Data mining and machine learning in HIV infection risk research: An overview and recommendations.

In the contemporary era, the applications of data mining and machine learning have permeated extensively into medical research, significantly contributing to areas such as HIV studies. By reviewing 38 articles published in the past 15 years, the study presents a roadmap based on seven different aspects, utilizing various machine learning techniques for both novice researchers and experienced researchers seeking to comprehend the current state of the art in this area. While traditional regression modeling techniques have been commonly used, researchers are increasingly adopting more advanced fully supervised machine learning and deep learning techniques, which often outperform the traditional methods in predictive performance. Additionally, the study identifies nine new open research issues and outlines possible future research plans to enhance the outcomes of HIV infection risk research. This review is expected to be an insightful guide for researchers, illuminating current practices and suggesting advancements in the field.

Microbial metabolite enhances immunotherapy efficacy by modulating T cell stemness in pan-cancer.

The immune checkpoint blockade (ICB) response in human cancers is closely linked to the gut microbiota. Here, we report that the abundance of commensal Lactobacillus johnsonii is positively correlated with the responsiveness of ICB. Supplementation with Lactobacillus johnsonii or tryptophan-derived metabolite indole-3-propionic acid (IPA) enhances the efficacy of CD8+ T cell-mediated αPD-1 immunotherapy. Mechanistically, Lactobacillus johnsonii collaborates with Clostridium sporogenes to produce IPA. IPA modulates the stemness program of CD8+ T cells and facilitates the generation of progenitor exhausted CD8+ T cells (Tpex) by increasing H3K27 acetylation at the super-enhancer region of Tcf7. IPA improves ICB responsiveness at the pan-cancer level, including melanoma, breast cancer, and colorectal cancer. Collectively, our findings identify a microbial metabolite-immune regulatory pathway and suggest a potential microbial-based adjuvant approach to improve the responsiveness of immunotherapy.

Lactobacillus Intestinalis Primes Epithelial Cells to Suppress Colitis-Related Th17 Response by Host-Microbe Retinoic Acid Biosynthesis.

Gut microbiome is integral to the pathogenesis of ulcerative colitis. A novel probiotic Lactobacillus intestinalis (L. intestinalis) exerts a protective effect against dextran sodium sulfate-induced colitis in mice. Based on flow cytometry, colitis-associated Th17 cells are the target of L. intestinalis, which is supported by the lack of protective effects of L. intestinalis in T cell-null Rag1-/- mice or upon anti-IL-17-A antibody-treated mice. Although L. intestinalis exerts no direct effect on T cell differentiation, it decreases C/EBPA-driven gut epithelial SAA1 and SAA2 production, which in turn impairs Th17 cell differentiation. Cometabolism of L. intestinalis ALDH and host ALDH1A2 contributed to elevated biosynthesis of retinoic acid (RA), which accounts for the anti-colitis effect in RAR-α -mediated way. In a cohort of ulcerative colitis patients, it is observed that fecal abundance of L. intestinalis is negatively associated with the C/EBPA-SAA1/2-Th17 axis. Finally, L. intestinalis has a synergistic effect with mesalazine in alleviating murine colitis. In conclusion, L. intestinalis and associated metabolites, RA, have potential therapeutic effects for suppressing colonic inflammation by modulating the crosstalk between intestinal epithelia and immunity.

Heat-inactivated Bifidobacterium adolescentis ameliorates colon senescence through Paneth-like-cell-mediated stem cell activation.

Declined numbers and weakened functions of intestinal stem cells (ISCs) impair the integrity of the intestinal epithelium during aging. However, the impact of intestinal microbiota on ISCs in this process is unclear. Here, using premature aging mice (telomerase RNA component knockout, Terc-/-), natural aging mice, and in vitro colonoid models, we explore how heat-inactivated Bifidobacterium adolescentis (B. adolescentis) affects colon senescence. We find that B. adolescentis could mitigate colonic senescence-related changes by enhancing intestinal integrity and stimulating the regeneration of Lgr5+ ISCs via Wnt/ß-catenin signaling. Furthermore, we uncover the involvement of Paneth-like cells (PLCs) within the colonic stem-cell-supporting niche in the B. adolescentis-induced ISC regeneration. In addition, we identify soluble polysaccharides (SPS) as potential effective components of B. adolescentis. Overall, our findings reveal the role of heat-inactivated B. adolescentis in maintaining the ISCs regeneration and intestinal barrier, and propose a microbiota target for ameliorating colon senescence.

Bifidobacterium adolescentis orchestrates CD143+ cancer-associated fibroblasts to suppress colorectal tumorigenesis by Wnt signaling-regulated GAS1.

BACKGROUND: The interplay between gut microbiota and tumor microenvironment (TME) in the pathogenesis of colorectal cancer (CRC) is not well explored. Here, we elucidated the functional role of Bifidobacterium adolescentis (B.a) on CRC and investigated its possible mechanism on the manipulation of cancer-associated fibroblasts (CAFs) in CRC. METHODS: Different CRC animal models and various cell line models were established to explore the function of B.a on CRC. The single-cell RNA sequencing (scRNA-seq) or flow cytometry was used to detect the cell subsets in the TME of CRC. Western blot, quantitative real-time polymerase chain reaction (qRT-PCR), or immunofluorescence staining were performed to examine the activation of Wnt signaling and growth arrest specific 1 (GAS1) on CD143+ CAFs. Chromatin immunoprecipitation quantitative real-time PCR (CHIP-qPCR) was performed to investigate the regulation of transcription factor 4 (TCF4) on GAS1. Multi-immunofluorescence assay examined the expression level of CD143 and GAS1 on tissue microarray. RESULTS: We found that B.a abundance was significantly reduced in CRC patients from two independent cohorts and the bacteria database of GMrepo. Supplementation with B.a suppressed ApcMin/+ spontaneous or AOM/DSS-induced tumorigenesis in mice. scRNA-seq revealed that B.a facilitated a subset of CD143+ CAFs by inhibiting the infiltration of Th2 cells, while promoting the TNF-alpha+ B cells in TME. CD143+ CAFs highly expressed GAS1 and exhibited tumor suppressive effect. Mechanistically, GAS1 was activated by the Wnt/ß-catenin signaling in CD143+ CAFs. B.a abundance was correlated with the expression level of CD143 and GAS1. The level of CD143+ CAFs predicted the better survival outcome in CRC patients. CONCLUSIONS: These results highlighted that B.a induced a new subset of CD143+ CAFs by Wnt signaling-regulated GAS1 to suppress tumorigenesis and provided a novel therapeutic target for probiotic-based modulation of TME in CRC.

dbCAN3: automated carbohydrate-active enzyme and substrate annotation.

Carbohydrate active enzymes (CAZymes) are made by various organisms for complex carbohydrate metabolism. Genome mining of CAZymes has become a routine data analysis in (meta-)genome projects, owing to the importance of CAZymes in bioenergy, microbiome, nutrition, agriculture, and global carbon recycling. In 2012, dbCAN was provided as an online web server for automated CAZyme annotation. dbCAN2 (https://bcb.unl.edu/dbCAN2) was further developed in 2018 as a meta server to combine multiple tools for improved CAZyme annotation. dbCAN2 also included CGC-Finder, a tool for identifying CAZyme gene clusters (CGCs) in (meta-)genomes. We have updated the meta server to dbCAN3 with the following new functions and components: (i) dbCAN-sub as a profile Hidden Markov Model database (HMMdb) for substrate prediction at the CAZyme subfamily level; (ii) searching against experimentally characterized polysaccharide utilization loci (PULs) with known glycan substates of the dbCAN-PUL database for substrate prediction at the CGC level; (iii) a majority voting method to consider all CAZymes with substrate predicted from dbCAN-sub for substrate prediction at the CGC level; (iv) improved data browsing and visualization of substrate prediction results on the website. In summary, dbCAN3 not only inherits all the functions of dbCAN2, but also integrates three new methods for glycan substrate prediction.

The Impact of Customized Short Message Service on High-Risk Behaviors Among MSM in China, a Randomized Controlled Trial Study.

An individual based randomized controlled trial (RCT) was designed to evaluate the impact of a customized short message service (SMS) intervention on HIV-related high-risk behaviors among Men who have sex with men (MSM). In total, 631 HIV-negative MSM were enrolled at baseline and divided into intervention and control groups randomly. Nine months later, the intervention group who received additional customized SMS intervention reported significantly lower rates of multiple partners, unclear partner infection status and condomless anal intercourse compared to the control group who received the routine intervention only. Six months post stopping the SMS intervention, the rates of unclear partner infection status and condomless anal intercourse still remained lower report in the intervention group. Our study shown that the customized SMS interventions can significantly reduce the HIV-related high-risk behaviors among MSM and with sustained effects over a period of time.

dbCAN-seq update: CAZyme gene clusters and substrates in microbiomes.

Carbohydrate Active EnZymes (CAZymes) are significantly important for microbial communities to thrive in carbohydrate rich environments such as animal guts, agricultural soils, forest floors, and ocean sediments. Since 2017, microbiome sequencing and assembly have produced numerous metagenome assembled genomes (MAGs). We have updated our dbCAN-seq database (https://bcb.unl.edu/dbCAN_seq) to include the following new data and features: (i) ∼498 000 CAZymes and ∼169 000 CAZyme gene clusters (CGCs) from 9421 MAGs of four ecological (human gut, human oral, cow rumen, and marine) environments; (ii) Glycan substrates for 41 447 (24.54%) CGCs inferred by two novel approaches (dbCAN-PUL homology search and eCAMI subfamily majority voting) (the two approaches agreed on 4183 CGCs for substrate assignments); (iii) A redesigned CGC page to include the graphical display of CGC gene compositions, the alignment of query CGC and subject PUL (polysaccharide utilization loci) of dbCAN-PUL, and the eCAMI subfamily table to support the predicted substrates; (iv) A statistics page to organize all the data for easy CGC access according to substrates and taxonomic phyla; and (v) A batch download page. In summary, this updated dbCAN-seq database highlights glycan substrates predicted for CGCs from microbiomes. Future work will implement the substrate prediction function in our dbCAN2 web server.

Distribution and characterization of extrachromosomal circular DNA in colorectal cancer.

Extrachromosomal circular DNA (eccDNA) has been shown to play an important role in the amplification of tumor genes and the maintenance of intra-tumor genetic heterogeneity, although its complex functional mechanism still remains to be elucidated. As the top three common malignancies in the world, colorectal cancer (CRC) has been threatening human life and health, whose tumorigenesis and development may have elusive connection with eccDNAs. Here, we described the extensive distribution of eccDNAs in the CRC tissues using Circle-seq, which range in size from hundreds to thousands of base pairs (bp). The distribution in tumor tissues had aggregation and tendency compared with random in tumor-adjacent tissues, accompanied with smaller and more regular circle lengths. After sequencing and restoring, we found that the shedding sites of eccDNAs in CRC had similar tendency in chromosome distribution, and focused on tumor-associated genes. Meanwhile, we combined RNA sequencing to explore the correlation of eccDNA differential expression in the gene transcription and signaling pathways, confirming a connection between eccDNA and RNA somewhere. Subsequently, we validated eccDNAs in CRC cell lines and the potential consistency of the junction sites of eccDNAs in CRC tissues and cell lines. Using fragments of the cationic amino acid transporter SLC7A1 to synthesize eccDNAs, we discovered the role of eccDNAs in different regions within the gene.

Identification of novel lncRNAs associated with sensitivity of HIV antiretroviral therapy: A two-stage matched case-control study.

BACKGROUND: To identify long non-coding RNAs (lncRNAs) that may be used as potential biomarkers of sensitivity to antiretroviral therapy (ART) against human immunodeficiency virus (HIV) infection. METHOD: A two-stage matched case-control study was conducted. First, in the screening stage, peripheral blood lymphocytes (PBLs) of six subjects receiving lamivudine-based ART (3 ART-resistant and 3 ART-sensitive subjects with matching durations of ART) were subjected to comprehensive microarray expression profiling in order to screen out lncRNAs associated with ART sensitivity. Secondly, during the validation stage, promising lncRNAs were evaluated via a 1:4 matched case-control study using 50 subjects (10 ART-resistant and 40 ART-sensitive subjects with matching durations of ART). RESULTS: Seven lncRNAs were screened out (P < 1.06 × 10-3) in the first stage. Among these, two lncRNAs (n341598 and n407911) survived validation conducted at the second stage (n341598: P < 0.001; n407911: P = 0.007), while another lncRNA n406445 showed marginally significant (P = 0.049). All three showed higher expression in ART-resistant subjects compared to that in ART-sensitive subjects. The area under the ROC curve (AUC) for n341598 was 0.867 (95 % CI: 0.796-0.966; P < 0.001), which was better than that for n406445 (0.702) and n407911 (0.780). Meanwhile, the AUC for n341598 was better than that of any combination of the three lncRNAs. CONCLUSION: Our study identified three highly expressed lncRNAs in patients with HIV ART-resistant, among which the lncRNA n341598 may be utilized as an optimal biomarker to distinguish ART-resistant and ART-sensitive patients. Further studies aimed at revealing the molecular mechanisms underlying the regulation of ART sensitivity by n341598 are warranted to complement our findings.

Lactobacillus johnsonii alleviates colitis by TLR1/2-STAT3 mediated CD206+ macrophagesIL-10 activation.

Imbalance of gut microbiota homeostasis is related to the occurrence of ulcerative colitis (UC), and probiotics are thought to modulate immune microenvironment and repair barrier function. Here, in order to reveal the interaction between UC and gut microbiota, we screened a new probiotic strain by 16S rRNA sequencing from Dextran Sulfate Sodium (DSS)-induced colitis mice, and explored the mechanism and clinical relevance. Lactobacillus johnsonii (L. johnsonii), as a potential anti-inflammatory bacterium was decreased colonization in colitis mice. Gavage L. johnsonii could alleviate colitis by specifically increasing the proportion of intestinal macrophages and the secretion of Il-10 with macrophages depleted model and in Il10-/- mice. We identified this subset of immune cells activated by L. johnsonii as CD206+ macrophagesIL-10. Mechanistically, L. johnsonii supplementation enhanced the mobilization of CD206+ macrophagesIL-10 through the activation of STAT3 in vivo and in vitro. In addition, we revealed that TLR1/2 was essential for the activation of STAT3 and the recognition of L. johnsonii by macrophages. Clinically, there was positive correlation between the abundance of L. johnsonii and the expression level of MRC1, IL10 and TLR1/2 in UC tissues. L. johnsonii could activate native macrophages into CD206+ macrophages and release IL-10 through TLR1/2-STAT3 pathway to relieve experimental colitis. L. johnsonii may serve as an immunomodulator and anti-inflammatory therapeutic target for UC.

Subcellular distribution, localization, and function of noncoding RNAs.

Eukaryotic cells contain subcellular organelles with spatiotemporal regulation to coordinate various biochemical reactions. The various organelles perform their essential biological functions by employing specific biomolecules, including nucleic acids. Recent studies have revealed that noncoding RNAs (ncRNAs) are highly compartmentalized in cells and that their spatial distribution is intimately related to their functions. Dysregulation of subcellular ncRNAs can disrupt cellular homeostasis and cause human diseases. Mitochondria are responsible for energy generation to fuel cell growth and proliferation. Therefore, identifying mitochondria-associated ncRNAs helps to reveal new regulatory mechanisms and physiological functions of mitochondria. In this review, we summarize the latest advances in subcellular ncRNAs derived from either the nuclear or mitochondrial genome. We also discuss available biological approaches for investigating organelle-specific ncRNAs. Exploring the distribution and function of subcellular ncRNAs may facilitate the understanding of endomembrane dynamics and provide potential strategies for clinical transformation. This article is categorized under: RNA Export and Localization > RNA Localization Regulatory RNAs/RNAi/Riboswitches > Regulatory RNAs RNA Methods > RNA Analyses in Cells.

Comparison of different obesity indices associated with type 2 diabetes mellitus among different sex and age groups in Nantong, China: a cross-section study.

BACKGROUND: Obesity is associated with type 2 diabetes mellitus (T2DM). However, the obesity index that is most closely related to type 2 diabetes remains controversial. Therefore, the aim of this study was to compare the associations of five anthropometric indices (body mass index [BMI], body adiposity index, waist circumference [WC], waist-to-hip ratio, and waist-to-height ratio [WHtR]) with T2DM among Chinese adults divided into four groups according to sex and age. METHODS: A total of 4007 adult participants (1669 men and 2338 women) were included in the study. Odds ratios (ORs) and 95% confidence intervals were used with binary logistic regression models to estimate the risk of T2DM for each obesity index. Furthermore, we compared the area under the receiver operating characteristic curve (AUC) of each obesity index for the criterion of T2DM under the influence of risk factors. RESULTS: WC had the highest OR (3.211 and 1.452) and AUC (0.783 and 0.614) in both age groups of men. However, WHtR (OR = 2.366, AUC = 0.771) and BMI (OR = 1.596, AUC = 0.647) were the optimal criteria for predicting T2DM among females in the 18-59 and ≥ 60 years age groups, respectively. CONCLUSIONS: This study suggests that there is a positive association between obesity-related anthropometric indices and T2DM in different sex and age groups. WC appears to be the optimal anthropometric index for predicting T2DM in men. The optimal obesity indices related to T2DM were WHtR and BMI for women aged 18-59 and ≥ 60 years, respectively.

ZnS@BSA Nanoclusters Potentiate Efficacy of Cancer Immunotherapy.

Although immunotherapy such as immune checkpoint inhibitors has shown promising efficacy in cancer treatment, the responsiveness among patients is relatively limited. Activation of the cyclic guanosine monophosphate-adenosine monophosphate synthase/interferon gene stimulator (cGAS/STING) signaling pathway to upregulate innate immunity has become an emerging strategy for enhancing tumor immunotherapy. Herein, ZnS@BSA (bovine serum albumin) nanoclusters synthesized via a self-assembly approach are reported, where the released zinc ions under acidic tumor microenvironment significantly enhance cGAS/STING signals. Meanwhile, intracellular zinc ions can produce reactive oxygen species, which is further facilitated by the generated H2 S gas from ZnS@BSA via specifically inhibiting catalase in hepatocellular carcinoma cells. It is found that the nanoclusters activate the cGAS/STING signals in mice, which promotes the infiltration of CD8+ T cells at the tumor site and cross-presentation of dendritic cells, leading to an improved immunotherapy efficacy against hepatocellular carcinoma.

Micropeptide ASAP encoded by LINC00467 promotes colorectal cancer progression by directly modulating ATP synthase activity.

Emerging evidence has shown that open reading frames inside long noncoding RNAs (lncRNAs) could encode micropeptides. However, their roles in cellular energy metabolism and tumor progression remain largely unknown. Here, we identified a 94 amino acid-length micropeptide encoded by lncRNA LINC00467 in colorectal cancer. We also characterized its conservation across higher mammals, localization to mitochondria, and the concerted local functions. This peptide enhanced the ATP synthase construction by interacting with the subunits α and γ (ATP5A and ATP5C), increased ATP synthase activity and mitochondrial oxygen consumption rate, and thereby promoted colorectal cancer cell proliferation. Hence, this micropeptide was termed ATP synthase-associated peptide (ASAP). Furthermore, loss of ASAP suppressed patient-derived xenograft growth with attenuated ATP synthase activity and mitochondrial ATP production. Clinically, high expression of ASAP and LINC00467 predicted poor prognosis of colorectal cancer patients. Taken together, our findings revealed a colorectal cancer-associated micropeptide as a vital player in mitochondrial metabolism and provided a therapeutic target for colorectal cancer.

Construction of a human body model for acupuncture and moxibustion treatment by colored Petri nets.

Acupuncture and moxibustion treatment has been widely spread all over the world because it has few side effects and is effective for ahead sick and incurable disease. However, the treatment is often performed empirically and clinically, and the mechanism and process of the treatment are not yet scientifically elucidated. Therefore, it is required to establish objective and unified research methods and evaluation criteria that incorporate modern Western medicine and scientific and technological viewpoints. In this paper, a human body model is constructed, which includes the internal organs and the meridians for acupuncture and moxibustion treatment based on traditional Chinese medicine using colored Petri nets. This model aims at expressing the relationship between acupoints and internal organs realistically and accurately in acupuncture and moxibustion treatment, and leading to realization of an objective analysis method of the mechanism and process of acupuncture and moxibustion treatment. Firstly, the calculation of the acupoints' efficacy on internal organs is discussed, and measurement equations and model construction methods are proposed. Next, an interface is established as a bridge to connect the internal organs and the meridians with acupoints. By Java language, a simulation system is developed based on the proposed Petri net model. Finally, simulations of acupuncture and moxibustion treatment are performed to verify the validity of model.

A. Muciniphila Suppresses Colorectal Tumorigenesis by Inducing TLR2/NLRP3-Mediated M1-Like TAMs.

The interplay between gut microbiota and the host immune system is emerging as a factor in the pathogenesis of colorectal cancer. Here, we set out to identify the effect of Akkermansia muciniphila (A. muciniphila) on colorectal cancer pathogenesis. A. muciniphila abundance was significantly reduced in patients with colorectal cancer from two independent clinical cohorts and the GMrepo dataset. Supplementation with A. muciniphila suppressed colonic tumorigenesis in ApcMin/+ mice and the growth of implanted HCT116 or CT26 tumors in nude mice. Mechanistically, A. muciniphila facilitated enrichment of M1-like macrophages in an NLRP3-dependent manner in vivo and in vitro. As a consequence, NLRP3 deficiency in macrophages attenuated the tumor-suppressive effect of A. muciniphila. In addition, we revealed that TLR2 was essential for the activation of the NF-κB/NLRP3 pathway and A. muciniphila induced M1-like macrophage response. We observed positive correlations between M1-like macrophages, NLRP3/TLR2 and A. muciniphila in patients with colorectal cancer, which corroborated these findings. In summary, A. muciniphila-induced M1-like macrophages provide a therapeutic target in the colorectal cancer tumor microenvironment.

A phosphatidic acid-binding lncRNA SNHG9 facilitates LATS1 liquid-liquid phase separation to promote oncogenic YAP signaling.

Long noncoding RNAs (lncRNAs) are emerging as a new class of important regulators of signal transduction in tissue homeostasis and cancer development. Liquid-liquid phase separation (LLPS) occurs in a wide range of biological processes, while its role in signal transduction remains largely undeciphered. In this study, we uncovered a lipid-associated lncRNA, small nucleolar RNA host gene 9 (SNHG9) as a tumor-promoting lncRNA driving liquid droplet formation of Large Tumor Suppressor Kinase 1 (LATS1) and inhibiting the Hippo pathway. Mechanistically, SNHG9 and its associated phosphatidic acids (PA) interact with the C-terminal domain of LATS1, promoting LATS1 phase separation and inhibiting LATS1-mediated YAP phosphorylation. Loss of SNHG9 suppresses xenograft breast tumor growth. Clinically, expression of SNHG9 positively correlates with YAP activity and breast cancer progression. Taken together, our results uncover a novel regulatory role of a tumor-promoting lncRNA (i.e., SNHG9) in signal transduction and cancer development by facilitating the LLPS of a signaling kinase (i.e., LATS1).

Comparison of different obesity indices related with hypertension among different sex and age groups in China.

BACKGROUND AND AIMS: To compare the relationships of five obesity-related routine anthropometric indicators (body mass index (BMI), body adiposity index (BAI), waist circumference (WC), waist-to-hip ratio (WHR), waist-to-height ratio (WHtR)) for hypertension in both sexes and among different age groups of the Chinese population. METHODS AND RESULTS: A total of 12,064 adult participants (5638 males and 6426 females) were included. Odds ratios (OR) and 95% confidence intervals were used with binary logistic regression models to estimate the risk of hypertension for each obesity index. For the males, WHtR had the highest OR value in all age groups. The degrees of correlation between hypertension and the obesity indices for different age groups were different among the females. WC, BMI, and WHtR were the highest in the 18-44, 45-59, and ≥60 years age groups, respectively. Furthermore, we compared the area under the ROC curve (AUC) of each obesity index for the criterion of hypertension under the influence of risk factors. For the males, the AUC of WHtR was the largest (0.814, 0.710, and 0.662). WC (AUC = 0.820), BMI (AUC = 0.765), and WHtR (AUC = 0.668) tended to be the best criteria for hypertension among females in the 18-44, 45-59, and ≥60 years age groups respectively. In addition, BAI, as an obesity indicator proposed in recent years, has a positive association with hypertension except in 18-44 years women, which was not stronger than other obesity indicators. CONCLUSIONS: For males, WHtR appears to be the best obesity index related with hypertension. For young, middle-aged, and elderly women, the best obesity indices related with hypertension are WC, BMI, and WHtR, respectively.

Mitochondrial long non-coding RNA GAS5 tunes TCA metabolism in response to nutrient stress.

Organelles use specialized molecules to regulate their essential cellular processes. However, systematically elucidating the subcellular distribution and function of molecules such as long non-coding RNAs (lncRNAs) in cellular homeostasis and diseases has not been fully achieved. Here, we reveal the diverse and abundant subcellular distribution of organelle-associated lncRNAs from mitochondria, lysosomes and endoplasmic reticulum. Among them, we identify the mitochondrially localized lncRNA growth-arrest-specific 5 (GAS5) as a tumour suppressor in maintaining cellular energy homeostasis. Mechanistically, energy-stress-induced GAS5 modulates mitochondrial tricarboxylic acid flux by disrupting metabolic enzyme tandem association of fumarate hydratase, malate dehydrogenase and citrate synthase, the canonical members of the tricarboxylic acid cycle. GAS5 negatively correlates with levels of its associated mitochondrial metabolic enzymes in tumours and benefits overall survival in individuals with breast cancer. Together, our detailed annotation of subcellular lncRNA distribution identifies a functional role for lncRNAs in regulating cellular metabolic homeostasis, highlighting organelle-associated lncRNAs as potential clinical targets to manipulate cellular metabolism and diseases.