Crotonylation of NAE1 Modulates Cardiac Hypertrophy via Gelsolin Neddylation.

BACKGROUND: Cardiac hypertrophy and its associated remodeling are among the leading causes of heart failure. Lysine crotonylation is a recently discovered posttranslational modification whose role in cardiac hypertrophy remains largely unknown. NAE1 (NEDD8 [neural precursor cell expressed developmentally downregulated protein 8]-activating enzyme E1 regulatory subunit) is mainly involved in the neddylation modification of protein targets. However, the function of crotonylated NAE1 has not been defined. This study aims to elucidate the effects and mechanisms of NAE1 crotonylation on cardiac hypertrophy. METHODS: Crotonylation levels were detected in both human and mouse subjects with cardiac hypertrophy through immunoprecipitation and Western blot assays. Tandem mass tag (TMT)-labeled quantitative lysine crotonylome analysis was performed to identify the crotonylated proteins in a mouse cardiac hypertrophic model induced by transverse aortic constriction. We generated NAE1 knock-in mice carrying a crotonylation-defective K238R (lysine to arginine mutation at site 238) mutation (NAE1 K238R) and NAE1 knock-in mice expressing a crotonylation-mimicking K238Q (lysine to glutamine mutation at site 238) mutation (NAE1 K238Q) to assess the functional role of crotonylation of NAE1 at K238 in pathological cardiac hypertrophy. Furthermore, we combined coimmunoprecipitation, mass spectrometry, and dot blot analysis that was followed by multiple molecular biological methodologies to identify the target GSN (gelsolin) and corresponding molecular events contributing to the function of NAE1 K238 (lysine residue at site 238) crotonylation. RESULTS: The crotonylation level of NAE1 was increased in mice and patients with cardiac hypertrophy. Quantitative crotonylomics analysis revealed that K238 was the main crotonylation site of NAE1. Loss of K238 crotonylation in NAE1 K238R knock-in mice attenuated cardiac hypertrophy and restored the heart function, while hypercrotonylation mimic in NAE1 K238Q knock-in mice significantly enhanced transverse aortic constriction-induced pathological hypertrophic response, leading to impaired cardiac structure and function. The recombinant adenoviral vector carrying NAE1 K238R mutant attenuated, while the K238Q mutant aggravated Ang II (angiotensin II)-induced hypertrophy. Mechanistically, we identified GSN as a direct target of NAE1. K238 crotonylation of NAE1 promoted GSN neddylation and, thus, enhanced its protein stability and expression. NAE1 crotonylation-dependent increase of GSN promoted actin-severing activity, which resulted in adverse cytoskeletal remodeling and progression of pathological hypertrophy. CONCLUSIONS: Our findings provide new insights into the previously unrecognized role of crotonylation on nonhistone proteins during cardiac hypertrophy. We found that K238 crotonylation of NAE1 plays an essential role in mediating cardiac hypertrophy through GSN neddylation, which provides potential novel therapeutic targets for pathological hypertrophy and cardiac remodeling.

The function and therapeutic potential of transfer RNA-derived small RNAs in cardiovascular diseases: A review.

Transfer RNA-derived small RNAs (tsRNAs) are a class of small non-coding RNA (sncRNA) molecules derived from tRNA, including tRNA derived fragments (tRFs) and tRNA halfs (tiRNAs). tsRNAs can affect cell functions by participating in gene expression regulation, translation regulation, intercellular signal transduction, and immune response. They have been shown to play an important role in various human diseases, including cardiovascular diseases (CVDs). Targeted regulation of tsRNAs expression can affect the progression of CVDs. The tsRNAs induced by pathological conditions can be detected when released into the extracellular, giving them enormous potential as disease biomarkers. Here, we review the biogenesis, degradation process and related functional mechanisms of tsRNAs, and discuss the research progress and application prospects of tsRNAs in different CVDs, to provide a new perspective on the treatment of CVDs.

ABRO1 arrests cardiomyocyte proliferation and myocardial repair by suppressing PSPH.

The role of Abraxas 2 (ABRO1 or KIAA0157), a component of the lysine63-linked deubiquitinating system, in the cardiomyocyte proliferation and myocardial regeneration is unknown. Here, we found that ABRO1 regulates cardiomyocyte proliferation and cardiac regeneration in the postnatal heart by targeting METTL3-mediated m6A methylation of Psph mRNA. The deletion of ABRO1 increased cardiomyocyte proliferation in hearts and restored the heart function after myocardial injury. On the contrary, ABRO1 overexpression significantly inhibited the neonatal cardiomyocyte proliferation and cardiac regeneration in mouse hearts. The mechanism by which ABRO1 regulates cardiomyocyte proliferation mainly involved METTL3-mediated Psph mRNA methylation and CDK2 phosphorylation. In the early postnatal period, METTL3-dependent m6A methylation promotes cardiomyocyte proliferation by hypermethylation of Psph mRNA and upregulating PSPH expression. PSPH dephosphorylates cyclin-dependent kinase 2 (CDK2), a positive regulator of cell cycle, at Thr14/Tyr15 and increases its activity. Upregulation of ABRO1 restricts METTL3 activity and halts the cardiomyocyte proliferation in the postnatal hearts. Thus, our study reveals that ABRO1 is an essential contributor in the cell cycle withdrawal and attenuation of proliferative response in the postnatal cardiomyocytes and could act as a potential target to accelerate cardiomyocyte proliferation and cardiac repair in the adult heart.

MicroRNA-485-3p Promotes the Inflammatory Response and Extracellular Matrix Deposition by Activating Wnt/ß-Catenin Signaling in Human Airway Smooth Muscle Cells.

The aim of this study was to study the effects of microRNA (miR)-485-3p on the inflammatory response and extracellular matrix deposition of human airway smooth muscle cells (HASMCs). The levels of miR-485-3p and WIF1 in peripheral blood of pediatric asthma (PA) patients and controls were examined by quantitative real-time polymerase chain reaction (qRT-PCR). miR-485-3p inhibitor and mimic, together with negative control (NC) inhibitor/ mimic, were transfected into HASMCs treated with tumor necrosis factor (TNF)-α. The levels of eotaxin, interleukin (IL)-8, and IL-6 were analyzed by enzyme-linked immunosorbent assay (ELISA). Cellular immunofluorescence analysis of fibronectin was also performed. The target genes of miR-485-3p were predicted and validated using TargetScan and dual-luciferase reporter gene assay. The protein levels of IL-6, eotaxin, IL-8, collagen III, collagen I, MMP-9, TIMP-1, MMP-2, axin, ß-catenin, phosphorylated ß-catenin, GSK3ß, p-GSK3ß, and WIF1 were tested by Western blot. The level of miR-485-3p was increased, whereas expression of WIF1 was low in PA patients. In TNF-α-induced HASMCs, miR-485-3p overexpression promoted the inflammatory response and the accumulation of extracellular matrix. WIF1 was a direct target of miR-485-3p. Silencing miR-485-3p inhibited activation of Wnt/ß-catenin signaling. The reductions in the inflammatory response and ECM accumulation caused by silencing miR-485-3p were induced by blocking Wnt/ß-catenin signaling. Thus, miRNA-485-3p targets WIF1 and activates Wnt/ß-catenin signaling, facilitating activation of the inflammatory response and ECM accumulation in HASMCs.

circRNA is a potential target for cardiovascular diseases treatment.

Circular RNAs (circRNAs), a novel class of endogenous noncoding RNA, are characterized by their covalently closed-loop structures without a 5' cap or a 3' poly(A) tail. With the evolution of high-throughput sequencing technology and bioinformatics, an increasing number of circRNAs have been discovered, and their functions were highlighted. Cardiovascular diseases (CVDs) have become the world's leading killers, with serious impacts on human health. Although significant progress has been made in clarifying the development of CVDs from the molecular to the cellular level, CVDs remain one of the leading causes of death in humans. circRNAs mainly function as a "sponge" to absorb microRNAs, which results in the positive control of downstream proteins. They play important regulatory roles in the development of CVDs. This paper reviews current knowledge on the biogenesis, detection and validation, translation, translocation and degradation, and general functions of circRNAs, with a focus on their roles in CVDs.

Human brucellosis and fever of unknown origin.

BACKGROUND: Human brucellosis has become one of the major public health problems in China, and increases atypical manifestations, such as fever of unknown origin (FUO), and misdiagnosis rates has complicated the diagnosis of brucellosis. To date, no relevant study on the relationship between brucellosis and FUO has been conducted. METHODS: We retrospectively reviewed the medical charts of 35 patients with confirmed human brucellosis and prospectively recorded their outcomes by telephone interview. The patients were admitted to the Second Affiliated Hospital of Nanchang University between January 01, 2013 and October 31, 2019. Patient data were collected from hospital medical records. RESULTS: The percentage of males was significantly higher than that of female in FUO (78.95% vs. 21.05%, P < 0.05), and 80% of the patients had a clear history of exposure to cattle and sheep. Moreover, 19 (54%) cases were hospitalized with FUO, among which the patients with epidemiological histories were significantly more than those without (P < 0.05). The incidence of toxic hepatitis in FUO patients was higher than that in non-FUO patients (89% vs. 50%, P < 0.05). Meanwhile, the misdiagnosis rate was considerably higher in the FUO group than in the non-FUO group (100% vs. 63%; P < 0.05). CONCLUSION: Brucellosis is predominantly FUO admission in a non-endemic area of China, accompanied by irregular fever and toxic hepatitis. Careful examination of the epidemiological history and timely improvement of blood and bone marrow cultures can facilitate early diagnosis and prevent misdiagnosis.

Sensitive naked-eye detection of telomerase activity based on exponential amplification reaction and lateral flow assay.

Telomerase is a promising diagnostic and prognostic biomarker for cancers. Sensitive, simple, and reliable telomerase activity detection is vital for cancer diagnosis. Herein, we developed an ultrasensitive visualized assay for telomerase activity that combined the exponential amplification reaction (EXPAR) and lateral flow assay for easy and quick signal readout, which we termed as a lateral flow readout-EXPAR (LFR-EXPAR) assay. In the LFR-EXPAR assay, telomerase elongation products initiate the exponential amplification reaction, the generated trigger hybridizes with the reporter to form the recognition site of the nicking enzyme, and the nicking enzyme cuts the reporter strand. The degradation of the reporter can be detected with a universal lateral flow dipstick and read out with the naked eye. After conducting a series of proof-of-concept investigations, the LFR-EXPAR assay was found to achieve a sensitivity comparable to that of a TRAP (telomere repeat amplification protocol) assay. The LFR-EXPAR assay can be used to realize ultrasensitive and point-of-care detection of telomerase without requiring specialized instruments, holding great promise for early cancer diagnosis.

Migration and transformation of nitrogen in sediment-water system within storm sewers.

In the sediment-water system of storm sewers (e.g., sediments, interstitial water, and the water column), the migration of nitrogen and its biological transformation with different dissolved oxygen conditions were investigated. Results showed that in an aerobic segment, γ-proteobacteria, α-proteobacteria, and nitrospira, which are aerobic, grew actively in water column and interstitial water through ammonification and nitrification. In anoxic segment, ammonification depended mainly on clostridia, whereas nitrification was inhibited. Thus, after 20 days, the concentration of NH4+-N in the aerobic segment became noticeably lower (5.97 mg/L) than that in the anoxic segment (18.09 mg/L). In sediments, the biological transformation of organic nitrogen in the anoxic environment was more complete, resulting in elevating amino acid nitrogen and NH4+-N in the anoxic segment compared to the aerobic segment. Furthermore, the concentration gradient of NH4+-N between interstitial water and water column in aerobic and anoxic segments, thereby causing NH4+-N to migrate from interstitial water to the water column. In the sediment-water system, the different forms of nitrogen changes were the common result of biological transformation and material migration.

Analysis and calculation of sediment scouring rate at different locations of storm sewer.

To explore the migration differences of sediments at the front, middle, and end sections of a storm sewer when scoured by water, and further evaluate the pollution load, the scouring process of sediments at different locations of a storm sewer was simulated and mathematical models were built to calculate the scouring rate. Results show that scouring rate is affected by sediment particle size, pipeline slope, sediment thickness, and water flow velocity. As the slope increased, scouring rate at the end section increased more obviously. The scouring rate at the front section slightly decreased with increasing sediment thickness, but opposite trends were observed at the middle and end sections. When the particle size (0.33 mm-0.83 mm) and flow velocity (0.15 m/s-0.65 m/s) increased within their ranges, scouring rate increased across all three locations. Models for calculating scouring rate were established via two data fitting. The calculated values were compared with measured values at a scouring time of 1 min. Under different particle sizes, the difference between the calculated and measured values at front, middle, and end sections were in the ranges of -0.63% to 0.63%, -0.01% to 0.02%, and -0.13% to 0.16%, respectively, all of which showed good consistency.

Long Noncoding RNA CPR (Cardiomyocyte Proliferation Regulator) Regulates Cardiomyocyte Proliferation and Cardiac Repair.

BACKGROUND: The adult mammalian cardiomyocytes lose their proliferative capacity, which is responsible for cardiac dysfunction and heart failure following injury. The molecular mechanisms underlying the attenuation of adult cardiomyocyte proliferation remain largely unknown. Because long noncoding RNAs (lncRNAs) have a critical role in the development of cardiovascular problems, we investigated whether lncRNAs have any role in the regulation of cardiomyocyte proliferation and cardiac repair. METHODS: Using bioinformatics and initial analysis, we identified an lncRNA, named CPR (cardiomyocyte proliferation regulator), that has a potential regulatory role in cardiomyocyte proliferation. For in vivo experiments, we generated CPR knockout and cardiac-specific CPR-overexpressing mice. In isolated cardiomyocytes, we used adenovirus for silencing (CPR-small interfering RNA) or overexpressing CPR. To investigate the mechanisms of CPR function in cardiomyocyte proliferation, we performed various analyses including quantitative reverse transcription-polymerase chain reaction, Western blot, histology, cardiac function (by echocardiography), transcriptome analyses (microarray assay), RNA pull-down assay, and chromatin immunoprecipitation assay. RESULTS: CPR level is comparatively higher in the adult heart than in the fetal stage. The silencing of CPR significantly increased cardiomyocyte proliferation in postnatal and adult hearts. Moreover, CPR deletion restored the heart function after myocardial injury, which was evident from increased cardiomyocyte proliferation, improvement of myocardial function, and reduced scar formation. In contrast, the neonatal cardiomyocyte proliferation and cardiac regeneration were remarkably suppressed in CPR-overexpressing mice or adeno-associated virus serotype 9-CPR-overexpressing heart. These results indicate that CPR acts as a negative regulator of cardiomyocyte proliferation and regeneration. Next, we found that CPR targets minichromosome maintenance 3, an initiator of DNA replication and cell cycle progression, to suppress cardiomyocyte proliferation. CPR silenced minichromosome maintenance 3 expression through directly interacting and recruiting DNMT3A to its promoter cysteine-phosphate-guanine sites, as evident from decreased minichromosome maintenance 3 promoter methylation and increased minichromosome maintenance 3 expression in CPR knocked-down cardiomyocytes and CPR knockout mouse heart. These results were confirmed in CPR-overexpressing cardiomyocytes and CPR-overexpressing mouse heart. CONCLUSIONS: Together, our findings identified that CPR is a suppressor of cardiomyocyte proliferation and indicated that lncRNAs take part in the regulation of cardiomyocyte proliferation and cardiac repair. Our study provides an lncRNA-based therapeutic strategy for effective cardiac repair and regeneration.

Stepwise Ethanol-Water Fractionation of Enzymatic Hydrolysis Lignin to Improve Its Performance as a Cationic Dye Adsorbent.

In this work, lignin fractionation is proposed as an effective approach to reduce the heterogeneity of lignin and improve the adsorption and recycle performances of lignin as a cationic dye adsorbent. By stepwise dissolution of enzymatic hydrolysis lignin in 95% and 80% ethanol solutions, three lignin subdivisions (95% ethanol-soluble subdivision, 80% ethanol-soluble subdivision, and 80% ethanol-insoluble subdivision) were obtained. The three lignin subdivisions were characterized by gel permeation chromatography (GPC), FTIR, 2D-NMR and scanning electron microscopy (SEM), and their adsorption capacities for methylene blue were compared. The results showed that the 80% ethanol-insoluble subdivision exhibited the highest adsorption capacity and its value (396.85 mg/g) was over 0.4 times higher than that of the unfractionated lignin (281.54 mg/g). The increased adsorption capacity was caused by the enhancement of both specific surface area and negative Zeta potential. The maximum monolayer adsorption capacity of 80% ethanol-insoluble subdivision by adsorption kinetics and isotherm studies was found to be 431.1 mg/g, which was much higher than most of reported lignin-based adsorbents. Moreover, the 80% ethanol-insoluble subdivision had much higher regeneration yield (over 90% after 5 recycles) compared with the other two subdivisions. Consequently, the proposed fractionation method is proved to be a novel and efficient non-chemical modification approach that significantly improves adsorption capacity and recyclability of lignin.

Flavone-based natural product agents as new lysine-specific demethylase 1 inhibitors exhibiting cytotoxicity against breast cancer cells in vitro.

Lysine-specific demethylase 1 (LSD1) has recently emerged as a therapeutic target for cancer. However, almost all LSD1 inhibitors developed to date are chemo-synthesised molecules. In this study, the LSD1 inhibitory activity of 12 natural flavones, including four aglycones and their corresponding monoglycosides and diglucosides, was evaluated. Based on the structure-activity relationships, LSD1 inhibition activity was greater for flavonoid monoglycosides than their aglycones lacking the sugar moiety. The effects of isoquercitrin, which exhibited optimal LSD1 inhibitory activity, on cancer cell properties were evaluated. Isoquercitrin induced the expression of key proteins in the mitochondrial-mediated apoptosis pathway and caused apoptosis in LSD1-overexpressing MDA-MB-231 cells via the inhibition of LSD1. These findings suggest that natural LSD1 inhibitors, and particularly isoquercitrin, are promising for cancer treatment.

lncRNA SNHG7 sponges miR-425 to promote proliferation, migration, and invasion of hepatic carcinoma cells via Wnt/ß-catenin/EMT signalling pathway.

Increasing evidence has indicated the important roles of long noncoding RNA small nucleolar RNA host gene 7 (SNHG7) in tumourigenesis as a potential oncogene. However, the function of SNHG7 in hepatic carcinoma remains unclear. In the present study, we found that SNHG7 expression was significantly upregulated in hepatic carcinoma tissues, especially in aggressive cases, and it was closely correlated with the poor prognosis. Furthermore, knockdown of SNHG7 inhibited the proliferation, migration, and invasion of hepatic carcinoma cell lines in vitro. Mechanistically, SNHG7 directly interacted with miR-425 as a ceRNA. Moreover, knockdown of SNHG7 significantly inhibited the tumorigenic Wnt/ß-catenin/EMT pathway. SNHG7 regulated Wnt/ß-catenin/EMT pathway through sponging miR-425 and played an oncogenic role in hepatic carcinoma progression. Together, our study elucidated the role of SNHG7 as a ceRNA in hepatic carcinoma, provided new potential diagnosis and therapeutic application in hepatic carcinoma progression. SIGNIFICANCE OF THE STUDY: SNHG7 could promote proliferation and metastasis of hepatic carcinoma cell in vitro and in vivo, suggesting that SNHG7 exerts tumorigenic role in hepatic carcinoma progression. Further mechanism research revealed that SNHG7 exhibited the tumorigenic role through Wnt/ß-catenin/EMT pathway as a miR-425 sponge. These findings provided new cues to understand the molecular signalling network in carcinogenesis of hepatic carcinoma, and it may provide new evidence for therapeutic application in hepatic carcinoma.

Role of noncoding RNAs in regulation of cardiac cell death and cardiovascular diseases.

Loss of functional cardiomyocytes is a major underlying mechanism for myocardial remodeling and heart diseases, due to the limited regenerative capacity of adult myocardium. Apoptosis, programmed necrosis, and autophagy contribute to loss of cardiac myocytes that control the balance of cardiac cell death and cell survival through multiple intricate signaling pathways. In recent years, non-coding RNAs (ncRNAs) have received much attention to uncover their roles in cell death of cardiovascular diseases, such as myocardial infarction, cardiac hypertrophy, and heart failure. In addition, based on the view that mitochondrial morphology is linked to three types of cell death, ncRNAs are able to regulate mitochondrial fission/fusion of cardiomyocytes by targeting genes involved in cell death pathways. This review focuses on recent progress regarding the complex relationship between apoptosis/necrosis/autophagy and ncRNAs in the context of myocardial cell death in response to stress. This review also provides insight into the treatment for heart diseases that will guide novel therapies in the future.

Prostaglandin E2 increases migration and proliferation of human glioblastoma cells by activating transient receptor potential melastatin 7 channels.

Recent studies showed that both prostaglandin E2 (PGE2) and transient receptor potential melastatin 7 (TRPM7) play important roles in migration and proliferation of human glioblastoma cells. In this study, we tested the association between PGE2 and TRPM7. We found that PGE2 increased TRPM7 currents in HEK293 and human glioblastoma A172 cells. The PGE2 EP3 receptor antagonist L-798106 abrogated the PGE2 stimulatory effect, while EP3 agonist 17-phenyl trinor prostaglandin E2 (17-pt-PGE2) mimicked the effect of PEG2 on TRPM7. The TRPM7 phosphotransferase activity-deficient mutation, K1646R had no effect on PGE2 induced increase of TRPM7 currents. Inhibition of protein kinase A (PKA) activity by Rp-cAMP increased TRPM7 currents. TRPM7 PKA phosphorylation site mutation S1269A abolished the PGE2 effect on TRPM7 currents. PGE2 increased both mRNA and membrane protein expression of TRPM7 in A172 cells. Knockdown of TRPM7 by shRNA abrogated the PGE2 stimulated migration and proliferation of A172 cells. Blockage of TRPM7 with 2-aminoethoxydiphenyl borate (2-APB) or NS8593 had a similar effect as TRPM7-shRNA. In conclusion, our results demonstrate that PGE2 activates TRPM7 via EP3/PKA signalling pathway, and that PGE2 enhances migration and proliferation of human glioblastoma cells by up-regulation of the TRPM7 channel.

Deposition regularity in a rainwater pipeline based on variable transport flux.

Experiments of the deposition of suspended particles in a rainwater pipeline were combined with mathematical model fitting to explore deposition regularity under variable transport flux. The simulation results showed that four primary factors affected deposition regularity in a rainwater pipeline. In particular, the deposition and flushing processes alternately dominated when the flow and initial suspended solids (SS) concentration changed simultaneously. The migration of the easy deposition position (EDP, the position with the largest deposition velocity) displayed an obvious regularity, shifting from front to back along the pipe regularly at increasing flow, and from back to front when flow decreased.

MiR-485-5p modulates mitochondrial fission through targeting mitochondrial anchored protein ligase in cardiac hypertrophy.

The pathogenesis of cardiac hypertrophy is tightly associated with mitochondrial dysfunction. Disequilibrium of mitochondrial dynamic is one of the main drivers in the pathological processes during development of various cardiac diseases. However, the effect of mitochondrial dynamics on cardiac hypertrophy remains largely unclear. MicroRNAs (miRNAs) are small noncoding RNAs that can switch off expression of many genes. Mitochondrial anchored protein ligase (MAPL) is a small ubiquitin-like modifier (SUMO) E3 ligase, which is an important contributor in mitochondrial fission process. In this study, we found that hypertrophic agonist phenylephrine (PE) enhanced the expression of MAPL and promoted mitochondrial fission, while it decreased the expression of mitochondrial fusion protein2 (Mfn2) in hypertrophic cardiomyocytes. Silencing expression of MAPL by siRNA attenuated PE-induced depletion of Mfn2 and increase of mitochondrial fission as well as hypertrophic response in cultured primary cardiomyocytes. MiR-485-5p is screened as a candidate inhibitor of MAPL. Overexpression of miR-485-5p blocked mitochondrial fission and hypertrophy induced by PE through inhibiting MAPL expression and increasing the level of Mfn2 in cultured primary cardiomyocytes. In mice model of cardiac hypertrophy induced by PE, the administration of miR-485-5p agomir significantly decreased the PE induced increase in the expression of MAPL and hypertrophic markers (ANP and ß-MHC) along with protection of cardiac structure and function. Together, this study exhibits a novel signaling axis composed of miR-485-5p/MAPL/Mfn2, which regulates mitochondrial machinery and cardiac hypertrophy.

MDRL lncRNA regulates the processing of miR-484 primary transcript by targeting miR-361.

Long noncoding RNAs (lncRNAs) are emerging as new players in gene regulation, but whether lncRNAs operate in the processing of miRNA primary transcript is unclear. Also, whether lncRNAs are involved in the regulation of the mitochondrial network remains to be elucidated. Here, we report that a long noncoding RNA, named mitochondrial dynamic related lncRNA (MDRL), affects the processing of miR-484 primary transcript in nucleus and regulates the mitochondrial network by targeting miR-361 and miR-484. The results showed that miR-361 that predominantly located in nucleus can directly bind to primary transcript of miR-484 (pri-miR-484) and prevent its processing by Drosha into pre-miR-484. miR-361 is able to regulate mitochondrial fission and apoptosis by regulating miR-484 levels. In exploring the underlying molecular mechanism by which miR-361 is regulated, we identified MDRL and demonstrated that it could directly bind to miR-361 and downregulate its expression levels, which promotes the processing of pri-miR-484. MDRL inhibits mitochondrial fission and apoptosis by downregulating miR-361, which in turn relieves inhibition of miR-484 processing by miR-361. Our present study reveals a novel regulating model of mitochondrial fission program which is composed of MDRL, miR-361 and miR-484. Our work not only expands the function of the lncRNA pathway in gene regulation but also establishes a new mechanism for controlling miRNA expression.