department of Biomedical Sciences & Human Oncology, University of Bari Medical School, 70124 Bari, Italy; (A.D.C.); (H.S.); (M.K.); (L.B.)
| | - Mohamad Khalil
- Clinica Medica “A. Murri”, Department of Biomedical Sciences & Human Oncology, University of Bari Medical School, 70124 Bari, Italy; (A.D.C.); (H.S.); (M.K.); (L.B.)
| | - Leonilde Bonfrate
- Clinica Medica “A. Murri”, Department of Biomedical Sciences & Human Oncology, University of Bari Medical School, 70124 Bari, Italy; (A.D.C.); (H.S.); (M.K.); (L.B.)
| | - David Q.-H. Wang
- Marion Bessin Liver Research Center, Einstein-Mount Sinai Diabetes Research Center, Department of Medicine and Genetics, Division of Gastroenterology and Liver Diseases, Albert Einstein College of Medicine, Bronx, NY 10461, USA;
| | - Gyorgy Baffy
- Department of Medicine, VA Boston Healthcare System and Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02130, USA;
| | - Piero Portincasa
- Clinica Medica “A. Murri”, Department of Biomedical Sciences & Human Oncology, University of Bari Medical School, 70124 Bari, Italy; (A.D.C.); (H.S.); (M.K.); (L.B.)
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Bird aquaporins: Molecular machinery for urine concentration. BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES 2021; 1863:183688. [PMID: 34242632 DOI: 10.1016/j.bbamem.2021.183688] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Revised: 06/15/2021] [Accepted: 06/23/2021] [Indexed: 11/21/2022]
Abstract
Water conservation is one of the most challenging processes for terrestrial vertebrates and is necessary for their survival. Birds are the only vertebrate animals other than mammals that have the ability to concentrate their urine. Previously, we identified and characterized aquaporins (AQP)1-4 responsible for urine concentration in Japanese quail kidneys. Today, a total of 13 orthologs for these genes have been reported in birds. Bird AQPs can be classified into four subfamilies: 1) Classical AQPs (AQP0-5 and novel member, AQP4-like) that conserve the selectivity filter; 2) aquaglyceroporins (AQP3, 7, 9 and 10) that retain an aspartic acid residue in the second NPA box and expand the pore to accept larger molecules; 3) unorthodox AQPs (AQP11-12) which structurally resemble their mammalian counterparts; 4) AQP8-type, a subfamily that differs from mammalian AQP8. Interestingly, over the course of time, birds lost their mammalian counterpart AQP6 but obtained a novel AQP4-like aquaporin member. In quail and/or chicken kidneys, at least six AQPs are expressed. Quail AQP1 (qAQP1) is expressed in both cortical and medullary proximal tubules but is absent in the descending limb (DL) and the thick ascending limb (TAL), supporting our previous finding that the DL and TAL are water impermeable. AQP2, an arginine vasotocin (AVT)-sensitive water channel, is exclusively expressed in the principal cells of the collecting duct (CD). AQP4 is unlikely to participate in free water resorption from the collecting duct (CD), and only AQP3 may represent an exit pathway for water reabsorbed apically via AQP2. While AQP9 is not expressed in mammalian kidneys, AQP9 was recently found in chicken kidneys. This review summarizes the current knowledge of the structure, function and expression of bird AQPs.
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Li W, Song Y, Pan C, Yu J, Zhang J, Zhu X. Aquaporin-8 is a novel marker for progression of human cervical cancer cells. Cancer Biomark 2021; 32:391-400. [PMID: 34151838 PMCID: PMC8673491 DOI: 10.3233/cbm-203251] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND: Role of aquaporin-8 (AQP8) in cervical cancer has not been fully elucidated. OBJECTIVE: We aim to explore the impacts of AQP8 on viability, apoptosis and metastasis in cervical cancer cells. METHODS: AQP8 protein expression in cervical carcinoma specimens and cell lines was detected by IHC and western blot analysis. Lentivirus-mediated transfection was used to upregulate and knockdown AQP8 in cells. Cell viability and apoptosis were assessed by CCK-8 and flow cytometry assays, respectively. Transwell experiments were conducted to investigate cell invasive and migratory capabilities. EMT-related markers were detected by western blot analysis. RESULTS: A strong positive of AQP8 protein expression was observed in cervical cancer tissues. Western blot analysis confirmed overexpression and knockdown of AQP8 in SiHa cells. AQP8-overexpressed SiHa cells displayed an enhanced viability, reduced apoptotic rate, increased invasive and migratory abilities. Knockdown of AQP8 inhibited the viability, promoted the apoptosis, and suppressed invasion and migration. Furthermore, AQP8 overexpression significantly upregulated vimentin and N-cadherin, and downregulated E-cadherin, which were reversed by AQP8 knockdown. CONCLUSIONS: AQP8 increases viability, inhibits apoptosis, and facilitates metastasis in SiHa cells. This may be associated with EMT-related markers regulated by AQP8. AQP8 could serve as a potential marker for cervical cancer progression.
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Affiliation(s)
- Weibo Li
- Center of Uterine Cancer Diagnosis and Therapy Research of Zhejiang Province, Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.,Department of Obstetrics and Gynecology, Affiliated Taizhou Hospital of Wenzhou Medical University, Taizhou, Zhejiang, China.,Center of Uterine Cancer Diagnosis and Therapy Research of Zhejiang Province, Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Yizuo Song
- Center of Uterine Cancer Diagnosis and Therapy Research of Zhejiang Province, Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.,Center of Uterine Cancer Diagnosis and Therapy Research of Zhejiang Province, Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Chunyu Pan
- Center of Uterine Cancer Diagnosis and Therapy Research of Zhejiang Province, Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Junhui Yu
- Center of Uterine Cancer Diagnosis and Therapy Research of Zhejiang Province, Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Jianan Zhang
- Center of Uterine Cancer Diagnosis and Therapy Research of Zhejiang Province, Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Xueqiong Zhu
- Center of Uterine Cancer Diagnosis and Therapy Research of Zhejiang Province, Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
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Sassetti E, Clausen MH, Laraia L. Small-Molecule Inhibitors of Reactive Oxygen Species Production. J Med Chem 2021; 64:5252-5275. [PMID: 33856791 DOI: 10.1021/acs.jmedchem.0c01914] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Reactive oxygen species (ROS) are involved in physiological cellular processes including differentiation, proliferation, and apoptosis by acting as signaling molecules or regulators of transcription factors. The maintenance of appropriate cellular ROS levels is termed redox homeostasis, a balance between their production and neutralization. High concentrations of ROS may contribute to severe pathological events including cancer, neurodegenerative, and cardiovascular diseases. In recent years, approaches to target the sources of ROS production directly in order to develop tool compounds or potential therapeutics have been explored. Herein, we briefly outline the major sources of cellular ROS production and comprehensively review the targeting of these by small-molecule inhibitors. We critically assess the value of ROS inhibitors with different mechanisms-of-action, including their potency, mode-of-action, known off-target effects, and clinical or preclinical status, while suggesting future avenues of research in the field.
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Affiliation(s)
- Elisa Sassetti
- Center for Nanomedicine and Theranostics, Department of Chemistry, Technical University of Denmark, Kemitorvet 207, 2800 Kgs. Lyngby, Denmark
| | - Mads H Clausen
- Center for Nanomedicine and Theranostics, Department of Chemistry, Technical University of Denmark, Kemitorvet 207, 2800 Kgs. Lyngby, Denmark
| | - Luca Laraia
- Center for Nanomedicine and Theranostics, Department of Chemistry, Technical University of Denmark, Kemitorvet 207, 2800 Kgs. Lyngby, Denmark
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26
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Krüger C, Waldeck-Weiermair M, Kaynert J, Pokrant T, Komaragiri Y, Otto O, Michel T, Elsner M. AQP8 is a crucial H 2O 2 transporter in insulin-producing RINm5F cells. Redox Biol 2021; 43:101962. [PMID: 33892285 PMCID: PMC8082690 DOI: 10.1016/j.redox.2021.101962] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2020] [Revised: 03/28/2021] [Accepted: 03/28/2021] [Indexed: 02/08/2023] Open
Abstract
Peroxiporins are distinct aquaporins (AQP) which, beside water, also facilitate the bidirectional transport of hydrogen peroxide (H2O2) across cellular membranes. H2O2 serves as the major reactive oxygen species that mediates essential cell signaling events. In pancreatic β-cells, H2O2 has been associated with the regulation of cell growth but in excess it leads to failure of insulin secretion, making it important for diabetes mellitus (DM) pathogenesis. In the present study, the role of aquaporin-8 (AQP8) as a peroxiporin was investigated in RINm5F cells. The role of AQP8 was studied in an insulin-producing cell model, on the basis of stable AQP8 overexpression (AQP8↑) and CRISPR/Cas9-mediated AQP8 knockdown (KD). A complete AQP8 knock-out was found to result in cell death, however we demonstrate that mild lentiviral re-expression through a Tet-On-regulated genetically modified AQP8 leads to cell survival, enabling functional characterization. Proliferation and insulin content were found to be increased in AQP8↑ cells underlining the importance of AQP8 in the regulation of H2O2 homeostasis in pancreatic β-cells. Colocalization analyses of V5-tagged AQP8 proteins based on confocal microscopic imaging revealed its membrane targeting to both the mitochondria and the plasma membrane, but not to the ER, the Golgi apparatus, insulin vesicles, or peroxisomes. By using the fluorescence H2O2 specific biosensor HyPer together with endogenous generation of H2O2 using d-amino acid oxidase, live cell imaging revealed enhanced H2O2 flux to the same subcellular regions in AQP8 overexpressing cells pointing to its importance in the development of type-1 DM. Moreover, the novel ultrasensitive H2O2 sensor HyPer7.2 clearly unveiled AQP8 as a H2O2 transporter in RINm5F cells. In summary, these studies establish that AQP8 is an important H2O2 pore in insulin-producing RINm5F cells involved in the transport of H2O2 through the mitochondria and cell membrane and may help to explain the H2O2 transport and toxicity in pancreatic β-cells.
AQP8 KO is lethal for insulin-producing RINm5F cells. The peroxiporin AQP8 is localized in the plasma and mitochondrial membrane channeling H2O2 in RINm5F cells. Tet-On regulated low AQP8 re-expression and APQ8 overexpression are feasible models to study H2O2 transport in β-cells. Overexpression of AQP8 increases cell proliferation and cellular insulin content.
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Affiliation(s)
- Christina Krüger
- Institute of Clinical Biochemistry, Hannover Medical School, 30623, Hannover, Germany
| | - Markus Waldeck-Weiermair
- Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA
| | - Jonas Kaynert
- Institute of Clinical Biochemistry, Hannover Medical School, 30623, Hannover, Germany
| | - Thomas Pokrant
- Institute of Clinical Biochemistry, Hannover Medical School, 30623, Hannover, Germany
| | - Yesaswini Komaragiri
- Zentrum für Innovationskompetenz: Humorale Immunreaktion bei Kardiovaskulären Erkrankungen, Universität Greifswald, 17489, Greifswald, Germany; Deutsches Zentrum für Herz-Kreislauf-Forschung e. V., Standort Greifswald, Universitätsmedizin Greifswald, Fleischmannstr. 42, 17489, Greifswald, Germany
| | - Oliver Otto
- Zentrum für Innovationskompetenz: Humorale Immunreaktion bei Kardiovaskulären Erkrankungen, Universität Greifswald, 17489, Greifswald, Germany; Deutsches Zentrum für Herz-Kreislauf-Forschung e. V., Standort Greifswald, Universitätsmedizin Greifswald, Fleischmannstr. 42, 17489, Greifswald, Germany
| | - Thomas Michel
- Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA
| | - Matthias Elsner
- Institute of Clinical Biochemistry, Hannover Medical School, 30623, Hannover, Germany.
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Danielli M, Capiglioni AM, Marrone J, Marinelli RA. Further evidence for the involvement of mitochondrial aquaporin-8 in hepatocyte lipid synthesis. Biochimie 2021; 188:16-19. [PMID: 33493534 DOI: 10.1016/j.biochi.2021.01.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Revised: 01/15/2021] [Accepted: 01/15/2021] [Indexed: 11/17/2022]
Abstract
We recently provided evidence suggesting that mitochondrial aquaporin-8 (mtAQP8), a channel protein able to conduct H2O2, is involved in the modulation of hepatocyte cholesterogenesis. To expand that study, we cultured human hepatocyte-derived Huh-7 cells in medium with lipoprotein-deficient serum (LPDS) to induce the de novo synthesis of cholesterol and fatty acids. We found that LPDS induced mtAQP8 expression and that AQP8 gene silencing significantly down-regulated the LPDS-induced synthesis of cholesterol and fatty acids as well as the expression of the corresponding key biosynthetic enzymes, 3-hydroxy-3-methylglutaryl-CoA reductase and fatty acid synthase. Our data further support a regulatory role of mtAQP8 in hepatocyte lipid homeostasis.
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Affiliation(s)
- Mauro Danielli
- Instituto de Fisiología Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, 2000, Rosario, Santa Fe, Argentina
| | - Alejo M Capiglioni
- Instituto de Fisiología Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, 2000, Rosario, Santa Fe, Argentina
| | - Julieta Marrone
- Instituto de Fisiología Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, 2000, Rosario, Santa Fe, Argentina
| | - Raúl A Marinelli
- Instituto de Fisiología Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, 2000, Rosario, Santa Fe, Argentina.
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Kordowitzki P, Kranc W, Bryl R, Kempisty B, Skowronska A, Skowronski MT. The Relevance of Aquaporins for the Physiology, Pathology, and Aging of the Female Reproductive System in Mammals. Cells 2020; 9:cells9122570. [PMID: 33271827 PMCID: PMC7760214 DOI: 10.3390/cells9122570] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2020] [Revised: 11/23/2020] [Accepted: 11/29/2020] [Indexed: 12/26/2022] Open
Abstract
Aquaporins constitute a group of water channel proteins located in numerous cell types. These are pore-forming transmembrane proteins, which mediate the specific passage of water molecules through membranes. It is well-known that water homeostasis plays a crucial role in different reproductive processes, e.g., oocyte transport, hormonal secretion, completion of successful fertilization, blastocyst formation, pregnancy, and birth. Further, aquaporins are involved in the process of spermatogenesis, and they have been reported to be involved during the storage of spermatozoa. It is noteworthy that aquaporins are relevant for the physiological function of specific parts in the female reproductive system, which will be presented in detail in the first section of this review. Moreover, they are relevant in different pathologies in the female reproductive system. The contribution of aquaporins in selected reproductive disorders and aging will be summarized in the second section of this review, followed by a section dedicated to aquaporin-related proteins. Since the relevance of aquaporins for the male reproductive system has been reviewed several times in the recent past, this review aims to provide an update on the distribution and impact of aquaporins only in the female reproductive system. Therefore, this paper seeks to determine the physiological and patho-physiological relevance of aquaporins on female reproduction, and female reproductive aging.
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Affiliation(s)
- Paweł Kordowitzki
- Department of Basic and Preclinical Sciences, Institute for Veterinary Medicine, Nicolaus Copernicus University, 87-100 Torun, Poland;
- Institute of Animal Reproduction and Food Research of Polish Academy of Sciences, 10-243 Olsztyn, Poland
| | - Wiesława Kranc
- Department of Anatomy, Poznan University of Medical Sciences, 60-781 Poznan, Poland; (W.K.); (R.B.); (B.K.)
| | - Rut Bryl
- Department of Anatomy, Poznan University of Medical Sciences, 60-781 Poznan, Poland; (W.K.); (R.B.); (B.K.)
| | - Bartosz Kempisty
- Department of Anatomy, Poznan University of Medical Sciences, 60-781 Poznan, Poland; (W.K.); (R.B.); (B.K.)
- Department of Histology and Embryology, Poznan University of Medical Sciences, 60-781 Poznan, Poland
- Department of Veterinary Surgery, Institute for Veterinary Medicine, Nicolaus Copernicus University, 87-100 Torun, Poland
| | - Agnieszka Skowronska
- Department of Human Physiology and Pathophysiology, School of Medicine, Collegium Medicum, University of Warmia and Mazury, Warszawska Street 30, 10-082 Olsztyn, Poland;
| | - Mariusz T. Skowronski
- Department of Basic and Preclinical Sciences, Institute for Veterinary Medicine, Nicolaus Copernicus University, 87-100 Torun, Poland;
- Correspondence: ; Tel.: +48-56-611-2231
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Stein KT, Moon SJ, Nguyen AN, Sikes HD. Kinetic modeling of H2O2 dynamics in the mitochondria of HeLa cells. PLoS Comput Biol 2020; 16:e1008202. [PMID: 32925922 PMCID: PMC7515204 DOI: 10.1371/journal.pcbi.1008202] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2019] [Revised: 09/24/2020] [Accepted: 07/28/2020] [Indexed: 12/15/2022] Open
Abstract
Hydrogen peroxide (H2O2) promotes a range of phenotypes depending on its intracellular concentration and dosing kinetics, including cell death. While this qualitative relationship has been well established, the quantitative and mechanistic aspects of H2O2 signaling are still being elucidated. Mitochondria, a putative source of intracellular H2O2, have recently been demonstrated to be particularly vulnerable to localized H2O2 perturbations, eliciting a dramatic cell death response in comparison to similar cytosolic perturbations. We sought to improve our dynamic and mechanistic understanding of the mitochondrial H2O2 reaction network in HeLa cells by creating a kinetic model of this system and using it to explore basal and perturbed conditions. The model uses the most current quantitative proteomic and kinetic data available to predict reaction rates and steady-state concentrations of H2O2 and its reaction partners within individual mitochondria. Time scales ranging from milliseconds to one hour were simulated. We predict that basal, steady-state mitochondrial H2O2 will be in the low nM range (2-4 nM) and will be inversely dependent on the total pool of peroxiredoxin-3 (Prx3). Neglecting efflux of H2O2 to the cytosol, the mitochondrial reaction network is expected to control perturbations well up to H2O2 generation rates ~50 μM/s (0.25 nmol/mg-protein/s), above which point the Prx3 system would be expected to collapse. Comparison of these results with redox Western blots of Prx3 and Prx2 oxidation states demonstrated reasonable trend agreement at short times (≤ 15 min) for a range of experimentally perturbed H2O2 generation rates. At longer times, substantial efflux of H2O2 from the mitochondria to the cytosol was evidenced by peroxiredoxin-2 (Prx2) oxidation, and Prx3 collapse was not observed. A refined model using Monte Carlo parameter sampling was used to explore rates of H2O2 efflux that could reconcile model predictions of Prx3 oxidation states with the experimental observations.
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Affiliation(s)
- Kassi T. Stein
- Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, United States of America
| | - Sun Jin Moon
- Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, United States of America
| | - Athena N. Nguyen
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, United States of America
| | - Hadley D. Sikes
- Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, United States of America
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Li M, Xu G, Yang X, Zeng Y, Yu Y. Metal oxide nanoparticles facilitate the accumulation of bifenthrin in earthworms by causing damage to body cavity. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2020; 263:114629. [PMID: 33618460 DOI: 10.1016/j.envpol.2020.114629] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/13/2019] [Revised: 04/15/2020] [Accepted: 04/16/2020] [Indexed: 06/12/2023]
Abstract
In this study, we explored the influence of two metal oxide nanoparticles, nano CuO and nano ZnO (10, 50, 250 mg/kg), on accumulation of bifenthrin (100 μg/kg) in earthworms (Eisenia fetida) and its mechanism. The concentrations of bifenthrin in earthworms from binary exposure groups (bifenthrin + CuO and bifenthrin + ZnO) reached up to 23.2 and 28.9 μg/g, which were 2.65 and 3.32 times of that in bifenthrin exposure group without nanoparticles, respectively, indicating that nanoparticles facilitated the uptake of bifenthrin in earthworms. The contents of biomarkers (ROS, SOD, and MDA) in earthworms indicated that nanoparticles and bifenthrin caused damage to earthworms. Ex vivo test was utilized to investigate the toxic effects of the pollutants to cell membrane of earthworm coelomocytes and mechanism of increased bifenthrin accumulation. In ex vivo test, cell viability in binary exposure groups declined up to 30% and 21% compared to the control group after 24 h incubation, suggesting that coelomocyte membrane was injured by the pollutants. We conclude that nanoparticles damage the body cavity of earthworms, and thus lead to more accumulation of bifenthrin in earthworms. Our findings provide insights into the interactive accumulation and toxicity of nanoparticles and pesticides to soil organisms.
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Affiliation(s)
- Ming Li
- Key Laboratory of Wetland Ecology and Environment, Northeast Institute of Geography and Agroecology, Chinese Academy of Sciences, Changchun, 130102, China; University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Guanghui Xu
- Key Laboratory of Wetland Ecology and Environment, Northeast Institute of Geography and Agroecology, Chinese Academy of Sciences, Changchun, 130102, China; University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Xiutao Yang
- Key Laboratory of Wetland Ecology and Environment, Northeast Institute of Geography and Agroecology, Chinese Academy of Sciences, Changchun, 130102, China; University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Ying Zeng
- Key Laboratory of Wetland Ecology and Environment, Northeast Institute of Geography and Agroecology, Chinese Academy of Sciences, Changchun, 130102, China
| | - Yong Yu
- Key Laboratory of Wetland Ecology and Environment, Northeast Institute of Geography and Agroecology, Chinese Academy of Sciences, Changchun, 130102, China.
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Aquaporin-11 Contributes to TGF-β1-Induced Endoplasmic Reticulum Stress in Human Visceral Adipocytes: Role in Obesity-Associated Inflammation. Cells 2020; 9:cells9061403. [PMID: 32512939 PMCID: PMC7349025 DOI: 10.3390/cells9061403] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Revised: 05/27/2020] [Accepted: 05/31/2020] [Indexed: 02/06/2023] Open
Abstract
Aquaporin-11 (AQP11) is expressed in human adipocytes, but its functional role remains unknown. Since AQP11 is an endoplasmic reticulum (ER)-resident protein that transports water, glycerol, and hydrogen peroxide (H2O2), we hypothesized that this superaquaporin is involved in ER stress induced by lipotoxicity and inflammation in human obesity. AQP11 expression was assessed in 67 paired visceral and subcutaneous adipose tissue samples obtained from patients with morbid obesity and normal-weight individuals. We found that obesity and obesity-associated type 2 diabetes increased (p < 0.05) AQP11 mRNA and protein in visceral adipose tissue, but not subcutaneous fat. Accordingly, AQP11 mRNA was upregulated (p < 0.05) during adipocyte differentiation and lipolysis, two biological processes altered in the obese state. Subcellular fractionation and confocal microscopy studies confirmed its presence in the ER plasma membrane of visceral adipocytes. Proinflammatory factors TNF-α, and particularly TGF-β1, downregulated (p < 0.05) AQP11 mRNA and protein expression and reinforced its subcellular distribution surrounding lipid droplets. Importantly, the AQP11 gene knockdown increased (p < 0.05) basal and TGF-β1-induced expression of the ER markers ATF4 and CHOP. Together, the downregulation of AQP11 aggravates TGF-β1-induced ER stress in visceral adipocytes. Owing to its "peroxiporin" properties, AQP11 overexpression in visceral fat might constitute a compensatory mechanism to alleviate ER stress in obesity.
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Cell organelles as targets of mammalian cadmium toxicity. Arch Toxicol 2020; 94:1017-1049. [PMID: 32206829 DOI: 10.1007/s00204-020-02692-8] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2020] [Accepted: 02/25/2020] [Indexed: 02/07/2023]
Abstract
Ever increasing environmental presence of cadmium as a consequence of industrial activities is considered a health hazard and is closely linked to deteriorating global health status. General animal and human cadmium exposure ranges from ingestion of foodstuffs sourced from heavily polluted hotspots and cigarette smoke to widespread contamination of air and water, including cadmium-containing microplastics found in household water. Cadmium is promiscuous in its effects and exerts numerous cellular perturbations based on direct interactions with macromolecules and its capacity to mimic or displace essential physiological ions, such as iron and zinc. Cell organelles use lipid membranes to form complex tightly-regulated, compartmentalized networks with specialized functions, which are fundamental to life. Interorganellar communication is crucial for orchestrating correct cell behavior, such as adaptive stress responses, and can be mediated by the release of signaling molecules, exchange of organelle contents, mechanical force generated through organelle shape changes or direct membrane contact sites. In this review, cadmium effects on organellar structure and function will be critically discussed with particular consideration to disruption of organelle physiology in vertebrates.
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Zhou Y, Wang L, Wang C, Wu Y, Chen D, Lee TH. Potential implications of hydrogen peroxide in the pathogenesis and therapeutic strategies of gliomas. Arch Pharm Res 2020; 43:187-203. [PMID: 31956964 DOI: 10.1007/s12272-020-01205-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2019] [Accepted: 01/05/2020] [Indexed: 12/15/2022]
Abstract
Glioma is the most common type of primary brain tumor, and it has a high mortality rate. Currently, there are only a few therapeutic approaches for gliomas, and their effects are unsatisfactory. Therefore, uncovering the pathogenesis and exploring more therapeutic strategies for the treatment of gliomas are urgently needed to overcome the ongoing challenges. Cellular redox imbalance has been shown to be associated with the initiation and progression of gliomas. Among reactive oxygen species (ROS), hydrogen peroxide (H2O2) is considered the most suitable for redox signaling and is a potential candidate as a key molecule that determines the fate of cancer cells. In this review, we discuss the potential cellular and molecular roles of H2O2 in gliomagenesis and explore the potential implications of H2O2 in radiotherapy and chemotherapy and in the ongoing challenges of current glioma treatment. Moreover, we evaluate H2O2 as a potential redox sensor and potential driver molecule of nanocatalytic therapeutic strategies for glioma treatment.
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Affiliation(s)
- Ying Zhou
- Fujian Key Laboratory for Translational Research in Cancer and Neurodegenerative Diseases, Institute for Translational Medicine, School of Basic Medical Sciences, Fujian Medical University, 1 Xuefu North Road, Fuzhou, 350122, Fujian, China.,Key Laboratory of Brain Aging and Neurodegenerative Diseases of Fujian Provincial Universities and Colleges, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, 350122, Fujian, China
| | - Long Wang
- Fujian Key Laboratory for Translational Research in Cancer and Neurodegenerative Diseases, Institute for Translational Medicine, School of Basic Medical Sciences, Fujian Medical University, 1 Xuefu North Road, Fuzhou, 350122, Fujian, China
| | - Chaojia Wang
- The First Clinical Medical College, Heilongjiang University of Chinese Medicine, Harbin, 150040, Heilongjiang, China
| | - Yilin Wu
- The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, 518107, Guangdong, China
| | - Dongmei Chen
- Fujian Key Laboratory for Translational Research in Cancer and Neurodegenerative Diseases, Institute for Translational Medicine, School of Basic Medical Sciences, Fujian Medical University, 1 Xuefu North Road, Fuzhou, 350122, Fujian, China
| | - Tae Ho Lee
- Fujian Key Laboratory for Translational Research in Cancer and Neurodegenerative Diseases, Institute for Translational Medicine, School of Basic Medical Sciences, Fujian Medical University, 1 Xuefu North Road, Fuzhou, 350122, Fujian, China.
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Rashdan NA, Pattillo CB. Hydrogen peroxide in the ER: A tale of triage. Redox Biol 2019; 28:101358. [PMID: 31685402 PMCID: PMC6920092 DOI: 10.1016/j.redox.2019.101358] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2019] [Revised: 10/16/2019] [Accepted: 10/21/2019] [Indexed: 12/31/2022] Open
Abstract
Oxidative protein folding in the endoplasmic reticulum (ER) is a significant source of hydrogen peroxide (H2O2). For correct protein folding the redox state of the ER must be efficiently regulated. As such, several mechanisms with varying degrees of overlap manage the redox state of the ER. H2O2 also functions as a second messenger playing a role in most aspects of cellular physiology and pathology, requiring tight control of the concentration and flux of H2O2. Bestetti et al. have demonstrated a role for Aquaporin 11 in transport of H2O2 out of the ER.
Protein folding is a major source of H2O2 in the endoplasmic reticulum (ER). Aquaporin-11 mediates H2O2 transport across the ER membrane. HyPer is sensitive to pH.
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Affiliation(s)
- Nabil A Rashdan
- Molecular and Cellular Physiology, LSU Health Science Center, 1501 Kings Highway, Shreveport, 71130, LA, USA
| | - Christopher B Pattillo
- Molecular and Cellular Physiology, LSU Health Science Center, 1501 Kings Highway, Shreveport, 71130, LA, USA.
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Lipid Profile and Aquaporin Expression under Oxidative Stress in Breast Cancer Cells of Different Malignancies. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2019; 2019:2061830. [PMID: 31379986 PMCID: PMC6657669 DOI: 10.1155/2019/2061830] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/09/2019] [Revised: 06/11/2019] [Accepted: 06/20/2019] [Indexed: 12/31/2022]
Abstract
Breast cancer is the major cause of tumor-associated mortality in women worldwide, with prognosis depending on the early discovery of the disease and on the type of breast cancer diagnosed. Among many factors, lipids could contribute to breast cancer malignancy by participating in cellular processes. Also, aquaporins are membrane channels found aberrantly expressed in cancer tissues that were correlated with tumor aggressiveness, progression, and metastasis. However, the differences in lipid profile and aquaporin expression between cell types of different malignant potential have never been investigated. Here, we selected three breast cancer cell lines representing the three major breast cancer types (hormone positive, HER2NEU positive, and triple negative) and analyzed their lipid profile and steady state lipid hydroperoxide levels to correlate with cell sensitivity to H2O2. Additionally, the expression profiles of AQP1, AQP3, and AQP5 and the Nrf2 transcription factor were evaluated, before and after oxidative challenge. We found that the lipid profile was dependent on the cell type, with the HER2-positive cells having the lowest level PUFA, whereas the triple negative showed the highest. However, in triple-negative cancer cells, a lower level of the Nrf2 may be responsible for a higher sensitivity to H2O2 challenge. Interestingly, HER2-positive cells showed the highest increase in intracellular ROS after oxidative challenge, concomitant with a significantly higher level of AQP1, AQP3, and AQP5 expression compared to the other cell types, with AQP3 always being the most expressed isoform. The AQP3 gene expression was stimulated by H2O2 treatment in hormone-positive and HER2NEU cells, together with Nrf2 expression, but was downregulated in triple-negative cells that showed instead upregulation of AQP1 and AQP5. The lipid profile and AQP gene expression after oxidative challenge of these particularly aggressive cell types may represent metabolic reprogramming of cancer cells and reflect a role in adaptation to stress and therapy resistance.
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36
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Peroxiporins in Cancer. Int J Mol Sci 2019; 20:ijms20061371. [PMID: 30893772 PMCID: PMC6471688 DOI: 10.3390/ijms20061371] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2019] [Revised: 03/09/2019] [Accepted: 03/15/2019] [Indexed: 02/07/2023] Open
Abstract
The transport of H2O2 across membranes by specific aquaporins (AQPs) has been considered the last milestone in the timeline of hydrogen peroxide discoveries in biochemistry. According to its concentration and localization, H2O2 can be dangerous or acts as a signaling molecule in various cellular processes as either a paracrine (intercellular) and/or an autocrine (intracellular) signal. In this review, we investigate and critically examine the available information on AQP isoforms able to facilitate H2O2 across biological membranes (“peroxiporins”), focusing in particular on their role in cancer. Moreover, the ability of natural compounds to modulate expression and/or activity of peroxiporins is schematically reported and discussed.
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Danielli M, Marrone J, Capiglioni AM, Marinelli RA. Data of H 2O 2 release from AQP8-knockdown rat hepatocyte mitochondria. Data Brief 2019; 23:103722. [PMID: 31372390 PMCID: PMC6660618 DOI: 10.1016/j.dib.2019.103722] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2018] [Revised: 01/23/2019] [Accepted: 01/25/2019] [Indexed: 12/20/2022] Open
Abstract
This article reports experimental data related to the research article entitled "Mitochondrial aquaporin-8 is involved in SREBP-controlled hepatocyte cholesterol biosynthesis" [Danielli et al., 2019]. We present data about hydrogen peroxide (H2O2) release from mitochondria isolated from rat hepatocytes with or without silencing of aquaporin-8 (AQP8) protein expression. The rate of mitochondrial H2O2 release (pmoles/min/mg mitochondrial protein) was found to be decreased by about 50% in AQP8-knockdown mitochondria.
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Affiliation(s)
- Mauro Danielli
- Instituto de Fisiología Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Suipacha 570, 2000, Rosario, Santa Fe, Argentina
| | - Julieta Marrone
- Instituto de Fisiología Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Suipacha 570, 2000, Rosario, Santa Fe, Argentina
| | - Alejo M Capiglioni
- Instituto de Fisiología Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Suipacha 570, 2000, Rosario, Santa Fe, Argentina
| | - Raúl A Marinelli
- Instituto de Fisiología Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Suipacha 570, 2000, Rosario, Santa Fe, Argentina
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Aikman B, de Almeida A, Meier-Menches SM, Casini A. Aquaporins in cancer development: opportunities for bioinorganic chemistry to contribute novel chemical probes and therapeutic agents. Metallomics 2019; 10:696-712. [PMID: 29766198 DOI: 10.1039/c8mt00072g] [Citation(s) in RCA: 48] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Aquaporins (AQPs) are membrane proteins allowing permeation of water, glycerol & hydrogen peroxide across biomembranes, and playing an important role in water homeostasis in different organs, exocrine gland secretion, urine concentration, skin moisturization, fat metabolism and neural signal transduction. Notably, a large number of studies showed that AQPs are closely associated with cancer biological functions and expressed in more than 20 human cancer cell types. Furthermore, AQP expression is positively correlated with tumour types, grades, proliferation, migration, angiogenesis, as well as tumour-associated oedema, rendering these membrane channels attractive as both diagnostic and therapeutic targets in cancer. Recent developments in the field of AQPs modulation have identified coordination metal-based complexes as potent and selective inhibitors of aquaglyceroporins, opening new avenues in the application of inorganic compounds in medicine and chemical biology. The present review is aimed at providing an overview on AQP structure and function, mainly in relation to cancer. In this context, the exploration of coordination metal compounds as possible inhibitors of aquaporins may open the way to novel chemical approaches to study AQP roles in tumour growth and potentially to new drug families. Thus, we describe recent results in the field and reflect upon the potential of inorganic chemistry in providing compounds to modulate the activity of "elusive" membrane targets as the aquaporins.
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Affiliation(s)
- Brech Aikman
- School of Chemistry, Cardiff University, Main Building, Park Place, Cardiff CF10 3AT, UK.
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39
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Danielli M, Marrone J, Capiglioni AM, Marinelli RA. Mitochondrial aquaporin-8 is involved in SREBP-controlled hepatocyte cholesterol biosynthesis. Free Radic Biol Med 2019; 131:370-375. [PMID: 30579780 DOI: 10.1016/j.freeradbiomed.2018.12.016] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2018] [Revised: 11/20/2018] [Accepted: 12/14/2018] [Indexed: 01/06/2023]
Abstract
Cholesterol, via sterol regulatory element-binding protein (SREBP) transcription factors, activates or represses genes involved in its hepatic biosynthetic pathway, and also modulates the expression of hepatocyte mitochondrial aquaporin-8 (mtAQP8), a channel that can function as peroxiporin by facilitating the transmembrane diffusion of H2O2. Here we tested the hypothesis that mtAQP8 is involved in the SREBP-mediated regulation of hepatocyte cholesterol biosynthesis. Using human hepatocyte-derived Huh-7 cells and primary rat hepatocytes, we found that mtAQP8 knockdown significantly downregulated de novo cholesterol synthesis as well as protein expressions of SREBP-2 and its target gene, a rate-limiting enzyme in cholesterol synthesis 3-Hydroxy-3-Methylglutaryl-CoA Reductase (HMGCR). In contrast, adenovirus-mediated human AQP8 mitochondrial expression significantly increased de novo cholesterol synthesis and protein expressions of SREBP-2 and HMGCR. In mtAQP8-overexpressed hepatocytes, mitochondrial H2O2 release was found to be increased; and a mitochondria-targeted antioxidant prevented the upregulation of mitochondrial H2O2 release and that of cholesterol synthesis. Our results suggest that peroxiporin mtAQP8 plays a role in the SREBP-controlled hepatocyte cholesterogenesis, a finding that might be relevant to cholesterol-related metabolic disorders.
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Affiliation(s)
- Mauro Danielli
- Instituto de Fisiología Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Rosario, Argentina
| | - Julieta Marrone
- Instituto de Fisiología Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Rosario, Argentina
| | - Alejo M Capiglioni
- Instituto de Fisiología Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Rosario, Argentina
| | - Raúl A Marinelli
- Instituto de Fisiología Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Rosario, Argentina.
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40
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Treberg JR, Braun K, Selseleh P. Mitochondria can act as energy-sensing regulators of hydrogen peroxide availability. Redox Biol 2018; 20:483-488. [PMID: 30466061 PMCID: PMC6249968 DOI: 10.1016/j.redox.2018.11.002] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2018] [Revised: 10/26/2018] [Accepted: 11/06/2018] [Indexed: 01/04/2023] Open
Abstract
Mitochondria are widely recognized as sources of reactive oxygen species in animal cells, with H2O2 being of particular note because it can act not only in oxidative stress but also is important to several signalling pathways. Lesser recognized is that mitochondria can have far greater capacity to consume H2O2 than to produce it; however, the consumption of H2O2 may be kinetically constrained by H2O2 availability especially at the low nanomolar (or lower) concentrations that occur in vivo. The production of H2O2 is a function of many factors, not the least of which are respiratory substrate availability and the protonmotive force (Δp). The Δp, which is predominantly membrane potential (ΔΨ), can be a strong indicator of mitochondrial energy status, particularly if respiratory substrate supply is either not meeting or exceeding demand. The notion that mitochondria may functionally act in regulating H2O2 concentrations may be somewhat implicit but little evidence demonstrating this is available. Here we demonstrate key assumptions that are required for mitochondria to act as regulators of H2O2 by an integrated system of production and concomitant consumption. In particular we show the steady-state level of H2O2 mitochondria approach is a function of both mitochondrial H2O2 consumption and production capacity, the latter of which is strongly influenced by ΔΨ. Our results are consistent with mitochondria being able to manipulate extramitochondrial H2O2 as a means of signalling mitochondrial energetic status, in particular the Δp or ΔΨ. Such a redox-based signal could operate with some independence from other energy sensing mechanisms such as those that transmit information using the cytosolic adenylate pool.
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Affiliation(s)
- Jason R Treberg
- Department of Biological Sciences, University of Manitoba, Winnipeg, MB, Canada; Department of Food and Human Nutritional Sciences, University of Manitoba, Winnipeg, MB, Canada; Centre on Aging, University of Manitoba, Winnipeg, MB, Canada.
| | - Kristen Braun
- Department of Biological Sciences, University of Manitoba, Winnipeg, MB, Canada
| | - Parisa Selseleh
- Department of Biological Sciences, University of Manitoba, Winnipeg, MB, Canada
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Ježek P, Holendová B, Garlid KD, Jabůrek M. Mitochondrial Uncoupling Proteins: Subtle Regulators of Cellular Redox Signaling. Antioxid Redox Signal 2018; 29:667-714. [PMID: 29351723 PMCID: PMC6071544 DOI: 10.1089/ars.2017.7225] [Citation(s) in RCA: 80] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
SIGNIFICANCE Mitochondria are the energetic, metabolic, redox, and information signaling centers of the cell. Substrate pressure, mitochondrial network dynamics, and cristae morphology state are integrated by the protonmotive force Δp or its potential component, ΔΨ, which are attenuated by proton backflux into the matrix, termed uncoupling. The mitochondrial uncoupling proteins (UCP1-5) play an eminent role in the regulation of each of the mentioned aspects, being involved in numerous physiological events including redox signaling. Recent Advances: UCP2 structure, including purine nucleotide and fatty acid (FA) binding sites, strongly support the FA cycling mechanism: UCP2 expels FA anions, whereas uncoupling is achieved by the membrane backflux of protonated FA. Nascent FAs, cleaved by phospholipases, are preferential. The resulting Δp dissipation decreases superoxide formation dependent on Δp. UCP-mediated antioxidant protection and its impairment are expected to play a major role in cell physiology and pathology. Moreover, UCP2-mediated aspartate, oxaloacetate, and malate antiport with phosphate is expected to alter metabolism of cancer cells. CRITICAL ISSUES A wide range of UCP antioxidant effects and participations in redox signaling have been reported; however, mechanisms of UCP activation are still debated. Switching off/on the UCP2 protonophoretic function might serve as redox signaling either by employing/releasing the extra capacity of cell antioxidant systems or by directly increasing/decreasing mitochondrial superoxide sources. Rapid UCP2 degradation, FA levels, elevation of purine nucleotides, decreased Mg2+, or increased pyruvate accumulation may initiate UCP-mediated redox signaling. FUTURE DIRECTIONS Issues such as UCP2 participation in glucose sensing, neuronal (synaptic) function, and immune cell activation should be elucidated. Antioxid. Redox Signal. 29, 667-714.
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Affiliation(s)
- Petr Ježek
- 1 Department of Mitochondrial Physiology, Institute of Physiology of the Czech Academy of Sciences , Prague, Czech Republic
| | - Blanka Holendová
- 1 Department of Mitochondrial Physiology, Institute of Physiology of the Czech Academy of Sciences , Prague, Czech Republic
| | - Keith D Garlid
- 2 UCLA Cardiovascular Research Laboratory, David Geffen School of Medicine at UCLA , Los Angeles, California
| | - Martin Jabůrek
- 1 Department of Mitochondrial Physiology, Institute of Physiology of the Czech Academy of Sciences , Prague, Czech Republic
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Chauvigné F, Parhi J, Ducat C, Ollé J, Finn RN, Cerdà J. The cellular localization and redistribution of multiple aquaporin paralogs in the spermatic duct epithelium of a maturing marine teleost. J Anat 2018; 233:177-192. [PMID: 29806093 DOI: 10.1111/joa.12829] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/25/2018] [Indexed: 12/15/2022] Open
Abstract
Aquaporin-mediated fluid transport in the mammalian efferent duct and epididymis is believed to play a role in sperm maturation and concentration. In fish, such as the marine teleost gilthead seabream (Sparus aurata), the control of fluid homeostasis in the spermatic duct seems also to be crucial for male fertility, but no information exists on the expression and distribution of aquaporins. In this study, reverse transcriptase-polymerase chain reaction and immunoblotting analyses, employing available and newly raised paralog-specific antibodies for seabream aquaporins, indicate that up to nine functional aquaporins, Aqp0a, -1aa, -1ab, -3a, -4a, -7, -8bb, -9b and -10b, are expressed in the spermatic duct. Immunolocalization of the channels in the resting spermatic duct reveals that Aqp0a, -1aa, -4a, -7 and -10b are expressed in the monolayered luminal epithelium, Aqp8b and -9b in smooth muscle fibers, and Aqp1ab and -3a in different interstitial lamina cells. In the epithelial cells, Aqp0a and -1aa are localized in the short apical microvilli, and Aqp4a and -10b show apical and basolateral staining, whereas Aqp7 is solely detected in vesicular compartments. Upon spermiation, an elongation of the epithelial cells sterocilia, as well as the folding of the epithelium, is observed. At this stage, single- and double-immunostaining, using two aquaporin paralogs or the Na+ /K+ -ATPase membrane marker, indicate that Aqp1ab, -3a, -7, -8bb and -9b staining remains unchanged, whereas in epithelial cells Aqp1aa translation is supressed, Aqp4a internalizes, and Aqp0a and -10b accumulate in the apical, lateral and basal plasma membrane. These findings uncover a cell type- and region-specific distribution of multiple aquaporins in the piscine spermatic duct, which shares conserved features of the mammalian system. The data therefore suggest that aquaporins may play different roles in the regulation of fluid homeostasis and sperm maturation in the male reproductive tract of fish.
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Affiliation(s)
- François Chauvigné
- Group of Comparative Molecular Physiology, IRTA-Institut de Ciències del Mar, Consejo Superior de Investigaciones Científicas (CSIC), Barcelona, Spain
| | - Janmejay Parhi
- Fish Genetics and Reproduction Department, College of Fisheries, Central Agricultural University, Lembucherra, Tripura, India
| | - Carla Ducat
- Group of Comparative Molecular Physiology, IRTA-Institut de Ciències del Mar, Consejo Superior de Investigaciones Científicas (CSIC), Barcelona, Spain
| | - Judith Ollé
- Group of Comparative Molecular Physiology, IRTA-Institut de Ciències del Mar, Consejo Superior de Investigaciones Científicas (CSIC), Barcelona, Spain
| | - Roderick Nigel Finn
- Group of Comparative Molecular Physiology, IRTA-Institut de Ciències del Mar, Consejo Superior de Investigaciones Científicas (CSIC), Barcelona, Spain.,Department of Biological Sciences, Bergen High Technology Centre, University of Bergen, Bergen, Norway
| | - Joan Cerdà
- Group of Comparative Molecular Physiology, IRTA-Institut de Ciències del Mar, Consejo Superior de Investigaciones Científicas (CSIC), Barcelona, Spain
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Aquaporin Membrane Channels in Oxidative Stress, Cell Signaling, and Aging: Recent Advances and Research Trends. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2018; 2018:1501847. [PMID: 29770164 PMCID: PMC5892239 DOI: 10.1155/2018/1501847] [Citation(s) in RCA: 81] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/19/2017] [Revised: 01/29/2018] [Accepted: 02/20/2018] [Indexed: 02/07/2023]
Abstract
Reactive oxygen species (ROS) are produced as a result of aerobic metabolism and as by-products through numerous physiological and biochemical processes. While ROS-dependent modifications are fundamental in transducing intracellular signals controlling pleiotropic functions, imbalanced ROS can cause oxidative damage, eventually leading to many chronic diseases. Moreover, increased ROS and reduced nitric oxide (NO) bioavailability are main key factors in dysfunctions underlying aging, frailty, hypertension, and atherosclerosis. Extensive investigation aims to elucidate the beneficial effects of ROS and NO, providing novel insights into the current medical treatment of oxidative stress-related diseases of high epidemiological impact. This review focuses on emerging topics encompassing the functional involvement of aquaporin channel proteins (AQPs) and membrane transport systems, also allowing permeation of NO and hydrogen peroxide, a major ROS, in oxidative stress physiology and pathophysiology. The most recent advances regarding the modulation exerted by food phytocompounds with antioxidant action on AQPs are also reviewed.
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Redox crosstalk at endoplasmic reticulum (ER) membrane contact sites (MCS) uses toxic waste to deliver messages. Cell Death Dis 2018; 9:331. [PMID: 29491367 PMCID: PMC5832433 DOI: 10.1038/s41419-017-0033-4] [Citation(s) in RCA: 169] [Impact Index Per Article: 24.1] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2017] [Revised: 09/29/2017] [Accepted: 10/03/2017] [Indexed: 12/17/2022]
Abstract
Many cellular redox reactions housed within mitochondria, peroxisomes and the endoplasmic reticulum (ER) generate hydrogen peroxide (H2O2) and other reactive oxygen species (ROS). The contribution of each organelle to the total cellular ROS production is considerable, but varies between cell types and also over time. Redox-regulatory enzymes are thought to assemble at a “redox triangle” formed by mitochondria, peroxisomes and the ER, assembling “redoxosomes” that sense ROS accumulations and redox imbalances. The redoxosome enzymes use ROS, potentially toxic by-products made by some redoxosome members themselves, to transmit inter-compartmental signals via chemical modifications of downstream proteins and lipids. Interestingly, important components of the redoxosome are ER chaperones and oxidoreductases, identifying ER oxidative protein folding as a key ROS producer and controller of the tri-organellar membrane contact sites (MCS) formed at the redox triangle. At these MCS, ROS accumulations could directly facilitate inter-organellar signal transmission, using ROS transporters. In addition, ROS influence the flux of Ca2+ ions, since many Ca2+ handling proteins, including inositol 1,4,5 trisphosphate receptors (IP3Rs), SERCA pumps or regulators of the mitochondrial Ca2+ uniporter (MCU) are redox-sensitive. Fine-tuning of these redox and ion signaling pathways might be difficult in older organisms, suggesting a dysfunctional redox triangle may accompany the aging process.
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Kirscht A, Sonntag Y, Kjellbom P, Johanson U. A structural preview of aquaporin 8 via homology modeling of seven vertebrate isoforms. BMC STRUCTURAL BIOLOGY 2018; 18:2. [PMID: 29454339 PMCID: PMC5816522 DOI: 10.1186/s12900-018-0081-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/13/2017] [Accepted: 01/25/2018] [Indexed: 11/10/2022]
Abstract
Background Aquaporins (AQPs) facilitate the passage of small neutral polar molecules across membranes of the cell. In animals there are four distinct AQP subfamilies, whereof AQP8 homologues constitute one of the smallest subfamilies with just one member in man. AQP8 conducts water, ammonia, urea, glycerol and H2O2 through various membranes of animal cells. This passive channel has been connected to a number of phenomena, such as volume change of mitochondria, ammonia neurotoxicity, and mitochondrial dysfunction related to oxidative stress. Currently, there is no experimentally determined structure of an AQP8, hence the structural understanding of this subfamily is limited. The recently solved structure of the plant AQP, AtTIP2;1, which has structural and functional features in common with AQP8s, has opened up for construction of homology models that are likely to be more accurate than previous models. Results Here we present homology models of seven vertebrate AQP8s. Modeling based on the AtTIP2;1 structure alone resulted in reasonable models except for the pore being blocked by a phenylalanine that is not present in AtTIP2;1. To achieve an open pore, these models were supplemented with models based on the bacterial water specific AQP, EcAqpZ, creating a chimeric monomeric model for each AQP8 isoform. The selectivity filter (also named the aromatic/arginine region), which defines the permeant substrate profile, comprises five amino acid residues in AtTIP2;1, including a histidine coming from loop C. Compared to AtTIP2;1, the selectivity filters of modelled AQP8s only deviates in that they are slightly more narrow and more hydrophobic due to a phenylalanine replacing the histidine from loop C. Interestingly, the models do not exclude the existence of a side pore beneath loop C similar to that described in the structure of AtTIP2;1. Conclusions Our models concur that AQP8s are likely to have an AtTIP2;1-like selectivity filter. The detailed description of the expected configuration of residues in the selectivity filters of AQP8s provides an excellent starting point for planning of as well as rationalizing the outcome of mutational studies. Our strategy to compile hybrid models based on several templates may prove useful also for other AQPs for which structural information is limited. Electronic supplementary material The online version of this article (10.1186/s12900-018-0081-8) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Andreas Kirscht
- Division of Biochemistry and Structural Biology, Center for Molecular Protein Science, Department of Chemistry, Lund University, Box 124, SE-221 00, Lund, Sweden
| | - Yonathan Sonntag
- Division of Biochemistry and Structural Biology, Center for Molecular Protein Science, Department of Chemistry, Lund University, Box 124, SE-221 00, Lund, Sweden
| | - Per Kjellbom
- Division of Biochemistry and Structural Biology, Center for Molecular Protein Science, Department of Chemistry, Lund University, Box 124, SE-221 00, Lund, Sweden
| | - Urban Johanson
- Division of Biochemistry and Structural Biology, Center for Molecular Protein Science, Department of Chemistry, Lund University, Box 124, SE-221 00, Lund, Sweden.
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Cuillerier A, Honarmand S, Cadete VJJ, Ruiz M, Forest A, Deschênes S, Beauchamp C, Charron G, Rioux JD, Des Rosiers C, Shoubridge EA, Burelle Y. Loss of hepatic LRPPRC alters mitochondrial bioenergetics, regulation of permeability transition and trans-membrane ROS diffusion. Hum Mol Genet 2018; 26:3186-3201. [PMID: 28575497 DOI: 10.1093/hmg/ddx202] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2017] [Accepted: 05/19/2017] [Indexed: 12/19/2022] Open
Abstract
The French-Canadian variant of Leigh Syndrome (LSFC) is an autosomal recessive oxidative phosphorylation (OXPHOS) disorder caused by a mutation in LRPPRC, coding for a protein involved in the stability of mitochondrially-encoded mRNAs. Low levels of LRPPRC are present in all patient tissues, but result in a disproportionately severe OXPHOS defect in the brain and liver, leading to unpredictable subacute metabolic crises. To investigate the impact of the OXPHOS defect in the liver, we analyzed the mitochondrial phenotype in mice harboring an hepatocyte-specific inactivation of Lrpprc. Loss of LRPPRC in the liver caused a generalized growth delay, and typical histological features of mitochondrial hepatopathy. At the molecular level, LRPPRC deficiency caused destabilization of polyadenylated mitochondrial mRNAs, altered mitochondrial ultrastructure, and a severe complex IV (CIV) and ATP synthase (CV) assembly defect. The impact of LRPPRC deficiency was not limited to OXPHOS, but also included impairment of long-chain fatty acid oxidation, a striking dysregulation of the mitochondrial permeability transition pore, and an unsuspected alteration of trans-membrane H2O2 diffusion, which was traced to the ATP synthase assembly defect, and to changes in the lipid composition of mitochondrial membranes. This study underscores the value of mitochondria phenotyping to uncover complex and unexpected mechanisms contributing to the pathophysiology of mitochondrial disorders.
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Affiliation(s)
| | - Shamisa Honarmand
- Department of Human Genetics, Montreal Neurological Institute McGill University, Montreal, QC H3A 2B4, Canada
| | | | - Matthieu Ruiz
- Research Center, Montreal Heart Institute, Montreal, QC H1T 1C8, Canada
| | - Anik Forest
- Research Center, Montreal Heart Institute, Montreal, QC H1T 1C8, Canada
| | - Sonia Deschênes
- Faculty of Pharmacy, University of Montreal, Montreal, QC H3C 3J7, Canada.,Faculty of Medicine and Department of Nutrition, Université de Montréal, Montreal, QC H3C 3J7, Canada
| | | | | | - Guy Charron
- Research Center, Montreal Heart Institute, Montreal, QC H1T 1C8, Canada
| | - John D Rioux
- Research Center, Montreal Heart Institute, Montreal, QC H1T 1C8, Canada
| | - Christine Des Rosiers
- Research Center, Montreal Heart Institute, Montreal, QC H1T 1C8, Canada.,Faculty of Medicine and Department of Nutrition, Université de Montréal, Montreal, QC H3C 3J7, Canada
| | - Eric A Shoubridge
- Department of Human Genetics, Montreal Neurological Institute McGill University, Montreal, QC H3A 2B4, Canada
| | - Yan Burelle
- Faculty of Pharmacy, University of Montreal, Montreal, QC H3C 3J7, Canada
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Hayashi R, Hayashi S, Fukuda K, Sakai M, Machida S. Immunolocation of Aquaporin 8 in Human Cataractous Lenticular Epithelial Cells. Biomed Hub 2017; 2:1-5. [PMID: 31988920 PMCID: PMC6945952 DOI: 10.1159/000480290] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2017] [Accepted: 08/14/2017] [Indexed: 12/11/2022] Open
Abstract
Purpose/Aim Aquaporin 8 (AQP8) is a diffusion facilitator of hydrogen peroxide (H<sub>2</sub>O<sub>2</sub>) through cell membranes. The purpose of this study was to confirm and localize AQP8 in human lenticular epithelial cells (LECs). Materials and Methods Lenticular anterior capsule samples, including LECs, were collected during cataract surgery of cataract patients after informed consent. The localization of AQP8 was detected by immunohistochemical staining using an antibody to AQP8. Real-time polymerase chain reaction (RT-PCR) was also used to determine the AQP8 mRNA expression levels. The PCR products were analyzed by gel electrophoresis following analyses of band density. Results Immunohistochemical staining showed AQP8 was distributed throughout the whole area of the anterior capsulotomy. AQP8 labeling was observed surrounding and within the cytoplasm of LECs. RT-PCR and gel electrophoresis also revealed the presence of AQP8 mRNA in the lenticular anterior capsule. The results of immunohistochemical staining were comparable to those of RT-PCR and gel electrophoresis. Conclusions The results of this study indicate the distribution of AQP8 in human LECs. This is the first investigation confirming the presence of AQP8 in human LECs.
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Affiliation(s)
- Rijo Hayashi
- Department of Ophthalmology, Koshigaya Hospital, Dokkyo Medical University, Koshigaya, Japan
| | - Shimmin Hayashi
- Department of Ophthalmology, Koshigaya Hospital, Dokkyo Medical University, Lively Eye Clinic, Koshigaya, Japan
| | - Kazunori Fukuda
- Koshigaya Hospital Joint Research Center, Dokkyo Medical University, Koshigaya, Japan
| | - Miki Sakai
- Department of Ophthalmology, Koshigaya Hospital, Dokkyo Medical University, Koshigaya, Japan
| | - Shigeki Machida
- Department of Ophthalmology, Koshigaya Hospital, Dokkyo Medical University, Koshigaya, Japan
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Rottenberg H, Hoek JB. The path from mitochondrial ROS to aging runs through the mitochondrial permeability transition pore. Aging Cell 2017; 16:943-955. [PMID: 28758328 PMCID: PMC5595682 DOI: 10.1111/acel.12650] [Citation(s) in RCA: 185] [Impact Index Per Article: 23.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/21/2017] [Indexed: 12/23/2022] Open
Abstract
Excessive production of mitochondrial reactive oxygen species (mROS) is strongly associated with mitochondrial and cellular oxidative damage, aging, and degenerative diseases. However, mROS also induces pathways of protection of mitochondria that slow aging, inhibit cell death, and increase lifespan. Recent studies show that the activation of the mitochondrial permeability transition pore (mPTP), which is triggered by mROS and mitochondrial calcium overloading, is enhanced in aged animals and humans and in aging-related degenerative diseases. mPTP opening initiates further production and release of mROS that damage both mitochondrial and nuclear DNA, proteins, and phospholipids, and also releases matrix NAD that is hydrolyzed in the intermembrane space, thus contributing to the depletion of cellular NAD that accelerates aging. Oxidative damage to calcium transporters leads to calcium overload and more frequent opening of mPTP. Because aging enhances the opening of the mPTP and mPTP opening accelerates aging, we suggest that mPTP opening drives the progression of aging. Activation of the mPTP is regulated, directly and indirectly, not only by the mitochondrial protection pathways that are induced by mROS, but also by pro-apoptotic signals that are induced by DNA damage. We suggest that the integration of these contrasting signals by the mPTP largely determines the rate of cell aging and the initiation of cell death, and thus animal lifespan. The suggestion that the control of mPTP activation is critical for the progression of aging can explain the conflicting and confusing evidence regarding the beneficial and deleterious effects of mROS on health and lifespan.
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Affiliation(s)
- Hagai Rottenberg
- New Hope Biomedical R&D; 23 W. Bridge Street New Hope PA 18038 USA
| | - Jan B. Hoek
- Department of Anatomy, Pathology and Cell Biology; MitoCare Center; Thomas Jefferson University; Philadelphia PA 19107 USA
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Tao X, Li K, Wang J, Zhang L, Li W, Kan B, Yu G, Jian X. Tetramethylpyrazine can ameliorate hepatocellular mitochondrial dysfunction by decreasing the inflammatory response and increasing AQP8 protein expression in septic rats. EUR J INFLAMM 2017. [DOI: 10.1177/1721727x17731003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Sepsis, which could lead to mitochondrial dysfunction and cellular energy loss, always induces acute liver injury and has a high mortality rate. Tetramethylpyrazine (TMP) is an active extract from the Chinese herb Ligusticum chuanxiong and exhibits anti-sepsis activity. In this study, a rat sepsis model was first established via cecal ligation and puncture (CLP). Then, 48 Sprague Dawley male rats were randomly divided into four groups (12 rats in each group): control group (C), sepsis group (S), TMP treatment group (T), and TMP prevention group (P). Serum aspartate aminotransferase (AST), serum alanine aminotransferase (ALT), mitochondrial aspartate aminotransferase (mAST), and adenosine triphosphate (ATP) levels and mitochondrial membrane potential (MMP) were measured and used as indicators of hepatic dysfunction severity and mitochondrial function. In addition, the activities of Na+-K+-ATPase, Mg2+-ATPase, Ca2+-ATPase, and Ca2+-Mg2+-ATPase in the mitochondrial membrane, the expression level of AQP8 and some inflammatory factors, and the level of oxidative stress were measured to explore potential mechanisms. We found that AQP8 accepts signals from inflammatory factors upon stimulation and during various infections, and low AQP8 expression levels could result in further downstream mitochondrial dysfunction. In conclusion, our data demonstrated that TMP could ameliorate hepatocellular mitochondrial dysfunction by decreasing the inflammatory response and increasing AQP8 protein expression.
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Affiliation(s)
- Xiaogen Tao
- Department of Poisoning and Occupational Diseases, Qilu Hospital of Shandong University, Jinan, China
- Intensive Care Unit (ICU), Anhui Provincial Hospital Affiliated Anhui Medical University, Hefei, China
| | - Kun Li
- Intensive Care Unit (ICU), Anhui Provincial Hospital Affiliated Anhui Medical University, Hefei, China
| | - Jinquan Wang
- Intensive Care Unit (ICU), Anhui Provincial Hospital Affiliated Anhui Medical University, Hefei, China
| | - Lin Zhang
- Intensive Care Unit (ICU), Anhui Provincial Hospital Affiliated Anhui Medical University, Hefei, China
| | - Wei Li
- School of Pharmacy, University College London, London, UK
| | - Baotian Kan
- Department of Poisoning and Occupational Diseases, Qilu Hospital of Shandong University, Jinan, China
| | - Guangcai Yu
- Department of Poisoning and Occupational Diseases, Qilu Hospital of Shandong University, Jinan, China
| | - Xiangdong Jian
- Department of Poisoning and Occupational Diseases, Qilu Hospital of Shandong University, Jinan, China
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Benfeitas R, Uhlen M, Nielsen J, Mardinoglu A. New Challenges to Study Heterogeneity in Cancer Redox Metabolism. Front Cell Dev Biol 2017; 5:65. [PMID: 28744456 PMCID: PMC5504267 DOI: 10.3389/fcell.2017.00065] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2017] [Accepted: 06/26/2017] [Indexed: 12/13/2022] Open
Abstract
Reactive oxygen species (ROS) are important pathophysiological molecules involved in vital cellular processes. They are extremely harmful at high concentrations because they promote the generation of radicals and the oxidation of lipids, proteins, and nucleic acids, which can result in apoptosis. An imbalance of ROS and a disturbance of redox homeostasis are now recognized as a hallmark of complex diseases. Considering that ROS levels are significantly increased in cancer cells due to mitochondrial dysfunction, ROS metabolism has been targeted for the development of efficient treatment strategies, and antioxidants are used as potential chemotherapeutic drugs. However, initial ROS-focused clinical trials in which antioxidants were supplemented to patients provided inconsistent results, i.e., improved treatment or increased malignancy. These different outcomes may result from the highly heterogeneous redox responses of tumors in different patients. Hence, population-based treatment strategies are unsuitable and patient-tailored therapeutic approaches are required for the effective treatment of patients. Moreover, due to the crosstalk between ROS, reducing equivalents [e.g., NAD(P)H] and central metabolism, which is heterogeneous in cancer, finding the best therapeutic target requires the consideration of system-wide approaches that are capable of capturing the complex alterations observed in all of the associated pathways. Systems biology and engineering approaches may be employed to overcome these challenges, together with tools developed in personalized medicine. However, ROS- and redox-based therapies have yet to be addressed by these methodologies in the context of disease treatment. Here, we review the role of ROS and their coupled redox partners in tumorigenesis. Specifically, we highlight some of the challenges in understanding the role of hydrogen peroxide (H2O2), one of the most important ROS in pathophysiology in the progression of cancer. We also discuss its interplay with antioxidant defenses, such as the coupled peroxiredoxin/thioredoxin and glutathione/glutathione peroxidase systems, and its reducing equivalent metabolism. Finally, we highlight the need for system-level and patient-tailored approaches to clarify the roles of these systems and identify therapeutic targets through the use of the tools developed in personalized medicine.
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Affiliation(s)
- Rui Benfeitas
- Science for Life Laboratory, KTH Royal Institute of TechnologyStockholm, Sweden
| | - Mathias Uhlen
- Science for Life Laboratory, KTH Royal Institute of TechnologyStockholm, Sweden
| | - Jens Nielsen
- Science for Life Laboratory, KTH Royal Institute of TechnologyStockholm, Sweden.,Department of Biology and Biological Engineering, Chalmers University of TechnologyGothenburg, Sweden
| | - Adil Mardinoglu
- Science for Life Laboratory, KTH Royal Institute of TechnologyStockholm, Sweden.,Department of Biology and Biological Engineering, Chalmers University of TechnologyGothenburg, Sweden
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