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Wang Y, Tan J, Li L, Liu S, Li X, Shan H, Yin H, Yang HT. Uncoupling protein 3 protects against pathological cardiac hypertrophy via downregulation of aspartate. J Mol Cell Cardiol 2025; 202:1-12. [PMID: 40037428 DOI: 10.1016/j.yjmcc.2025.03.001] [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: 10/24/2024] [Revised: 02/12/2025] [Accepted: 03/01/2025] [Indexed: 03/06/2025]
Abstract
Metabolic remodeling involving alterations in the substrate utilization is a key feature of cardiac hypertrophy. However, the molecular mechanisms underlying regulation of tricarboxylic acid cycle intermediates by mitochondrial membrane proteins during cardiac hypertrophy have not yet been fully clarified. Mitochondrial uncoupling protein 3 (UCP3), an anion transporter located on the inner mitochondrial membrane, exerts cardioprotective effects against ischemia/reperfusion injury and its insufficiency exacerbates left ventricular (LV) diastolic dysfunction during hypertension. However, its role in pressure overload-induced cardiac hypertrophy remains unknown. Here, we found that UCP3 was downregulated in the mouse LV with transverse aortic constriction (TAC)-induced pathological hypertrophy and in phenylephrine (PE)-stimulated hypertrophic neonatal rat cardiomyocytes (NRCMs). The TAC-induced hypertrophy and LV dysfunction were aggravated in global and cardiac specific knockout of UCP3 (UCP3cKO) mice but improved by cardiac specific overexpression of UCP3 (UCP3cOE). Similar alterations in hypertrophy were observed in PE-treated NRCMs with UCP3-knockdown/overexpression. Moreover, the TAC-increased aspartate and glutamic-oxaloacetic transaminase 2 (GOT2) activity were enhanced in UCP3cKO hearts but reversed in UCP3cOE ones. PE-induced increases of GOT2 activity were enhanced in the UCP3-knockdown NRCMs but attenuated in the UCP3 overexpression ones, accompanied with the downregulation of aspartate. The endogenous interaction of UCP3 and GOT2 was weakened in the PE-treated NRCMs compared with the PE-untreated cells. Furthermore, aspartate supplementation reversed the UCP3 overexpression-attenuated hypertrophy in the PE-stimulated NRCMs. In conclusion, UCP3 expression is downregulated in hypertrophic hearts and cardiomyocytes, whereas the increase of UCP3 mitigates cardiac hypertrophy by downregulation of the enhanced aspartate. These findings provide new knowledge for the function of UCP3 and therapeutic target for cardiac hypertrophy.
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Affiliation(s)
- Yajun Wang
- Laboratory of Molecular Cardiology, CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences (CAS), Shanghai 200031, PR China
| | - Jiliang Tan
- Laboratory of Molecular Cardiology, CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences (CAS), Shanghai 200031, PR China
| | - Luxiao Li
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, CAS, Shanghai 200031, PR China
| | - Shenyan Liu
- Laboratory of Molecular Cardiology, CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences (CAS), Shanghai 200031, PR China
| | - Xuxia Li
- Laboratory of Molecular Cardiology, CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences (CAS), Shanghai 200031, PR China; Jiading Branch, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200031, PR China
| | - Huitong Shan
- Laboratory of Molecular Cardiology, CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences (CAS), Shanghai 200031, PR China
| | - Huiyong Yin
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, CAS, Shanghai 200031, PR China; Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, PR China.
| | - Huang-Tian Yang
- Laboratory of Molecular Cardiology, CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences (CAS), Shanghai 200031, PR China.
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Zhou X, Medina-Ramirez IE, Su G, Liu Y, Yan B. All Roads Lead to Rome: Comparing Nanoparticle- and Small Molecule-Driven Cell Autophagy. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2024; 20:e2310966. [PMID: 38616767 DOI: 10.1002/smll.202310966] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Revised: 03/27/2024] [Indexed: 04/16/2024]
Abstract
Autophagy, vital for removing cellular waste, is triggered differently by small molecules and nanoparticles. Small molecules, like rapamycin, non-selectively activate autophagy by inhibiting the mTOR pathway, which is essential for cell regulation. This can clear damaged components but may cause cytotoxicity with prolonged use. Nanoparticles, however, induce autophagy, often causing oxidative stress, through broader cellular interactions and can lead to a targeted form known as "xenophagy." Their impact varies with their properties but can be harnessed therapeutically. In this review, the autophagy induced by nanoparticles is explored and small molecules across four dimensions: the mechanisms behind autophagy induction, the outcomes of such induction, the toxicological effects on cellular autophagy, and the therapeutic potential of employing autophagy triggered by nanoparticles or small molecules. Although small molecules and nanoparticles each induce autophagy through different pathways and lead to diverse effects, both represent invaluable tools in cell biology, nanomedicine, and drug discovery, offering unique insights and therapeutic opportunities.
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Affiliation(s)
- Xiaofei Zhou
- College of Science & Technology, Hebei Agricultural University, Baoding, 071001, China
- Hebei Key Laboratory of Analysis and Control of Zoonotic Pathogenic Microorganism, Baoding, 071100, China
| | - Iliana E Medina-Ramirez
- Department of Chemistry, Universidad Autónoma de Aguascalientes, Av Universidad 940, Aguascalientes, Aguascalientes, México
| | - Gaoxing Su
- School of Pharmacy, Nantong University, Nantong, 226001, China
| | - Yin Liu
- School of Environment, Hangzhou Institute for Advanced Study, UCAS, Hangzhou, 10024, China
| | - Bing Yan
- Institute of Environmental Research at the Greater Bay Area, Key Laboratory for Water Quality and Conservation of the Pearl River Delta, Ministry of Education, Guangzhou University, Guangzhou, 510006, China
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Nesci S, Rubattu S. UCP2, a Member of the Mitochondrial Uncoupling Proteins: An Overview from Physiological to Pathological Roles. Biomedicines 2024; 12:1307. [PMID: 38927514 PMCID: PMC11201685 DOI: 10.3390/biomedicines12061307] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2024] [Revised: 06/07/2024] [Accepted: 06/10/2024] [Indexed: 06/28/2024] Open
Abstract
UCP2 is an uncoupling protein homolog to UCP1. Unlike UCP1, which participates in non-shivering thermogenesis by uncoupling oxidative phosphorylation (OXPHOS), UCP2 does not perform a canonical H+ leak, consuming the protonmotive force (Δp) through the inner mitochondrial membrane. The UCP2 biological role is elusive. It can counteract oxidative stress, acting with a "mild uncoupling" process to reduce ROS production, and, in fact, UCP2 activities are related to inflammatory processes, triggering pathological conditions. However, the Δp dissipation by UCP2 activity reduces the mitochondrial ATP production and rewires the bioenergetic metabolism of the cells. In all likelihood, UCP2 works as a carrier of metabolites with four carbon atoms (C4), reversing the anaerobic glycolysis-dependent catabolism to OXPHOS. Indeed, UCP2 can perform catalysis in dual mode: mild uncoupling of OXPHOS and metabolite C4 exchange of mitochondria. In vivo, the UCP2 features in the biology of mitochondria promote healthy ageing, increased lifespan, and can assure cerebro- and cardiovascular protection. However, the pathological conditions responsible for insulin secretion suppression are dependent on UCP2 activity. On balance, the uncertain biochemical mechanisms dependent on UCP2 do not allow us to depict the protective role in mitochondrial bioenergetics.
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Affiliation(s)
- Salvatore Nesci
- Department of Veterinary Medical Sciences, Alma Mater Studiorum University of Bologna, 40064 Ozzano Emilia, Italy;
| | - Speranza Rubattu
- Department of Clinical and Molecular Medicine, School of Medicine and Psychology, “Sapienza” University of Rome, 00189 Rome, Italy
- IRCCS Neuromed, 86077 Pozzilli, Italy
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Sánchez-Pérez P, Mata A, Torp MK, López-Bernardo E, Heiestad CM, Aronsen JM, Molina-Iracheta A, Jiménez-Borreguero LJ, García-Roves P, Costa ASH, Frezza C, Murphy MP, Stenslokken KO, Cadenas S. Energy substrate metabolism, mitochondrial structure and oxidative stress after cardiac ischemia-reperfusion in mice lacking UCP3. Free Radic Biol Med 2023; 205:244-261. [PMID: 37295539 DOI: 10.1016/j.freeradbiomed.2023.05.014] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2023] [Revised: 04/22/2023] [Accepted: 05/15/2023] [Indexed: 06/12/2023]
Abstract
Myocardial ischemia-reperfusion (IR) injury may result in cardiomyocyte dysfunction. Mitochondria play a critical role in cardiomyocyte recovery after IR injury. The mitochondrial uncoupling protein 3 (UCP3) has been proposed to reduce mitochondrial reactive oxygen species (ROS) production and to facilitate fatty acid oxidation. As both mechanisms might be protective following IR injury, we investigated functional, mitochondrial structural, and metabolic cardiac remodeling in wild-type mice and in mice lacking UCP3 (UCP3-KO) after IR. Results showed that infarct size in isolated perfused hearts subjected to IR ex vivo was larger in adult and old UCP3-KO mice than in equivalent wild-type mice, and was accompanied by higher levels of creatine kinase in the effluent and by more pronounced mitochondrial structural changes. The greater myocardial damage in UCP3-KO hearts was confirmed in vivo after coronary artery occlusion followed by reperfusion. S1QEL, a suppressor of superoxide generation from site IQ in complex I, limited infarct size in UCP3-KO hearts, pointing to exacerbated superoxide production as a possible cause of the damage. Metabolomics analysis of isolated perfused hearts confirmed the reported accumulation of succinate, xanthine and hypoxanthine during ischemia, and a shift to anaerobic glucose utilization, which all recovered upon reoxygenation. The metabolic response to ischemia and IR was similar in UCP3-KO and wild-type hearts, being lipid and energy metabolism the most affected pathways. Fatty acid oxidation and complex I (but not complex II) activity were equally impaired after IR. Overall, our results indicate that UCP3 deficiency promotes enhanced superoxide generation and mitochondrial structural changes that increase the vulnerability of the myocardium to IR injury.
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Affiliation(s)
- Patricia Sánchez-Pérez
- Centro de Biología Molecular "Severo Ochoa" (CSIC/UAM), 28049, Madrid, Spain; Instituto de Investigación Sanitaria Princesa (IIS-IP), 28006, Madrid, Spain
| | - Ana Mata
- Centro de Biología Molecular "Severo Ochoa" (CSIC/UAM), 28049, Madrid, Spain; Instituto de Investigación Sanitaria Princesa (IIS-IP), 28006, Madrid, Spain
| | - May-Kristin Torp
- Centro de Biología Molecular "Severo Ochoa" (CSIC/UAM), 28049, Madrid, Spain; Department of Molecular Medicine, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, PB1110, N-0317, Oslo, Norway
| | - Elia López-Bernardo
- Centro de Biología Molecular "Severo Ochoa" (CSIC/UAM), 28049, Madrid, Spain; Instituto de Investigación Sanitaria Princesa (IIS-IP), 28006, Madrid, Spain
| | - Christina M Heiestad
- Department of Molecular Medicine, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, PB1110, N-0317, Oslo, Norway
| | - Jan Magnus Aronsen
- Department of Molecular Medicine, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, PB1110, N-0317, Oslo, Norway; Bjørknes College, 0456, Oslo, Norway
| | | | - Luis J Jiménez-Borreguero
- Instituto de Investigación Sanitaria Princesa (IIS-IP), 28006, Madrid, Spain; Servicio de Cardiología, Hospital Universitario de La Princesa, 28006, Madrid, Spain; Centro de Investigación Biomédica en Red Enfermedades Cardiovasculares (CIBERCV), Instituto de Salud Carlos III, 28029, Madrid, Spain
| | - Pablo García-Roves
- Department of Physiological Sciences, Universitat de Barcelona, 08907, Barcelona, Spain; Nutrition, Metabolism and Gene Therapy Group, Diabetes and Metabolism Program, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Barcelona, Spain; Centro de Investigación Biomédica en Red Fisiopatología de la Obesidad y la Nutrición (CIBEROBN), Instituto de Salud Carlos III, 28029, Madrid, Spain
| | - Ana S H Costa
- MRC Cancer Unit, University of Cambridge, Hutchison/MRC Research Center, Cambridge Biomedical Campus, Cambridge, CB2 0XZ, UK
| | - Christian Frezza
- MRC Cancer Unit, University of Cambridge, Hutchison/MRC Research Center, Cambridge Biomedical Campus, Cambridge, CB2 0XZ, UK
| | - Michael P Murphy
- MRC Mitochondrial Biology Unit, University of Cambridge, Wellcome Trust/MRC Building, Cambridge, CB2 0XY, UK
| | - Kåre-Olav Stenslokken
- Department of Molecular Medicine, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, PB1110, N-0317, Oslo, Norway
| | - Susana Cadenas
- Centro de Biología Molecular "Severo Ochoa" (CSIC/UAM), 28049, Madrid, Spain; Instituto de Investigación Sanitaria Princesa (IIS-IP), 28006, Madrid, Spain.
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Potter LA, Toro CA, Harlow L, Lavin KM, Cardozo CP, Wende AR, Graham ZA. Assessing the impact of boldine on the gastrocnemius using multiomics profiling at 7 and 28 days post-complete spinal cord injury in young male mice. Physiol Genomics 2023; 55:297-313. [PMID: 37125768 PMCID: PMC10292965 DOI: 10.1152/physiolgenomics.00129.2022] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2022] [Revised: 04/13/2023] [Accepted: 04/24/2023] [Indexed: 05/02/2023] Open
Abstract
Spinal cord injury (SCI) results in rapid muscle loss. Exogenous molecular interventions to slow muscle atrophy after SCI have been relatively ineffective and require the search for novel therapeutic targets. Connexin hemichannels (CxHCs) allow nonselective passage of small molecules into and out of the cell. Boldine, a CxHC-inhibiting aporphine found in the boldo tree (Peumus boldus), has shown promising preclinical results in slowing atrophy during sepsis and restoring muscle function in dysferlinopathy. We administered 50 mg/kg/day of boldine to spinal cord transected mice beginning 3 days post-injury. Tissue was collected 7 and 28 days post-SCI and the gastrocnemius was used for multiomics profiling. Boldine did not prevent body or muscle mass loss but attenuated SCI-induced changes in the abundance of the amino acids proline, phenylalanine, leucine and isoleucine, as well as glucose, 7 days post-SCI. SCI resulted in the differential expression of ∼7,700 and ∼2,000 genes at 7 and 28 days, respectively, compared with Sham controls. Pathway enrichment of these genes highlighted ribosome biogenesis at 7 days and translation and oxidative phosphorylation at both timepoints. Boldine altered the expression of ∼150 genes at 7 days and ∼110 genes at 28 days post-SCI. Pathway enrichment of these genes indicated a potential role for boldine in suppressing protein ubiquitination and degradation at the 7-day timepoint. Methylation analyses showed minimal differences between groups. Taken together, boldine is not an efficacious therapy to preserve body and muscle mass after complete SCI, though it attenuated some SCI-induced changes across the metabolome and transcriptome.NEW & NOTEWORTHY This is the first study to describe the multiome of skeletal muscle paralyzed by a spinal cord injury (SCI) in mice across the acute and subacute timeframe after injury. We show large-scale changes in the metabolome and transcriptome at 7 days post-injury compared with 28 days. Furthermore, we show that the alkaloid boldine was able to prevent SCI-induced changes in muscle glucose and free amino acid levels at 7 days, but not 28 days, after SCI.
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Affiliation(s)
- Luke A Potter
- Division of Molecular and Cellular Pathology, Department of Pathology, The University of Alabama at Birmingham, Birmingham, Alabama, United States
| | - Carlos A Toro
- Spinal Cord Damage Research Center, Bronx, New York, United States
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, United States
| | - Lauren Harlow
- Spinal Cord Damage Research Center, Bronx, New York, United States
| | - Kaleen M Lavin
- Healthspan, Resilience & Performance, Florida Institute for Human and Machine Cognition, Pensacola, Florida, United States
| | - Christopher P Cardozo
- Spinal Cord Damage Research Center, Bronx, New York, United States
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, United States
- Medical Service, James J. Peters Veterans Affairs Medical Center, Bronx, New York, United States
| | - Adam R Wende
- Division of Molecular and Cellular Pathology, Department of Pathology, The University of Alabama at Birmingham, Birmingham, Alabama, United States
| | - Zachary A Graham
- Healthspan, Resilience & Performance, Florida Institute for Human and Machine Cognition, Pensacola, Florida, United States
- Research Service, Birmingham Veterans Affairs Health Care System, Birmingham, Alabama, United States
- Department of Cell, Developmental, and Integrative Biology, The University of Alabama at Birmingham, Birmingham, Alabama, United States
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Denzer ML, Pfeiffer M, Mafi GG, Ramanathan R. Metabolomics and bioinformatic analyses to determine the effects of oxygen exposure within longissimus lumborum steak on beef discoloration. J Anim Sci 2023; 101:skad155. [PMID: 37184234 PMCID: PMC10294556 DOI: 10.1093/jas/skad155] [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: 03/08/2023] [Accepted: 05/10/2023] [Indexed: 05/16/2023] Open
Abstract
Meat discoloration starts from the interior and spreads to oxymyoglobin layer on the surface. The effects of oxygen exposure within a steak on the metabolome have not been evaluated. Therefore, the objective of this study was to evaluate the impact of oxygen exposure on the metabolome of the longissimus lumborum muscle. Six United States Department of Agriculture (USDA) Low Choice beef strip loins were sliced into steaks (1.91-cm) and packaged in polyvinyl chloride overwrap trays for 3 or 6 d of retail display. The oxygen exposed (OE) surface was the display surface during retail, and the non-oxygen exposed (NOE) surface was the intact interior muscle. The instrumental color was evaluated using a HunterLab MiniScan spectrophotometer. To analyze the NOE surface on days 3 and 6, steaks were sliced parallel to the OE surface to expose the NOE surface. Metmyoglobin reducing ability (MRA) was determined by nitrite-induced metmyoglobin reduction. A gas chromatography-mass spectrometry was used to identify metabolites. The a* values of steaks decreased (P < 0.05) with display time. MRA was greater (P < 0.05) in the NOE surface compared with the OE surface on days 3 and 6. The KEGG pathway analysis indicated the tricarboxylic acid (TCA) cycle, pentose and glucuronate interconversions, phenylalanine, tyrosine, and tryptophan metabolism were influenced by the oxygen exposure. The decrease in abundance of succinate from days 0 to 6 during retail display aligned with a decline in redness during display. Furthermore, citric acid and gluconic acid were indicated as important metabolites affected by oxygen exposure and retail display based on the variable importance in the projection in the PLS-DA plot. Citric acid was lower in the NOE surface than the OE surface on day 6 of retail display, which could relate to the formation of succinate for extended oxidative stability. Greater alpha-tocopherol (P < 0.05) in the NOE surface supported less oxidative changes compared to the OE surface during retail display. These results indicate the presence of oxygen can influence metabolite profile and promote migration of the metmyoglobin layer from interior to surface.
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Affiliation(s)
- Morgan L Denzer
- Department of Animal Sciences, Oklahoma State University, Stillwater, OK 74078, USA
| | - Morgan Pfeiffer
- Department of Animal Sciences, Oklahoma State University, Stillwater, OK 74078, USA
| | - Gretchen G Mafi
- Department of Animal Sciences, Oklahoma State University, Stillwater, OK 74078, USA
| | - Ranjith Ramanathan
- Department of Animal Sciences, Oklahoma State University, Stillwater, OK 74078, USA
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Kalantarzadeh E, Radahmadi M, Reisi P. The impact of different dark chocolate dietary patterns on synaptic potency and plasticity in the hippocampal CA1 area of the rats under chronic isolation stress. Nutr Neurosci 2022:1-10. [PMID: 35715981 DOI: 10.1080/1028415x.2022.2088946] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
INTRODUCTION Although, stress causes brain dysfunction, consumption of dark chocolate (DC) has positive effects on brain functions. The current study investigated the impact of different DC dietary patterns on synaptic potency and plasticity in the hippocampal CA1 area, as well as food intake and body weight in rats under chronic isolation stress. METHODS Thirty-five rats were allocated into five groups of control, stress, and stress accompanied by three DC dietary patterns (stress-compulsory, -optional, and -restricted DC). The stressed rats on a compulsory diet only received DC and the ones on an optional diet received unlimited chow and/or DC. Also, the stressed rats on a restricted diet each received chow freely and only 4 g DC daily. Subsequently, the slope and amplitude of field excitatory postsynaptic potentials (fEPSPs) were assessed based on the Input-Output (I/O) curves and after the longterm potentiation (LTP). Moreover, food intake and body weight were measured for all groups. RESULTS The fEPSP slope and amplitude in the I/O curves and after LTP decreased significantly in the stress group compared to the control group. Although the slope and amplitude both enhanced non-significantly in the optional DC diet, these parameters changed significantly in both compulsory and restricted DC dietary patterns compared to the stress group. Also, food intake and body weight decreased significantly in all DC groups. CONCLUSION The compulsory and restricted DC dietary patterns reversed the harmful effects of chronic isolation stress on the hippocampal synaptic potency, plasticity, learning, and memory. All DC diets, especially compulsory and restricted ones, reduced food intake and body weight.
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Affiliation(s)
- Elham Kalantarzadeh
- Department of Physiology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Maryam Radahmadi
- Department of Physiology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Parham Reisi
- Department of Physiology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
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Graham ZA, DeBerry JJ, Cardozo CP, Bamman MM. SS-31 does not prevent or reduce muscle atrophy 7 days after a 65 kdyne contusion spinal cord injury in young male mice. Physiol Rep 2022; 10:e15266. [PMID: 35611788 PMCID: PMC9131615 DOI: 10.14814/phy2.15266] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Revised: 01/22/2022] [Accepted: 01/25/2022] [Indexed: 05/02/2023] Open
Abstract
Spinal cord injury (SCI) leads to major reductions in function, independent living, and quality of life. Disuse and paralysis from SCI leads to rapid muscle atrophy, with chronic muscle loss likely playing a role in the development of the secondary metabolic disorders often seen in those with SCI. Muscle disuse is associated with mitochondrial dysfunction. Previous evidence has suggested targeting the mitochondria with the tetrapeptide SS-31 is beneficial for muscle health in preclinical models that lead to mitochondrial dysfunction, such as cast immobilization or burn injury. We gave young male mice a sham (n = 8) or 65 kdyne thoracic contusion SCI with (n = 9) or without (n = 9) daily administration of 5.0 mg/kg SS-31. Hindlimb muscle mass and muscle bundle respiration were measured at 7 days post-SCI and molecular targets were investigated using immunoblotting, RT-qPCR, and metabolomics. SS-31 did not preserve body mass or hindlimb muscle mass 7 days post-SCI. SS-31 had no effect on soleus or plantaris muscle bundle respiration. SCI was associated with elevated levels of protein carbonylation, led to reduced protein expression of activated DRP1 and reductions in markers of mitochondrial fusion. SS-31 administration did result in reduced total DRP1 expression, as well as greater expression of inhibited DRP1. Gene expression of proinflammatory cytokines and their receptors were largely stable across groups, although SS-31 treatment led to greater mRNA expression of IL1B, TNF, and TNFRSF12A. In summation, SS-31 was not an efficacious treatment acutely after a moderate thoracic contusion SCI in young male mice.
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Affiliation(s)
- Zachary A. Graham
- Research ServiceBirmingham VA Medical CenterBirminghamAlabamaUSA
- Department of Cell, Developmental, and Integrative BiologyUABBirminghamAlabamaUSA
| | - Jennifer J. DeBerry
- Department of Anesthesiology and Perioperative MedicineUABBirminghamAlabamaUSA
| | - Christopher P. Cardozo
- Center for the Medical Consequences of Spinal Cord InjuryBronxNew YorkUSA
- Medical ServiceJames J. Peters VA Medical CenterBronxNew YorkUSA
- Icahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
| | - Marcas M. Bamman
- Research ServiceBirmingham VA Medical CenterBirminghamAlabamaUSA
- Department of Cell, Developmental, and Integrative BiologyUABBirminghamAlabamaUSA
- UAB Center for Exercise MedicineBirminghamAlabamaUSA
- Florida Institute for Human and Machine CognitionPensacolaFloridaUSA
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Hoene M, Kappler L, Kollipara L, Hu C, Irmler M, Bleher D, Hoffmann C, Beckers J, Hrabě de Angelis M, Häring HU, Birkenfeld AL, Peter A, Sickmann A, Xu G, Lehmann R, Weigert C. Exercise prevents fatty liver by modifying the compensatory response of mitochondrial metabolism to excess substrate availability. Mol Metab 2021; 54:101359. [PMID: 34695608 PMCID: PMC8671118 DOI: 10.1016/j.molmet.2021.101359] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Revised: 10/07/2021] [Accepted: 10/15/2021] [Indexed: 02/06/2023] Open
Abstract
Objective Liver mitochondria adapt to high-calorie intake. We investigated how exercise alters the early compensatory response of mitochondria, thus preventing fatty liver disease as a long-term consequence of overnutrition. Methods We compared the effects of a steatogenic high-energy diet (HED) for six weeks on mitochondrial metabolism of sedentary and treadmill-trained C57BL/6N mice. We applied multi-OMICs analyses to study the alterations in the proteome, transcriptome, and lipids in isolated mitochondria of liver and skeletal muscle as well as in whole tissue and examined the functional consequences by high-resolution respirometry. Results HED increased the respiratory capacity of isolated liver mitochondria, both in sedentary and in trained mice. However, proteomics analysis of the mitochondria and transcriptomics indicated that training modified the adaptation of the hepatic metabolism to HED on the level of respiratory complex I, glucose oxidation, pyruvate and acetyl-CoA metabolism, and lipogenesis. Training also counteracted the HED-induced glucose intolerance, the increase in fasting insulin, and in liver fat by lowering diacylglycerol species and c-Jun N-terminal kinase (JNK) phosphorylation in the livers of trained HED-fed mice, two mechanisms that can reverse hepatic insulin resistance. In skeletal muscle, the combination of HED and training improved the oxidative capacity to a greater extent than training alone by increasing respiration of isolated mitochondria and total mitochondrial protein content. Conclusion We provide a comprehensive insight into the early adaptations of mitochondria in the liver and skeletal muscle to HED and endurance training. Our results suggest that exercise disconnects the HED-induced increase in mitochondrial substrate oxidation from pyruvate and acetyl-CoA-driven lipid synthesis. This could contribute to the prevention of deleterious long-term effects of high fat and sugar intake on hepatic mitochondrial function and insulin sensitivity.
High-energy diet promotes mitochondrial respiration in liver independent of training. High-energy diet combined with training disconnects substrate oxidation from lipid synthesis. High-energy diet combined with training reduces complex I formation in the liver. Trained skeletal muscle unburdens the liver from substrate overload. Comprehensive resource of mitochondrial adaptations to high-energy diet and training.
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Affiliation(s)
- Miriam Hoene
- Institute for Clinical Chemistry and Pathobiochemistry, Department for Diagnostic Laboratory Medicine, University Hospital Tuebingen, Tuebingen, Germany
| | - Lisa Kappler
- Institute for Clinical Chemistry and Pathobiochemistry, Department for Diagnostic Laboratory Medicine, University Hospital Tuebingen, Tuebingen, Germany
| | - Laxmikanth Kollipara
- Leibniz-Institut für Analytische Wissenschaften - ISAS - e.V., Dortmund, Germany
| | - Chunxiu Hu
- CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China
| | - Martin Irmler
- Helmholtz Center Munich, German Research Center for Environmental Health (GmbH), 85764, Neuherberg, Germany
| | - Daniel Bleher
- Institute for Clinical Chemistry and Pathobiochemistry, Department for Diagnostic Laboratory Medicine, University Hospital Tuebingen, Tuebingen, Germany
| | - Christoph Hoffmann
- Institute for Clinical Chemistry and Pathobiochemistry, Department for Diagnostic Laboratory Medicine, University Hospital Tuebingen, Tuebingen, Germany
| | - Johannes Beckers
- Helmholtz Center Munich, German Research Center for Environmental Health (GmbH), 85764, Neuherberg, Germany; Technische Universität München, Chair of Experimental Genetics, 85354, Freising, Germany; German Center for Diabetes Research (DZD), Germany
| | - Martin Hrabě de Angelis
- Helmholtz Center Munich, German Research Center for Environmental Health (GmbH), 85764, Neuherberg, Germany; Technische Universität München, Chair of Experimental Genetics, 85354, Freising, Germany; German Center for Diabetes Research (DZD), Germany
| | - Hans-Ulrich Häring
- German Center for Diabetes Research (DZD), Germany; Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tuebingen, Tuebingen, Germany
| | - Andreas L Birkenfeld
- German Center for Diabetes Research (DZD), Germany; Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tuebingen, Tuebingen, Germany; Department of Internal Medicine IV, University Hospital Tuebingen, Tuebingen, Germany
| | - Andreas Peter
- Institute for Clinical Chemistry and Pathobiochemistry, Department for Diagnostic Laboratory Medicine, University Hospital Tuebingen, Tuebingen, Germany; German Center for Diabetes Research (DZD), Germany; Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tuebingen, Tuebingen, Germany
| | - Albert Sickmann
- Leibniz-Institut für Analytische Wissenschaften - ISAS - e.V., Dortmund, Germany; Medizinische Fakultät, Medizinische Proteom-Center (MPC), Ruhr-Universität Bochum, Bochum, Germany; Department of Chemistry, College of Physical Sciences, University of Aberdeen, Aberdeen, Scotland, United Kingdom
| | - Guowang Xu
- CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China
| | - Rainer Lehmann
- Institute for Clinical Chemistry and Pathobiochemistry, Department for Diagnostic Laboratory Medicine, University Hospital Tuebingen, Tuebingen, Germany; German Center for Diabetes Research (DZD), Germany; Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tuebingen, Tuebingen, Germany
| | - Cora Weigert
- Institute for Clinical Chemistry and Pathobiochemistry, Department for Diagnostic Laboratory Medicine, University Hospital Tuebingen, Tuebingen, Germany; German Center for Diabetes Research (DZD), Germany; Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tuebingen, Tuebingen, Germany.
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10
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Nicholls DG. Mitochondrial proton leaks and uncoupling proteins. BIOCHIMICA ET BIOPHYSICA ACTA-BIOENERGETICS 2021; 1862:148428. [PMID: 33798544 DOI: 10.1016/j.bbabio.2021.148428] [Citation(s) in RCA: 76] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Revised: 03/15/2021] [Accepted: 03/25/2021] [Indexed: 01/02/2023]
Abstract
Non-shivering thermogenesis in brown adipose tissue is mediated by uncoupling protein 1 (UCP1), which provides a carefully regulated proton re-entry pathway across the mitochondrial inner membrane operating in parallel to the ATP synthase and allowing respiration, and hence thermogenesis, to be released from the constraints of respiratory control. In the 40 years since UCP1 was first described, an extensive, and frequently contradictory, literature has accumulated, focused on the acute physiological regulation of the protein by fatty acids, purine nucleotides and possible additional factors. The purpose of this review is to examine, in detail, the experimental evidence underlying these proposed mechanisms. Emphasis will be placed on the methodologies employed and their relation to the physiological constraints under which the protein functions in the intact cell. The nature of the endogenous, UCP1-independent, proton leak will also be discussed. Finally, the troubled history of the putative novel uncoupling proteins, UCP2 and UCP3, will be evaluated.
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11
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Yuan Y, Xu P, Jiang Q, Cai X, Wang T, Peng W, Sun J, Zhu C, Zhang C, Yue D, He Z, Yang J, Zeng Y, Du M, Zhang F, Ibrahimi L, Schaul S, Jiang Y, Wang J, Sun J, Wang Q, Liu L, Wang S, Wang L, Zhu X, Gao P, Xi Q, Yin C, Li F, Xu G, Zhang Y, Shu G. Exercise-induced α-ketoglutaric acid stimulates muscle hypertrophy and fat loss through OXGR1-dependent adrenal activation. EMBO J 2020; 39:e103304. [PMID: 32104923 PMCID: PMC7110140 DOI: 10.15252/embj.2019103304] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2019] [Revised: 01/25/2020] [Accepted: 01/28/2020] [Indexed: 12/24/2022] Open
Abstract
Beneficial effects of resistance exercise on metabolic health and particularly muscle hypertrophy and fat loss are well established, but the underlying chemical and physiological mechanisms are not fully understood. Here, we identified a myometabolite‐mediated metabolic pathway that is essential for the beneficial metabolic effects of resistance exercise in mice. We showed that substantial accumulation of the tricarboxylic acid cycle intermediate α‐ketoglutaric acid (AKG) is a metabolic signature of resistance exercise performance. Interestingly, human plasma AKG level is also negatively correlated with BMI. Pharmacological elevation of circulating AKG induces muscle hypertrophy, brown adipose tissue (BAT) thermogenesis, and white adipose tissue (WAT) lipolysis in vivo. We further found that AKG stimulates the adrenal release of adrenaline through 2‐oxoglutarate receptor 1 (OXGR1) expressed in adrenal glands. Finally, by using both loss‐of‐function and gain‐of‐function mouse models, we showed that OXGR1 is essential for AKG‐mediated exercise‐induced beneficial metabolic effects. These findings reveal an unappreciated mechanism for the salutary effects of resistance exercise, using AKG as a systemically derived molecule for adrenal stimulation of muscle hypertrophy and fat loss.
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Affiliation(s)
- Yexian Yuan
- Guangdong Laboratory of Lingnan Modern Agriculture, Guangdong Province Key Laboratory of Animal Nutritional Regulation and National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, China
| | - Pingwen Xu
- Division of Endocrinology, Department of Medicine, The University of Illinois at Chicago, Chicago, IL, USA
| | - Qingyan Jiang
- Guangdong Laboratory of Lingnan Modern Agriculture, Guangdong Province Key Laboratory of Animal Nutritional Regulation and National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, China
| | - Xingcai Cai
- Guangdong Laboratory of Lingnan Modern Agriculture, Guangdong Province Key Laboratory of Animal Nutritional Regulation and National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, China
| | - Tao Wang
- Guangdong Laboratory of Lingnan Modern Agriculture, Guangdong Province Key Laboratory of Animal Nutritional Regulation and National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, China
| | - Wentong Peng
- Guangdong Laboratory of Lingnan Modern Agriculture, Guangdong Province Key Laboratory of Animal Nutritional Regulation and National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, China
| | - Jiajie Sun
- Guangdong Laboratory of Lingnan Modern Agriculture, Guangdong Province Key Laboratory of Animal Nutritional Regulation and National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, China
| | - Canjun Zhu
- Guangdong Laboratory of Lingnan Modern Agriculture, Guangdong Province Key Laboratory of Animal Nutritional Regulation and National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, China
| | - Cha Zhang
- Guangdong Laboratory of Lingnan Modern Agriculture, Guangdong Province Key Laboratory of Animal Nutritional Regulation and National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, China
| | - Dong Yue
- Guangdong Laboratory of Lingnan Modern Agriculture, Guangdong Province Key Laboratory of Animal Nutritional Regulation and National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, China
| | - Zhihui He
- Guangdong Laboratory of Lingnan Modern Agriculture, Guangdong Province Key Laboratory of Animal Nutritional Regulation and National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, China
| | - Jinping Yang
- Guangdong Laboratory of Lingnan Modern Agriculture, Guangdong Province Key Laboratory of Animal Nutritional Regulation and National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, China
| | - Yuxian Zeng
- Guangdong Laboratory of Lingnan Modern Agriculture, Guangdong Province Key Laboratory of Animal Nutritional Regulation and National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, China
| | - Man Du
- Guangdong Laboratory of Lingnan Modern Agriculture, Guangdong Province Key Laboratory of Animal Nutritional Regulation and National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, China
| | - Fenglin Zhang
- Guangdong Laboratory of Lingnan Modern Agriculture, Guangdong Province Key Laboratory of Animal Nutritional Regulation and National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, China
| | - Lucas Ibrahimi
- Division of Endocrinology, Department of Medicine, The University of Illinois at Chicago, Chicago, IL, USA
| | - Sarah Schaul
- Division of Endocrinology, Department of Medicine, The University of Illinois at Chicago, Chicago, IL, USA
| | - Yuwei Jiang
- Department of Physiology and Biophysics, The University of Illinois at Chicago, Chicago, IL, USA
| | - Jiqiu Wang
- Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jia Sun
- Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Qiaoping Wang
- School of Pharmaceutical Sciences (Shenzhen), Sun Yat-Sen University Guangzhou, Guangzhou, China
| | - Liming Liu
- State Key Laboratory of Food Science and Technology and Key Laboratory of Industrial Biotechnology, Ministry of Education, Jiangnan University, Wuxi, China
| | - Songbo Wang
- Guangdong Laboratory of Lingnan Modern Agriculture, Guangdong Province Key Laboratory of Animal Nutritional Regulation and National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, China
| | - Lina Wang
- Guangdong Laboratory of Lingnan Modern Agriculture, Guangdong Province Key Laboratory of Animal Nutritional Regulation and National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, China
| | - Xiaotong Zhu
- Guangdong Laboratory of Lingnan Modern Agriculture, Guangdong Province Key Laboratory of Animal Nutritional Regulation and National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, China
| | - Ping Gao
- Guangdong Laboratory of Lingnan Modern Agriculture, Guangdong Province Key Laboratory of Animal Nutritional Regulation and National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, China
| | - Qianyun Xi
- Guangdong Laboratory of Lingnan Modern Agriculture, Guangdong Province Key Laboratory of Animal Nutritional Regulation and National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, China
| | - Cong Yin
- Guangdong Laboratory of Lingnan Modern Agriculture, Guangdong Province Key Laboratory of Animal Nutritional Regulation and National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, China
| | - Fan Li
- Guangdong Laboratory of Lingnan Modern Agriculture, Guangdong Province Key Laboratory of Animal Nutritional Regulation and National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, China
| | - Guli Xu
- Guangdong Laboratory of Lingnan Modern Agriculture, Guangdong Province Key Laboratory of Animal Nutritional Regulation and National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, China
| | - Yongliang Zhang
- Guangdong Laboratory of Lingnan Modern Agriculture, Guangdong Province Key Laboratory of Animal Nutritional Regulation and National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, China
| | - Gang Shu
- Guangdong Laboratory of Lingnan Modern Agriculture, Guangdong Province Key Laboratory of Animal Nutritional Regulation and National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, China
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12
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Graham ZA, Siedlik JA, Harlow L, Sahbani K, Bauman WA, Tawfeek HA, Cardozo CP. Key Glycolytic Metabolites in Paralyzed Skeletal Muscle Are Altered Seven Days after Spinal Cord Injury in Mice. J Neurotrauma 2019; 36:2722-2731. [PMID: 30869558 DOI: 10.1089/neu.2018.6144] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023] Open
Abstract
Spinal cord injury (SCI) results in rapid muscle atrophy and an oxidative-to-glycolytic fiber-type shift. Those with chronic SCI are more at risk for developing insulin resistance and reductions in glucose clearance than able-bodied individuals, but how glucose metabolism is affected after SCI is not well known. An untargeted metabolomics approach was utilized to investigate changes in whole-muscle metabolites at an acute (7-day) and subacute (28-day) time frame after a complete T9 spinal cord transection in 20-week-old female C57BL/6 mice. Two hundred one metabolites were detected in all samples, and 83 had BinBase IDs. A principal components analysis showed the 7-day group as a unique cluster. Further, 36 metabolites were altered after 7- and/or 28-day post-SCI (p values <0.05), with 12 passing further false discovery rate exclusion criteria; of those 12 metabolites, three important glycolytic molecules-glucose and downstream metabolites pyruvic acid and lactic acid-were reduced at 7 days compared to those values in sham and/or 28-day animals. These changes were associated with altered expression of proteins associated with glycolysis, as well as monocarboxylate transporter 4 gene expression. Taken together, our data suggest an acute disruption of skeletal muscle glucose uptake at 7 days post-SCI, which leads to reduced pyruvate and lactate levels. These levels recover by 28 days post-SCI, but a reduction in pyruvate dehydrogenase protein expression at 28 days post-SCI implies disruption in downstream oxidation of glucose.
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Affiliation(s)
- Zachary A Graham
- National Center for the Medical Consequences of Spinal Cord Injury, James J. Peters VA Medical Center, Bronx, New York.,Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York
| | | | - Lauren Harlow
- National Center for the Medical Consequences of Spinal Cord Injury, James J. Peters VA Medical Center, Bronx, New York
| | - Karim Sahbani
- National Center for the Medical Consequences of Spinal Cord Injury, James J. Peters VA Medical Center, Bronx, New York
| | - William A Bauman
- National Center for the Medical Consequences of Spinal Cord Injury, James J. Peters VA Medical Center, Bronx, New York.,Medical Service, James J. Peters VA Medical Center, Bronx, New York.,Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York.,Department of Rehabilitation Medicine and Human Performance, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Hesham A Tawfeek
- National Center for the Medical Consequences of Spinal Cord Injury, James J. Peters VA Medical Center, Bronx, New York.,Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Christopher P Cardozo
- National Center for the Medical Consequences of Spinal Cord Injury, James J. Peters VA Medical Center, Bronx, New York.,Medical Service, James J. Peters VA Medical Center, Bronx, New York.,Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York.,Department of Rehabilitation Medicine and Human Performance, Icahn School of Medicine at Mount Sinai, New York, New York
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13
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Mahapatra A, Sarkar S, Biswas SC, Chattopadhyay K. An aminoglycoside antibiotic inhibits both lipid-induced and solution-phase fibrillation of α-synuclein in vitro. Chem Commun (Camb) 2019; 55:11052-11055. [DOI: 10.1039/c9cc04251b] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
The aminoglycoside antibiotic kanamycin inhibits fibrillation of α-synuclein both in solution and in contact with lipid-membranes, forming amorphous/off-pathway aggregates instead.
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Affiliation(s)
- Anindita Mahapatra
- Structural Biology and Bio-informatics Division
- Indian Institute of Chemical Biology
- Kolkata-700032
- India
- Academy of Scientific and Innovative Research (AcSIR)
| | - Sukanya Sarkar
- Cell Biology and Physiology Division
- Indian Institute of Chemical Biology
- Kolkata-700032
- India
| | - Subhash Chandra Biswas
- Cell Biology and Physiology Division
- Indian Institute of Chemical Biology
- Kolkata-700032
- India
| | - Krishnananda Chattopadhyay
- Structural Biology and Bio-informatics Division
- Indian Institute of Chemical Biology
- Kolkata-700032
- India
- Academy of Scientific and Innovative Research (AcSIR)
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14
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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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15
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Macher G, Koehler M, Rupprecht A, Kreiter J, Hinterdorfer P, Pohl EE. Inhibition of mitochondrial UCP1 and UCP3 by purine nucleotides and phosphate. BIOCHIMICA ET BIOPHYSICA ACTA. BIOMEMBRANES 2018; 1860:664-672. [PMID: 29212043 PMCID: PMC6118327 DOI: 10.1016/j.bbamem.2017.12.001] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/30/2017] [Revised: 11/04/2017] [Accepted: 12/01/2017] [Indexed: 11/26/2022]
Abstract
Mitochondrial membrane uncoupling protein 3 (UCP3) is not only expressed in skeletal muscle and heart, but also in brown adipose tissue (BAT) alongside UCP1, which facilitates a proton leak to support non-shivering thermogenesis. In contrast to UCP1, the transport function and molecular mechanism of UCP3 regulation are poorly investigated, although it is generally agreed upon that UCP3, analogous to UCP1, transports protons, is activated by free fatty acids (FFAs) and is inhibited by purine nucleotides (PNs). Because the presence of two similar uncoupling proteins in BAT is surprising, we hypothesized that UCP1 and UCP3 are differently regulated, which may lead to differences in their functions. By combining atomic force microscopy and electrophysiological measurements of recombinant proteins reconstituted in planar bilayer membranes, we compared the level of protein activity with the bond lifetimes between UCPs and PNs. Our data revealed that, in contrast to UCP1, UCP3 can be fully inhibited by all PNs and IC50 increases with a decrease in PN-phosphorylation. Experiments with mutant proteins demonstrated that the conserved arginines in the PN-binding pocket are involved in the inhibition of UCP1 and UCP3 to different extents. Fatty acids compete with all PNs bound to UCP1, but only with ATP bound to UCP3. We identified phosphate as a novel inhibitor of UCP3 and UCP1, which acts independently of PNs. The differences in molecular mechanisms of the inhibition between the highly homologous transporters UCP1 and UCP3 indicate that UCP3 has adapted to fulfill a different role and possibly another transport function in BAT.
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Affiliation(s)
- Gabriel Macher
- Institute of Physiology, Pathophysiology and Biophysics, University of Veterinary Medicine, Vienna, Austria
| | - Melanie Koehler
- Institute of Biophysics, Johannes Kepler University, Linz, Austria
| | - Anne Rupprecht
- Institute of Physiology, Pathophysiology and Biophysics, University of Veterinary Medicine, Vienna, Austria
| | - Jürgen Kreiter
- Institute of Physiology, Pathophysiology and Biophysics, University of Veterinary Medicine, Vienna, Austria
| | | | - Elena E Pohl
- Institute of Physiology, Pathophysiology and Biophysics, University of Veterinary Medicine, Vienna, Austria.
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Bauerenol Acetate, the Pentacyclic Triterpenoid from Tabernaemontana longipes, is an Antitrypanosomal Agent. Molecules 2018; 23:molecules23020355. [PMID: 29419735 PMCID: PMC5911922 DOI: 10.3390/molecules23020355] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2017] [Revised: 02/02/2018] [Accepted: 02/06/2018] [Indexed: 01/11/2023] Open
Abstract
The Latin American plant Tabernaemontana longipes was studied in this work as a potential source of antiparasitic agents. The chloroform extract of T. longipes leaves was separated into several fractions, and tested for antitrypanosomal activity. One of the fractions displayed significant growth inhibitory activity against Trypanosoma brucei. The active principle in the fraction was isolated, purified, and characterized by NMR and mass spectrometry. The antitrypanosomal agent in the CHCl3 extract of T. longipes leaves is the pentacyclic triterpenoid bauerenol acetate. A metabolite profiling assay suggest that the triterpenoid influences cholesterol metabolism. The molecular target(s) of bauerenol and its acetate, like many other antiparasitic pentacyclic triterpenoids is/are unknown, but they present privileged structural scaffolds that can be explored for structure-based activity optimization studies using phenotypic assays.
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17
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Schofield Z, Reed MAC, Newsome PN, Adams DH, Günther UL, Lalor PF. Changes in human hepatic metabolism in steatosis and cirrhosis. World J Gastroenterol 2017; 23:2685-2695. [PMID: 28487605 PMCID: PMC5403747 DOI: 10.3748/wjg.v23.i15.2685] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2016] [Revised: 01/11/2017] [Accepted: 03/15/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To understand the underlying metabolic changes in human liver disease we have applied nuclear magnetic resonance (NMR) metabolomics analysis to human liver tissue.
METHODS We have carried out pilot study using 1H-NMR to derive metabolomic signatures from human liver from patients with steatosis, nonalcoholic steatohepatitis (NASH) or alcohol-related liver damage (ARLD) to identify species that can predict outcome and discriminate between alcohol and metabolic-induced liver injuries.
RESULTS Changes in branched chain amino acid homeostasis, tricarboxylic acid cycle and purine biosynthesis intermediates along with betaine were associated with the development of cirrhosis in both ARLD and nonalcoholic fatty liver disease. Species such as propylene glycol and as yet unidentified moieties that allowed discrimination between NASH and ARLD samples were also detected using our approach.
CONCLUSION Our high throughput, non-destructive technique for multiple analyte quantification in human liver specimens has potential for identification of biomarkers with prognostic and diagnostic significance.
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