Uncoupling Protein 2 Alleviates Myocardial Ischemia/Reperfusion Injury by Inhibiting Cardiomyocyte Ferroptosis.

INTRODUCTION: Following our recent finding that Ucp2 knockout promotes ferroptosis, we aimed to examine whether UCP2 alleviates myocardial ischemia/reperfusion injury (MI/RI) by inhibiting ferroptosis. METHODS: The left anterior descending coronary arteries of wild-type and Ucp2-/- C57BL/6 mice were ligated for 30 min and reperfused for 2 h to establish an MI/RI model. The effects of UCP2 on ferroptosis and MI/RI were determined by echocardiography, 2,3,5-triphenylttrazolium chloride staining, hematoxylin-eosin staining, Masson's trichrome staining, Sirius red staining, and analysis of myocardial injury markers and ferroptosis indicators. Ferrostatin-1 (Fer-1) and erastin (Era) were used to investigate whether UCP2 alleviated MI/RI by inhibiting ferroptosis and the molecular mechanism. RESULTS: UCP2 was upregulated in the MI/RI model in WT mice. Deletion of Ucp2 exacerbated ferroptosis, altered the expression levels of multiple ferroptosis-related genes, and significantly exacerbated MI/RI. Knockout of Ucp2 promoted ferroptosis induced by Era and inhibited the antiferroptotic effects of Fer-1. Knockout of Ucp2 activated the p53/TfR1 pathway to exacerbate ferroptosis. CONCLUSION: Our results showed that UCP2 inhibited ferroptosis in MI/RI, which might be related to regulation of the p53/TfR1 pathway.

UCP2 overexpression activates SIRT3 to regulate oxidative stress and mitochondrial dynamics induced by myocardial injury.

OBJECTIVE: Our previous study found that overexpression of uncoupling protein-2 (UCP2) had a protective effect on lipopolysaccharide (LPS)-induced sepsis cardiomyocytes. The aim of this study was to explore the effect and mechanism of uncoupling protein-2 (UCP2) on myocardial ischemia-reperfusion injury. METHODS: In this study, we established hypoxia-reoxygenation (HR) injury model in rats and isolated cardiomyocytes of newborn rats. We also carried out following methods which include virus transfection technology, cell counting Kit-8 (CCK8), flow cytometry, enzyme linked immunosorbent assay (ELISA), Western blot (WB), quantitative reverse transcription PCR (RT qPCR), transmission electron microscopy, fluorescence colocalization and immunoprecipitation. MAIN RESULTS: The results of this study showed that hypoxia-reoxygenation treatment in cardiomyocytes increased UCP2, myocardial enzyme and myocardial apoptosis and weakened cardiomyocyte viability. We observed increased cardiomyocyte viability and mitochondrial membrane potential, decreased myocardial enzyme and myocardial apoptosis, Inhibition of oxidative stress when UCP2 was overexpressed in cardiomyocytes. It also can Increase ATP and stabilize mitochondrial dynamics. Further studies founded that Sirtuin-3(SIRT3) changed with the expression of UCP2, which was confirmed by fluorescence co-localization and immunoprecipitation. CONCLUSIONS: Our findings revealed that UCP2 and SIRT3 were important targets of anti-myocardial injury by inhibiting cellular oxidative stress and stabilizing mitochondrial dynamics.

Oxaloacetic acid induces muscle energy substrate depletion and fatigue by JNK-mediated mitochondrial uncoupling.

Fatigue is a common phenomenon closely related to physical discomfort and numerous diseases, which is severely threatening the life quality and health of people. However, the exact mechanisms underlying fatigue are not fully characterized. Herein, we demonstrate that oxaloacetic acid (OAA), a crucial tricarboxylic acid cycle intermediate, modulates the muscle fatigue. The results showed that serum OAA level was positively correlated with fatigue state of mice. OAA-treated induced muscle fatigue impaired the exercise performance of mice. Mechanistically, OAA increased the c-Jun N-terminal kinase (JNK) phosphorylation and uncoupling protein 2 (UCP2) levels in skeletal muscle, which led to decreased energy substrate and enhanced glycolysis. On the other hand, OAA boosted muscle mitochondrial oxidative phosphorylation uncoupled with energy production. In addition, either UCP2 knockout or JNK inhibition totally reversed the effects of OAA on skeletal muscle. Therein, JNK mediated UCP2 activation with OAA-treated. Our studies reveal a novel role of OAA in skeletal muscle metabolism, which would shed light on the mechanism of muscle fatigue and weakness.

UCP2-SIRT3 Signaling Relieved Hyperglycemia-Induced Oxidative Stress and Senescence in Diabetic Retinopathy.

Purpose: Diabetic retinopathy (DR) is one of the most common reasons for blindness. uncoupling protein 2 (UCP2), an uncoupling protein located in mitochondria, has been reported to be related to metabolic and vascular diseases. This research aimed to illustrate the function and mechanism of UCP2 in the pathogenesis of DR. Methods: Human epiretinal membranes were collected to investigate the expression of UCP2 by quantitative real-time polymerase chain reaction (qRT-PCR) and immunofluorescence. Primary human retinal microvascular endothelial cells (HRECs) were cultured in high glucose (HG) to establish an in vitro cell model for DR. Flow cytometry analysis was used to measure intracellular reactive oxygen species (ROS). Senescence levels were evaluated by the senescence-associated beta-galactosidase (SA-ß-gal) assay, the expression of senescence marker P21, and cell-cycle analysis. Adenovirus-mediated UCP2 overexpression or knockdown and specific inhibitors were administered to investigate the underlying regulatory mechanism. Results: Proliferative fibrovascular membranes from patients with DR illustrated the downregulation of UCP2 and sirtuin 3 (SIRT3) by qRT-PCR and immunofluorescence. Persistent hyperglycemia-induced UCP2 downregulation in the progress of DR and adenovirus-mediated UCP2 overexpression protected endothelial cells from hyperglycemia-induced oxidative stress and senescence. Under hyperglycemic conditions, UCP2 overexpression attenuated NAD+ downregulation; hence, it promoted the expression and activity of SIRT3, an NAD+-dependent deacetylase regulating mitochondrial function. 3-TYP, a selective SIRT3 inhibitor, abolished the UCP2-mediated protective effect against oxidative stress and senescence. Conclusions: UCP2 overexpression relieved oxidative stress and senescence based on a novel mechanism whereby UCP2 can regulate the NAD+-SIRT3 axis. Targeting oxidative stress and senescence amelioration, UCP2-SIRT3 signaling may serve as a method for the prevention and treatment of DR and other diabetic vascular diseases.

UCP2 promotes NSCLC proliferation and glycolysis via the mTOR/HIF-1α signaling.

BACKGROUND: Metabolic disturbance is a hallmark of cancers. Targeting key metabolic pathways and metabolism-related molecular could be a potential therapeutic approach. Uncoupling protein 2 (UCP2) plays a pivotal part in the malignancy of cancer and its capacity to develop resistance to pharmaceutical interventions. However, it is unclear about the mechanism of how UCP2 acts in the tumor growth and metabolic reprogramming process in non-small cell lung cancer (NSCLC). METHODS: Here, we conducted qRT-PCR to investigate the expression of UCP2 in both NSCLC tissues and cell lines. Subsequent functional studies including colony formation assay, CCK-8 assay, and glycolysis assay were conducted to investigate the functions of UCP2 in NSCLC. The regulatory mechanism of UCP2 toward the mammalian target of rapamycin (mTOR) and hypoxia-inducible factor-1 alpha (HIF-1α) signaling in NSCLC was confirmed through western blotting. RESULTS: We observed a significant upregulation of UCP2 in both NSCLC tissues and cell lines. The increased expression of UCP2 has a strong association with a worse outlook. Silencing UCP2 remarkably dampened NSCLC cell proliferation and glycolysis capacities. Mechanically, UCP2 promoted NSCLC tumorigenesis partially via regulating the mTOR/HIF-1α axis. CONCLUSION: Taken together, we explored the functions as well as the mechanisms of the UCP2/mTOR/HIF-1α axis in NSCLC progression, uncovering potential biological signatures and targets for NSCLC treatment.

Targeting altered calcium homeostasis and uncoupling protein-2 promotes sensitivity in drug-resistant breast cancer cells.

Metastatic breast cancer has the highest mortality rate among women owing to its poor clinical outcomes. Metastatic tumors pose challenges for treatment through conventional surgery or radiotherapy because of their diverse organ localization and resistance to various cytotoxic agents. Chemoresistance is a significant obstacle to effective breast cancer treatment owing to cancer's heterogeneous nature. Abnormalities in intracellular calcium signaling, coupled with altered mitochondrial metabolism, play a significant role in facilitating drug resistance and contribute to therapy resistance. Uncoupling protein-2 (UCP2) is considered as a marker of chemoresistance and is believed to play a major role in promoting metabolic shifts and tumor metastasis. In this context, it is imperative to understand the roles of altered calcium signaling and metabolic switching in the development of chemotherapeutic resistance. This study investigates the roles of UCP2 and intracellular calcium signaling (Ca2+ ) in promoting chemoresistance against cisplatin. Additionally, we explored the effectiveness of combining genipin (GP, a compound that reverses UCP2-mediated chemoresistance) and thapsigargin (TG, a calcium signaling modulator) in treating highly metastatic breast cancers. Our findings indicate that both aberrant Ca2+ signaling and metabolic shifts in cancer cells contribute to developing drug-resistant phenotypes, and the combination treatment of GP and TG significantly enhances drug sensitivity in these cells. Collectively, our study underscores the potential of these drug combinations as an effective approach to overcome drug resistance in chemoresistant cancers.

Loss of UCP2 causes mitochondrial fragmentation by OMA1-dependent proteolytic processing of OPA1 in podocytes.

Mitochondrial dysfunction plays an important role in the onset and progression of podocyte injury and proteinuria. However, the process by which the change in the podocyte mitochondria occurs is not well understood. Uncoupling protein 2 (UCP2) is a mitochondrial anion carrier protein, which is located in the mitochondrial inner membrane. Here, we reported that mice with podocyte-specific Ucp2 deficiency developed podocytopathy with proteinuria with aging. Furthermore, those mice exhibited increased proteinuria in experimental models evoked by Adriamycin. Our findings suggest that UCP2 mediates mitochondrial dysfunction by regulating mitochondrial dynamic balance. Ucp2-deleted podocytes exhibited increased mitochondrial fission and deficient in ATP production. Mechanistically, opacity protein 1 (OPA1), a key protein in fusion of mitochondrial inner membrane, was regulated by UCP2. Ucp2 deficiency promoted proteolysis of OPA1 by activation OMA1 which belongs to mitochondrial inner membrane zinc metalloprotease. Those finding demonstrate the role of UCP2 in mitochondrial dynamics in podocytes and provide new insights into pathogenesis associated with podocyte injury and proteinuria.

CircUCP2 promotes the tumor progression of non-small cell lung cancer through the miR-149/UCP2 pathway.

Non-small cell lung cancer (NSCLC) is a highly lethal cancer, and better treatments are urgently needed. Many studies have implicated circular RNAs (circRNAs) in the progression of multiple malignant tumors. Nonetheless, the functions of circRNAs in NSCLC remain unclear. To study new targets for the treatment of NSCLC, circRNA expression profiling was performed on NSCLC tissues and para-carcinoma nonmalignant tissues. RNA was isolated and used for circRNA sequencing. Biological studies were performed in vitro and in vivo to determine the functions of circRNAs in NSCLC, including their functions in cell proliferation and migration. How circRNAs function in NSCLC was explored to clarify the underlying regulatory mechanisms. We found that circUCP2 was upregulated in NSCLC tissues compared with neighboring nonmalignant tissues. circUCP2 promoted the proliferation and metastasis of NSCLC cells. circUCP2 promoted NSCLC progression by sponging miR-149 and upregulating UCP2. The circUCP2/miR-149/UCP2 axis accelerates the progression of NSCLC, and circUCP2 may therefore be a novel diagnostic biomarker for the progression of NSCLC.

[Effect of Wenyang Zhenshuai Granules on autophagy and apoptosis of myocardial cells in septic rats via regulating miR-132-3p/UCP2 expression].

This study aimed to investigate the effect of Wenyang Zhenshuai Granules(WYZSG) on autophagy and apoptosis of myocardial cells in rats with sepsis via regulating the expression of microRNA-132-3p(miR-132-3p)/uncoupling protein 2(UCP2). Sixty SD rats were randomly divided into modeling group(n=50) and sham operation group(n=10). The sepsis rat model was constructed by cecal ligation and perforation in the modeling group. The successfully modeled rats were randomly divided into WYZSG low-, medium-and high-dose groups, model group and positive control group. Rats in the sham operation group underwent opening and cecum division but without perforation and ligation. Hematoxylin-eosin(HE) staining was used to observe the pathological changes of rat myocardial tissue. Myocardial cell apoptosis was detected by TdT-mediated dUTP nick end labeling(TUNEL) assay. Real-time quantitative polymerase chain reaction(RT-qPCR) was performed to detect the expression of miR-132-3p and the mRNA expressions of UCP2, microtubule-associated protein light chain 3(LC3-Ⅱ/LC3-Ⅰ), Beclin-1 and caspase-3 in rat myocardial tissue. The protein expressions of UCP2, LC3-Ⅱ/LC3-Ⅰ, Beclin-1 and caspase-3 in myocardial tissue were detected by Western blot. Dual luciferase reporter assay was used to verify the regulatory relationship between miR-132-3p and UCP2. The myocardial fibers of sepsis model rats were disordered, and there were obvious inflammatory cell infiltration as well as myocardial cell edema and necrosis. With the increase of the WYZSG dose, the histopathological changes of myocardium were improved to varying degrees. Compared with the conditions in the sham operation group, the survival rate and left ventricular ejection fraction(LVEF) of rats in the model group, positive control group and WYZSG low-, medium-and high-dose groups were decreased, and the myocardial injury score and apoptosis rate were increased. Compared with the model group, the positive control group and WYZSG low-, medium-and high-dose groups had elevated survival rate and LVEF, and lowered myocardial injury score and apoptosis rate. The expression of miR-132-3p and the mRNA and protein expressions of UCP2 in myocardial tissue in the model group, positive control group and WYZSG low-, medium-and high-dose groups were lower, while the mRNA and protein expressions of LC3-Ⅱ/LC3-Ⅰ, Beclin-1 and caspase-3 were higher than those in the sham operation group. Compared with model group, the positive control group and the WYZSG low-, medium-and high-dose groups had an up-regulation in the expression of miR-132-3p and the mRNA and protein expressions of UCP2, while a down-regulation in the mRNA and protein expressions of LC3-Ⅱ/LC3-Ⅰ, Beclin-1 and caspase-3. WYZSG inhibited excessive autophagy and apoptosis of myocardial cells in septic rats and improved myocardial injury, possibly by regulating the expression of miR-132-3p/UCP2.

Role of UCP2 in the Energy Metabolism of the Cancer Cell Line A549.

The uncoupling protein UCP2 is a mitochondrial carrier for which transport activity remains controversial. The physiological contexts in which UCP2 is expressed have led to the assumption that, like UCP1, it uncouples oxidative phosphorylation and thereby reduces the generation of reactive oxygen species. Other reports have involved UCP2 in the Warburg effect, and results showing that UCP2 catalyzes the export of matrix C4 metabolites to facilitate glutamine utilization suggest that the carrier could be involved in the metabolic adaptations required for cell proliferation. We have examined the role of UCP2 in the energy metabolism of the lung adenocarcinoma cell line A549 and show that UCP2 silencing decreased the basal rate of respiration, although this inhibition was not compensated by an increase in glycolysis. Silencing did not lead to either changes in proton leakage, as determined by the rate of respiration in the absence of ATP synthesis, or changes in the rate of formation of reactive oxygen species. The decrease in energy metabolism did not alter the cellular energy charge. The decreased cell proliferation observed in UCP2-silenced cells would explain the reduced cellular ATP demand. We conclude that UCP2 does not operate as an uncoupling protein, whereas our results are consistent with its activity as a C4-metabolite carrier involved in the metabolic adaptations of proliferating cells.

UCP2 deficiency impairs podocyte autophagy in diabetic nephropathy.

OBJECTIVE: Podocytes have been indicated to be a critical factor for the development of diabetic kidney disease. Podocyte loss leads to irreversible glomerular injury and proteinuria in animal models. As terminal differentiated cells, autophagy is crucial for maintaining podocyte homeostasis. Previous studies have shown that Uncoupling proteins 2 (UCP2) regulate fatty acid metabolism, mitochondrial calcium uptake and reactive oxygen species (ROS) production. This study aimed to investigate whether UCP2 promote autophagy in podocyte and further explore the regulation mechanism of UCP2. METHODS: For podocyte-specific UCP2-KO mice, we cross bred UCP2fl/fl mouse strain with the podocin-Cre mice. Diabetic mice were obtained by daily intraperitoneally injections of 40 mg/kg streptozotocin for 3 days. After 6 weeks, mice were scarified, and kidney tissues were analyzed by histological stain, Western blot, Immunofluorescence, and immunohistochemistry. Also, urine samples were collected for protein quantification. For in vitro study, podocytes were primary cultured from UCP2fl/fl mouse or transfected with adeno-associated virus (AAV)-UCP2. RESULTS: Diabetic kidney showed elevated expression of UCP2 and specific ablation of UCP2 in podocyte aggravates diabetes-induced albuminuria and glomerulopathy. UCP2 protects hyperglycemia-induced podocyte injury by promoting autophagy in vivo and in vitro. Rapamycin treatment significantly ameliorates streptozotocin (STZ)-induced podocyte injury in UCP2-/- mice. CONCLUSION: UCP2 expression in podocyte increased under diabetic condition and appeared to be an initial compensatory response. UCP2 deficiency in podocyte impaired autophagy and exacerbates podocyte injury and proteinuria in diabetic nephropathy.

Expressions of mRNA and encoded proteins of mitochondrial uncoupling protein genes (UCP1, UCP2, and UCP3) in epicardial and mediastinal adipose tissue and associations with coronary artery disease.

Objective: To evaluate the expression of UCP1, UCP2, and UCP3 mRNA and encoded proteins in epicardial and mediastinal adipose tissues in patients with coronary artery disease (CAD). Subjects and methods: We studied 60 patients with CAD and 106 patients undergoing valve replacement surgery (controls). Expression levels of UCP1, UCP2, and UCP3 mRNA and encoded proteins were measured by quantitative real-time PCR and Western blot analysis, respectively. Results: : We found increased UCP1, UCP2, and UCP3 mRNA levels in the epicardial adipose tissue in the CAD versus the control group, and higher UCP1 and UCP3 mRNA expression in the epicardial compared with the mediastinal tissue in the CAD group. There was also increased expression of UCP1 protein in the epicardial tissue and UCP2 protein in the mediastinum tissue in patients with CAD. Finally, UCP1 expression was associated with levels of fasting plasma glucose, and UCP3 expression was associated with levels of high-density lipoprotein cholesterol and low-density cholesterol in the epicardial tissue. Conclusion: Our study supports the hypothesis that higher mRNA expression by UCP genes in the epicardial adipose tissue could be a protective mechanism against the production of reactive oxygen species and may guard the myocardium against damage. Thus, UCP levels are essential to maintain the adaptive phase of cardiac injury in the presence of metabolic disorders.

Fish oil and chicoric acid combination protects better against palmitate-induced lipid accumulation via regulating AMPK-mediated SREBP-1/FAS and PPARα/UCP2 pathways.

Non-alcoholic fatty liver disease (NAFLD) is associated with lipid accumulation and lipotoxicity. The main aim of this study is to evaluate the synergistic treatment effect of fish oils (FOs) and chicoric acid (CA) in palmitate (PA)-induced NAFLD HepG2 model. HepG2 cells were pre-treated with palmitate (0.75 mM) for 24 h, and then were exposed to CA, FOs and combination of these chemicals for another 24 h. Gene expression and protein levels were determined using qRT-PCR and western blotting or ELISA analysing, respectively. The combination index (CI) values of FOs and CA in HepG2 cells were calculated according to the Chou-Talalay equation using the CompuSyn software. FOs and CA acid together synergistically reduced lipid accumulation as indicated by decreased oil red O staining (vehicle-treated control: 1 ± 0.1; PA-treated control: 4.7 ± 0.4; PA + CA100: 3.9 ± 0.4; PA + CA200: 2.4 ± 0.3; PA + FOs: 2.7 ± 0.1; PA + CA200 + FOs: 1.5 ± 0.1) and triglyceride (vehicle-treatedcontrol:10 ± 1.2; PA-treated control: 25.8 ± 2.7; PA + CA100: 18.9 ± 2.5; PA + CA200: 14.4 ± 1.8; PA + FOs: 15.2 ± 2.4; PA + CA200 + FOs: 11.9 ± 1.5) levels in PA-treated HepG2 cells. Gene expression and Immunoblotting analysis confirmed the combination effect of FOs and CA in up-regulation of AMPK-mediated PPARα/UCP2 and down-regulation of AMPK-mediated SREBP-1/FAS signalling pathways. Collectively, these results suggest that combining FOs with CA can serve as a potential combination therapy for NAFLD.

Uncoupling protein 2 deficiency of non-cancerous tissues inhibits the progression of pancreatic cancer in mice.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a disease of the elderly mostly because its development from preneoplastic lesions depends on the accumulation of gene mutations and epigenetic alterations over time. How aging of non-cancerous tissues of the host affects tumor progression, however, remains largely unknown. METHODS: We took advantage of a model of accelerated aging, uncoupling protein 2-deficient (Ucp2 knockout, Ucp2 KO) mice, to investigate the growth of orthotopically transplanted Ucp2 wild-type (WT) PDAC cells (cell lines Panc02 and 6606PDA) in vivo and to study strain-dependent differences of the PDAC microenvironment. RESULTS: Measurements of tumor weights and quantification of proliferating cells indicated a significant growth advantage of Panc02 and 6606PDA cells in WT mice compared to Ucp2 KO mice. In tumors in the knockout strain, higher levels of interferon-γ mRNA despite similar numbers of tumor-infiltrating T cells were observed. 6606PDA cells triggered a stronger stromal reaction in Ucp2 KO mice than in WT animals. Accordingly, pancreatic stellate cells from Ucp2 KO mice proliferated at a higher rate than cells of the WT strain when they were incubated with conditioned media from PDAC cells. CONCLUSIONS: Ucp2 modulates PDAC microenvironment in a way that favors tumor progression and implicates an altered stromal response as one of the underlying mechanisms.

Mitochondrial uncoupling protein 2 (UCP2) gene polymorphism - 866 G/A in the promoter region is associated with type 2 diabetes mellitus among Kashmiri population of Northern India.

OBJECTIVE: The study aimed to evaluate the association of UCP2 gene polymorphism - 866 G/A and its expression with diabetes predisposition in the North Indian population. METHODS: The study involved 850 subjects, including 425 each T2DM and control subjects. The serum metabolic and clinical parameters were estimated using standard protocols. The PCR-RFLP based genotyping was performed to determine UCP2 gene polymorphism, while the expression was measured by real-time quantitative PCR. RESULTS: The genotypic and allelic frequencies showed a significant difference in cases compared to controls (p < 0.05). The diabetes patients had a 4.2-fold decrease in UCP2 gene expression. The expression was 29.8 and 8.4 fold lower in diabetes patients with homozygous (AA) and heterozygous (GA) mutation at - 866 locus of UCP2 nucleotide sequence, respectively. When categorized according to age and BMI, the T2DM subjects with age ≥ 50 and BMI ≥ 25 had a 5.53 and 8.2-fold decrease in UCP2 expression, respectively. The diabetes subjects with homozygous and heterozygous mutation demonstrated a pathological increase in serum metabolic and clinical parameters, which corroborated with UCP2 gene expression, indicating a strong association between the two. Intriguingly, we did not find any association between - 866 G/A polymorphism of UCP2 with serum insulin levels. CONCLUSION: Our investigation is the first among the studies conducted in Jammu and Kashmir to work on adipose tissue and UCP2 gene polymorphism. The association of - 866 G/A SNP of the UCP2 gene with its expression in diabetes patients appears to be an important genetic determinant in the progression of T2DM. Moreover, age ≥ 50 years and BMI ≥ 25 could be considered risk factors for developing T2DM in the studied population.

UCP2 as a Cancer Target through Energy Metabolism and Oxidative Stress Control.

Despite numerous therapies, cancer remains one of the leading causes of death worldwide due to the lack of markers for early detection and response to treatment in many patients. Technological advances in tumor screening and renewed interest in energy metabolism have allowed us to identify new cellular players in order to develop personalized treatments. Among the metabolic actors, the mitochondrial transporter uncoupling protein 2 (UCP2), whose expression is increased in many cancers, has been identified as an interesting target in tumor metabolic reprogramming. Over the past decade, a better understanding of its biochemical and physiological functions has established a role for UCP2 in (1) protecting cells from oxidative stress, (2) regulating tumor progression through changes in glycolytic, oxidative and calcium metabolism, and (3) increasing antitumor immunity in the tumor microenvironment to limit cancer development. With these pleiotropic roles, UCP2 can be considered as a potential tumor biomarker that may be interesting to target positively or negatively, depending on the type, metabolic status and stage of tumors, in combination with conventional chemotherapy or immunotherapy to control tumor development and increase response to treatment. This review provides an overview of the latest published science linking mitochondrial UCP2 activity to the tumor context.

UCP2 silencing restrains leukemia cell proliferation through glutamine metabolic remodeling.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy derived from early T cell progenitors. Since relapsed T-ALL is associated with a poor prognosis improving initial treatment of patients is essential to avoid resistant selection of T-ALL. During initiation, development, metastasis and even in response to chemotherapy, tumor cells face strong metabolic challenges. In this study, we identify mitochondrial UnCoupling Protein 2 (UCP2) as a tricarboxylic acid (TCA) cycle metabolite transporter controlling glutamine metabolism associated with T-ALL cell proliferation. In T-ALL cell lines, we show that UCP2 expression is controlled by glutamine metabolism and is essential for their proliferation. Our data show that T-ALL cell lines differ in their substrate dependency and their energetic metabolism (glycolysis and oxidative). Thus, while UCP2 silencing decreases cell proliferation in all leukemia cells, it also alters mitochondrial respiration of T-ALL cells relying on glutamine-dependent oxidative metabolism by rewiring their cellular metabolism to glycolysis. In this context, the function of UCP2 in the metabolite export of malate enables appropriate TCA cycle to provide building blocks such as lipids for cell growth and mitochondrial respiration. Therefore, interfering with UCP2 function can be considered as an interesting strategy to decrease metabolic efficiency and proliferation rate of leukemia cells.

AAV-ie-mediated UCP2 overexpression accelerates inner hair cell loss during aging in vivo.

BACKGROUND: Uncoupling protein 2 (UCP2), activated by excessive reactive oxygen species (ROS) in vivo, has the dual effect of reducing ROS to protect against oxidative stress and reducing ATP production to regulate cellular metabolism. Both the UCP2 and ROS are increased in cochleae in age-related hearing loss (ARHL). However, the role of UCP2 in sensory hair cells in ARHL remains unclear. METHODS: Male C57BL/6 J mice were randomly assigned to an 8-week-old group (Group 1), a 16-week-old group (Group 2), a 16-week-old + adeno-associated virus-inner ear (AAV-ie) group (Group 3), and a 16-week-old + AAV-ie-UCP2 group (Group 4). Mice aged 8 weeks were administrated with AAV-ie-GFP or AAV-ie-UCP2 via posterior semicircular canal injection. Eight weeks after this viral intervention, hearing thresholds and wave-I amplitudes were tested by auditory brainstem response (ABR). Subsequently, the cochlear basilar membrane was dissected for investigation. The number of hair cells and inner hair cell (IHC) synapses, the level of ROS, and the expression of AMP-activated protein kinase α (AMPKα), were assessed by immunofluorescence staining. In addition, mitochondrial function was determined, and the expression of AMPKα and UCP2 proteins was further evaluated using western blotting. RESULTS: Mice with early-onset ARHL exhibited enhanced oxidative stress and loss of outer hair cells and IHC synapses, while UCP2 overexpression aggravated hearing loss and cochlear pathophysiological changes in mice. UCP2 overexpression resulted in a notable decrease in the number of IHCs and IHC synapses, caused ATP depletion and excessive ROS generation, increased AMPKα protein levels, and promoted IHC apoptosis, especially in the apical and middle turns of the cochlea. CONCLUSION: Collectively, our data suggest that UCP2 overexpression may cause mitochondrial dysfunction via energy metabolism, which activates mitochondrion-dependent cellular apoptosis and leads to IHC loss, ultimately exacerbating ARHL.

Activating PPARß/δ Protects against Endoplasmic Reticulum Stress-Induced Astrocytic Apoptosis via UCP2-Dependent Mitophagy in Depressive Model.

As energy metabolism regulation factor, peroxisome proliferator-activated receptor (PPAR) is thought to be a potential target for the treatment of depression. The present study was performed to evaluate the effects of activating PPARß/δ, the most highly expressed subtype in the brain, in depressive in vivo and in vitro models. We observed that PPARß/δ agonist GW0742 significantly alleviated depressive behaviors in mice and promoted the formation of autophagosomes around the damaged mitochondria in hippocampal astrocytes. Our in vitro experiments showed that GW0742 could reduce mitochondrial oxidative stress, and thereby attenuate endoplasmic reticulum (ER) stress-mediated apoptosis pathway via inhibiting IRE1α phosphorylation, subsequently protect against astrocytic apoptosis and loss. Furthermore, we found that PPARß/δ agonist induces astrocytic mitophagy companied with the upregulated UCP2 expressions. Knocking down UCP2 in astrocytes could block the anti-apoptosis and pro-mitophagy effects of GW0742. In conclusion, our findings reveal PPARß/δ activation protects against ER stress-induced astrocytic apoptosis via enhancing UCP2-mediated mitophagy, which contribute to the anti-depressive action. The present study provides a new insight for depression therapy.

Mitochondrial uncoupling protein-2 reprograms metabolism to induce oxidative stress and myofibroblast senescence in age-associated lung fibrosis.

Mitochondrial dysfunction has been associated with age-related diseases, including idiopathic pulmonary fibrosis (IPF). We provide evidence that implicates chronic elevation of the mitochondrial anion carrier protein, uncoupling protein-2 (UCP2), in increased generation of reactive oxygen species, altered redox state and cellular bioenergetics, impaired fatty acid oxidation, and induction of myofibroblast senescence. This pro-oxidant senescence reprogramming occurs in concert with conventional actions of UCP2 as an uncoupler of oxidative phosphorylation with dissipation of the mitochondrial membrane potential. UCP2 is highly expressed in human IPF lung myofibroblasts and in aged fibroblasts. In an aging murine model of lung fibrosis, the in vivo silencing of UCP2 induces fibrosis regression. These studies indicate a pro-fibrotic function of UCP2 in chronic lung disease and support its therapeutic targeting in age-related diseases associated with impaired tissue regeneration and organ fibrosis.