bims-nenemi 2024-04-07 papers

bims-nenemi

Biomed News

on Neuroinflammation, neurodegeneration and mitochondria

Issue of 2024–04–07
fourteen papers selected by
Marco Tigano, Thomas Jefferson University

mtDNA analysis using Mitopore.
Mitochondrial injury induced by a Salmonella genotoxin triggers the proinflammatory senescence-associated secretory phenotype.
Ancestral allele of DNA polymerase gamma modifies antiviral tolerance.
Inhibition of mtDNA-PRRs pathway-mediated sterile inflammation by astragalus polysaccharide protects against transport stress-induced cardiac injury in chicks.
Vitamin B12 status and folic acid supplementation influence mitochondrial heteroplasmy levels in mice.
Ratiometric Near-Infrared Fluorescent Probe Monitors Ferroptosis in HCC Cells by Imaging HClO in Mitochondria.
Human CCDC51 and yeast Mdm33 are functionally conserved mitochondrial inner membrane proteins that demarcate a subset of organelle fission events.
A genetically encoded fluorescent protein sensor for mitochondrial membrane damage detection.
FAILLA MEMORIAL LECTUREHow We Got Here: One Laboratory's Odyssey in the Field of Radiation-Inducible Genes.
Chronic replication stress invokes mitochondria dysfunction via impaired parkin activity.
Metabolic Reprogramming of the Retinal Pigment Epithelium by Cytokines Associated with Age-related Macular Degeneration.
miR-146a-5p mediates inflammation-induced β cell mitochondrial dysfunction and apoptosis.
YTHDC1 cooperates with the THO complex to prevent RNA damage-induced DNA breaks.
Intracellular acidification and glycolysis modulate inflammatory pathway in senescent cells.

Mol Ther Methods Clin Dev. 2024 Jun 13. 32(2): 101231

mtDNA analysis using Mitopore.

Jochen Dobner, Thach Nguyen, Mario Gustavo Pavez-Giani, Lukas Cyganek, Felix Distelmaier, Jean Krutmann, Alessandro Prigione, Andrea Rossi.

  Mitochondrial DNA (mtDNA) analysis is crucial for the diagnosis of mitochondrial disorders, forensic investigations, and basic research. Existing pipelines are complex, expensive, and require specialized personnel. In many cases, including the diagnosis of detrimental single nucleotide variants (SNVs), mtDNA analysis is still carried out using Sanger sequencing. Here, we developed a simple workflow and a publicly available webserver named Mitopore that allows the detection of mtDNA SNVs, indels, and haplogroups. To simplify mtDNA analysis, we tailored our workflow to process noisy long-read sequencing data for mtDNA analysis, focusing on sequence alignment and parameter optimization. We implemented Mitopore with eliBQ (eliminate bad quality reads), an innovative quality enhancement that permits the increase of per-base quality of over 20% for low-quality data. The whole Mitopore workflow and webserver were validated using patient-derived and induced pluripotent stem cells harboring mtDNA mutations. Mitopore streamlines mtDNA analysis as an easy-to-use fast, reliable, and cost-effective analysis method for both long- and short-read sequencing data. This significantly enhances the accessibility of mtDNA analysis and reduces the cost per sample, contributing to the progress of mtDNA-related research and diagnosis.

Keywords:  Mitopore; ONT; clinical mtDNA diagnosis; forensic mtDNA analysis; haplogroups; iPSCs quality control; long-read sequencing; mtDNA analysis; mtDNA heteroplasmy; webserver

DOI:  https://doi.org/10.1016/j.omtm.2024.101231
Nat Commun. 2024 Mar 30. 15(1): 2778

Mitochondrial injury induced by a Salmonella genotoxin triggers the proinflammatory senescence-associated secretory phenotype.

Han-Yi Chen, Wan-Chen Hsieh, Yu-Chieh Liu, Huei-Ying Li, Po-Yo Liu, Yu-Ting Hsu, Shao-Chun Hsu, An-Chi Luo, Wei-Chen Kuo, Yi-Jhen Huang, Gan-Guang Liou, Meng-Yun Lin, Chun-Jung Ko, Hsing-Chen Tsai, Shu-Jung Chang.

Bacterial genotoxins damage host cells by targeting their chromosomal DNA. In the present study, we demonstrate that a genotoxin of Salmonella Typhi, typhoid toxin, triggers the senescence-associated secretory phenotype (SASP) by damaging mitochondrial DNA. The actions of typhoid toxin disrupt mitochondrial DNA integrity, leading to mitochondrial dysfunction and disturbance of redox homeostasis. Consequently, it facilitates the release of damaged mitochondrial DNA into the cytosol, activating type I interferon via the cGAS-STING pathway. We also reveal that the GCN2-mediated integrated stress response plays a role in the upregulation of inflammatory components depending on the STING signaling axis. These SASP factors can propagate the senescence effect on T cells, leading to senescence in these cells. These findings provide insights into how a bacterial genotoxin targets mitochondria to trigger a proinflammatory SASP, highlighting a potential therapeutic target for an anti-toxin intervention.

DOI: https://doi.org/10.1038/s41467-024-47190-y
Nature. 2024 Apr 03.

Ancestral allele of DNA polymerase gamma modifies antiviral tolerance.

Yilin Kang, Jussi Hepojoki, Rocio Sartori Maldonado, Takayuki Mito, Mügen Terzioglu, Tuula Manninen, Ravi Kant, Sachin Singh, Alaa Othman, Rohit Verma, Johanna Uusimaa, Kirmo Wartiovaara, Lauri Kareinen, Nicola Zamboni, Tuula Anneli Nyman, Anders Paetau, Anja Kipar, Olli Vapalahti, Anu Suomalainen.

Mitochondria are critical modulators of antiviral tolerance through the release of mitochondrial RNA and DNA (mtDNA and mtRNA) fragments into the cytoplasm after infection, activating virus sensors and type-I interferon (IFN-I) response1-4. The relevance of these mechanisms for mitochondrial diseases remains understudied. Here we investigated mitochondrial recessive ataxia syndrome (MIRAS), which is caused by a common European founder mutation in DNA polymerase gamma (POLG1)5. Patients homozygous for the MIRAS variant p.W748S show exceptionally variable ages of onset and symptoms5, indicating that unknown modifying factors contribute to disease manifestation. We report that the mtDNA replicase POLG1 has a role in antiviral defence mechanisms to double-stranded DNA and positive-strand RNA virus infections (HSV-1, TBEV and SARS-CoV-2), and its p.W748S variant dampens innate immune responses. Our patient and knock-in mouse data show that p.W748S compromises mtDNA replisome stability, causing mtDNA depletion, aggravated by virus infection. Low mtDNA and mtRNA release into the cytoplasm and a slow IFN response in MIRAS offer viruses an early replicative advantage, leading to an augmented pro-inflammatory response, a subacute loss of GABAergic neurons and liver inflammation and necrosis. A population databank of around 300,000 Finnish individuals6 demonstrates enrichment of immunodeficient traits in carriers of the POLG1 p.W748S mutation. Our evidence suggests that POLG1 defects compromise antiviral tolerance, triggering epilepsy and liver disease. The finding has important implications for the mitochondrial disease spectrum, including epilepsy, ataxia and parkinsonism.

DOI: https://doi.org/10.1038/s41586-024-07260-z
Poult Sci. 2024 Mar 13. pii: S0032-5791(24)00217-7. [Epub ahead of print]103(5): 103638

Inhibition of mtDNA-PRRs pathway-mediated sterile inflammation by astragalus polysaccharide protects against transport stress-induced cardiac injury in chicks.

Jian Chen, Wang-Ye Xu, Yuan Gu, Yi-Xi Tang, Xiang-Wen Xu, Xue-Nan Li, Jin-Long Li.

  Transport stress (TS) not only weakens poultry performance but also affects animal welfare. Additionally, TS can evoke cardiac damage by triggering sterile inflammation in chicks, but the underlying mechanism is not fully understood. Here, we aimed to elucidate how TS induces sterile inflammation and heart injury and to clarify the antagonism effect of astragalus polysaccharides (APS). We randomly divided 60 chicks (one-day-old female) into 5 groups (n = 12): Control_0h (Con_0h) group (chicks were slaughtered at initiation), Control group (stress-free control), TS group (simulated TS exposure for 8 h), TS plus water (TS+W) group, and TS plus APS (TS+APS) group. Before simulation transport, the chicks of TS+W and TS+APS groups were, respectively, dietary with 100 μL of water or APS (250 μg/mL). H&E staining was employed for cardiac histopathological observation. ELISA assay was used to measure oxidative stress marker levels (GSH, GPX, GST, and MDA). A commercial kit was used to isolate the mitochondrial portion, and qRT-PCR was employed to measure the mitochondrial DNA (mtDNA) levels. Furthermore, we evaluated the activity of mtDNA-mediated NF-κB, NLRP3 inflammasome, and cGAS-STING inflammatory pathways and the expression of downstream inflammatory factors by Western Blotting or qRT-PCR. Our findings revealed that APS notably relieved TS-induced myocardial histopathological lesions and infiltrations. Likewise, the decrease in proinflammatory factors (TNF-α, IL-1β, and IL-6) and IFN-β by APS further supported this result. Meanwhile, TS caused severe oxidative stress in the chick heart, as evidenced by decreased antioxidant enzymes and increased MDA. Importantly, APS prevented mtDNA stress and leakage by reducing oxidative stress. Interestingly, TS-induced mtDNA leakage caused a series of inflammation events via mtDNA-PRRs pathways, including TLR21-NF-κB, NLRP3 inflammasome, and cGAS-STING signaling. Encouragingly, all these adverse changes related to inflammation events induced by mtDNA-PRRs activation were all relieved by APS treatment. In summary, our findings provide the first evidence that inhibition of mtDNA-PRRs pathway-mediated sterile inflammation by APS could protect against TS-induced cardiac damage in chicks.

Keywords:  NF-κB; animal welfare; cGAS-STING pathway; chick; mitochondrial stress

DOI:  https://doi.org/10.1016/j.psj.2024.103638
PNAS Nexus. 2024 Apr;3(4): pgae116

Vitamin B12 status and folic acid supplementation influence mitochondrial heteroplasmy levels in mice.

Darren J Walsh, David J Bernard, Joanna L Fiddler, Faith Pangilinan, Madison Esposito, Denise Harold, Martha S Field, Anne Parle-McDermott, Lawrence C Brody.

  One-carbon metabolism is a complex network of metabolic reactions that are essential for cellular function including DNA synthesis. Vitamin B12 and folate are micronutrients that are utilized in this pathway and their deficiency can result in the perturbation of one-carbon metabolism and subsequent perturbations in DNA replication and repair. This effect has been well characterized in nuclear DNA but to date, mitochondrial DNA (mtDNA) has not been investigated extensively. Mitochondrial variants have been associated with several inherited and age-related disease states; therefore, the study of factors that impact heteroplasmy are important for advancing our understanding of the mitochondrial genome's impact on human health. Heteroplasmy studies require robust and efficient mitochondrial DNA enrichment to carry out in-depth mtDNA sequencing. Many of the current methods for mtDNA enrichment can introduce biases and false-positive results. Here, we use a method that overcomes these limitations and have applied it to assess mitochondrial heteroplasmy in mouse models of altered one-carbon metabolism. Vitamin B12 deficiency was found to cause increased levels of mitochondrial DNA heteroplasmy across all tissues that were investigated. Folic acid supplementation also contributed to elevated mitochondrial DNA heteroplasmy across all mouse tissues investigated. Heteroplasmy analysis of human data from the Framingham Heart Study suggested a potential sex-specific effect of folate and vitamin B12 status on mitochondrial heteroplasmy. This is a novel relationship that may have broader consequences for our understanding of one-carbon metabolism, mitochondrial-related disease and the influence of nutrients on DNA mutation rates.

Keywords:  cobalamin; folic acid; heteroplasmy; mitochondria; vitamin B12

DOI:  https://doi.org/10.1093/pnasnexus/pgae116
Anal Chem. 2024 Apr 04.

Ratiometric Near-Infrared Fluorescent Probe Monitors Ferroptosis in HCC Cells by Imaging HClO in Mitochondria.

Bo Zhao, Xionghao Xu, Xin Wen, Qingqing Liu, Chao Dong, Qingkun Yang, Chunhua Fan, Juyoung Yoon, Zhengliang Lu.

Hypochlorous acid (HClO) is a typical endogenous ROS produced mainly in mitochondria, and it has strong oxidative properties. Abnormal HClO levels lead to mitochondrial dysfunction, strongly associated with various diseases. It has been shown that HClO shows traces of overexpression in cells of both ferroptosis and hepatocellular carcinoma (HCC). Therefore, visualization of HClO levels during ferroptosis of HCC is important to explore its physiological and pathological roles. So far, there has been no report on the visualization of HClO in ferroptosis of HCC. Thus, we present a ratiometric near-infrared (NIR) fluorescent probe Mito-Rh-S which visualized for the first time the fluctuation of HClO in mitochondria during ferroptosis of HCC. Mito-Rh-S has an ultrafast response rate (2 s) and large emission shift (115 nm). Mito-Rh-S was constructed based on the PET sensing mechanism and thus has a high signal-to-noise ratio. The cell experiments of Mito-Rh-S demonstrated that Fe2+- and erastin-induced ferroptosis in HepG2 cells resulted in elevated levels of mitochondrial HClO and that high concentration levels of Fe2+ and erastin cause severe mitochondrial damage and oxidative stress and had the potential to kill HepG2 cells. By regulating the erastin concentration, erastin induction time, and treatment of the ferroptosis model, Mito-Rh-S can accurately detect the fluctuation of mitochondrial HClO levels during ferroptosis in HCC.

DOI: https://doi.org/10.1021/acs.analchem.4c00328
bioRxiv. 2024 Mar 22. pii: 2024.03.21.586162. [Epub ahead of print]

Human CCDC51 and yeast Mdm33 are functionally conserved mitochondrial inner membrane proteins that demarcate a subset of organelle fission events.

Alia R Edington, Olivia M Connor, Madeleine Marlar-Pavey, Jonathan R Friedman.

Mitochondria are highly dynamic double membrane-bound organelles that exist in a semi- continuous network. Mitochondrial morphology arises from the complex interplay of numerous processes, including opposing fission and fusion dynamics and the formation of highly organized cristae invaginations of the inner membrane. While extensive work has examined the mechanisms of mitochondrial fission, it remains unclear how fission is coordinated across two membrane bilayers and how mitochondrial inner membrane organization is coupled with mitochondrial fission dynamics. Previously, the yeast protein Mdm33 was implicated in facilitating fission by coordinating with inner membrane homeostasis pathways. However, Mdm33 is not conserved outside fungal species and its precise mechanistic role remains unclear. Here, we use a bioinformatic approach to identify a putative structural ortholog of Mdm33 in humans, CCDC51 (also called MITOK). We find that the mitochondrial phenotypes associated with altered CCDC51 levels implicate the protein in mitochondrial fission dynamics. Further, using timelapse microscopy, we spatially and temporally resolve Mdm33 and CCDC51 to a subset of mitochondrial fission events. Finally, we show that CCDC51 can partially rescue yeast Δ mdm33 cells, indicating the proteins are functionally analogous. Our data reveal that Mdm33/CCDC51 are conserved mediators of mitochondrial morphology and suggest the proteins play a crucial role in maintaining normal mitochondrial dynamics and organelle homeostasis.

DOI: https://doi.org/10.1101/2024.03.21.586162
Biochem Biophys Res Commun. 2024 Mar 27. pii: S0006-291X(24)00372-3. [Epub ahead of print]709 149836

A genetically encoded fluorescent protein sensor for mitochondrial membrane damage detection.

Qian Liu, Dianbing Wang, Mengmeng Cui, Min Li, Xian-En Zhang.

  Mitochondria are essential cellular organelles; detecting mitochondrial damage is crucial in cellular biology and toxicology. Compared with existing chemical probe detection methods, genetically encoded fluorescent protein sensors can directly indicate cellular and molecular events without involving exogenous reagents. In this study, we introduced a molecular sensor system, MMD-Sensor, for monitoring mitochondrial membrane damage. The sensor consists of two molecular modules. Module I is a fusion structure of the mitochondrial localization sequence (MLS), AIF cleavage site sequence (CSS), nuclear localization sequence (NLS), N-terminus of mNeonGreen and mCherry. Module II is a fusion structure of the C-terminus of mNeonGreen, NLS sequence, and mtagBFP2. Under normal condition, Module I is constrained in the inner mitochondrial membrane anchored by MLS, while Module II is restricted to the nucleus by its NLS fusion component. If the mitochondrial membrane is damaged, CSS is cut from the inner membrane, causing Module I to shift into the nucleus guided by the NLS fusion component. After Module I enters the nucleus, the N- and C-terminus of mNeonGreen meet each other and rebuild its intact 3D structure through fragment complementation and thus generates green fluorescence in the nucleus. Dynamic migration of red fluorescence from mitochondria to the nucleus and generation of green fluorescence in the nucleus indicate mitochondrial membrane damage. Using the MMD-Sensor, mitochondrial membrane damage induced by various reagents, such as uncoupling agents, ATP synthase inhibitors, monovalent cationic carriers, and ROS, in HeLa and 293T cells are directly observed and evaluated.

Keywords:  Apoptosis-inducing factor; Bimolecular fluorescence complementation; Biosensor; Genetically encoded fluorescent protein sensor; Mitochondrial membrane damage

DOI:  https://doi.org/10.1016/j.bbrc.2024.149836
Radiat Res. 2024 Apr 04.

FAILLA MEMORIAL LECTUREHow We Got Here: One Laboratory's Odyssey in the Field of Radiation-Inducible Genes.

Arslon Humayun, Lorreta Yun-Tien Lin, Henghong Li, Albert J Fornace.

This review focuses on early discoveries that contributed to our understanding and the scope of transcriptional responses after radiation damage. Before the development of modern approaches to assess overall global transcriptomic responses, the idea that mammalian cells could respond to DNA-damaging agents in a manner analogous to bacteria was not generally accepted. To investigate this possibility, the development of technology to identify differentially expressed low-abundance transcripts substantially facilitated our appreciation that DNA damaging agents like UV radiation and subsequently ionizing radiation did in fact produce robust transcriptional responses. Here we focus on our identification and characterization of radiation-inducible genes, and how even early studies on stress gene signaling highlighted the broad scope of transcriptional responses to radiation damage. Since then, the central role of transcriptional responses to radiation injury in maintaining genome integrity has been highlighted in many processes, including cell cycle checkpoint control, resistance to cancer by p53 and other key factors, cell senescence, and metabolism.

DOI: https://doi.org/10.1667/RADE-23-00205.1
Sci Rep. 2024 Apr 03. 14(1): 7877

Chronic replication stress invokes mitochondria dysfunction via impaired parkin activity.

Tsuyoshi Kawabata, Reiko Sekiya, Shinji Goto, Tao-Sheng Li.

Replication stress is a major contributor to tumorigenesis because it provides a source of chromosomal rearrangements via recombination events. PARK2, which encodes parkin, a regulator of mitochondrial homeostasis, is located on one of the common fragile sites that are prone to rearrangement by replication stress, indicating that replication stress may potentially impact mitochondrial homeostasis. Here, we show that chronic low-dose replication stress causes a fixed reduction in parkin expression, which is associated with mitochondrial dysfunction, indicated by an increase in mtROS. Consistent with the major role of parkin in mitophagy, reduction in parkin protein expression was associated with a slight decrease in mitophagy and changes in mitochondrial morphology. In contrast, cells expressing ectopic PARK2 gene does not show mtROS increases and changes in mitochondrial morphology even after exposure to chronic replication stress, suggesting that intrinsic fragility at PARK2 loci associated with parkin reduction is responsible for mitochondrial dysfunction caused by chronic replication stress. As endogenous replication stress and mitochondrial dysfunction are both involved in multiple pathophysiology, our data support the therapeutic development of recovery of parkin expression in human healthcare.

DOI: https://doi.org/10.1038/s41598-024-58656-w
Biosci Rep. 2024 Apr 03. pii: BSR20231904. [Epub ahead of print]

Metabolic Reprogramming of the Retinal Pigment Epithelium by Cytokines Associated with Age-related Macular Degeneration.

David S Hansman, Yuefang Ma, Daniel Thomas, Justine R Smith, Robert J Casson, Daniel Peet.

  The complex metabolic relationship between the retinal pigment epithelium (RPE) and photoreceptors is essential for maintaining retinal health. Recent evidence indicates the RPE acts as an adjacent lactate sink, suppressing glycolysis in the epithelium in order to maximize glycolysis in the photoreceptors. Dysregulated metabolism within the RPE has been implicated in the pathogenesis of age-related macular degeneration (AMD), a leading cause of vision loss. In this study, we investigate the effects of four cytokines associated with AMD, TNFα, TGF-β2, IL-6, and IL-1β, as well as a cocktail containing all four cytokines, on RPE metabolism using ARPE-19 cells, primary human RPE cells, and ex vivo rat eyecups. Strikingly, we found cytokine-specific changes in numerous metabolic markers including lactate production, glucose consumption, extracellular acidification rate, and oxygen consumption rate accompanied by increases in total mitochondrial volume and ATP production. Together, all four cytokines, could potently override the constitutive suppression of glycolysis in the RPE, through a mechanism independent by PI3K/AKT, MEK/ERK, or NF-κB. Finally, we observed changes in glycolytic gene expression with cytokine treatment, including in lactate dehydrogenase subunit and glucose transporter expression. Our findings provide new insights into the metabolic changes in the RPE under inflammatory conditions and highlight potential therapeutic targets for AMD.

Keywords:  carbohydrate metabolism; cytokines; glycolysis; inflammation; retinal degeneration; retinal pigment epithelium

DOI:  https://doi.org/10.1042/BSR20231904
bioRxiv. 2024 Mar 19. pii: 2024.03.18.585543. [Epub ahead of print]

miR-146a-5p mediates inflammation-induced β cell mitochondrial dysfunction and apoptosis.

Preethi Krishnan, Renato Chaves Souto Branco, Staci A Weaver, Garrick Chang, Chih-Chun Lee, Farooq Syed, Carmella Evans-Molina.

We previously showed that miR-146a-5p is upregulated in pancreatic islets treated with pro-inflammatory cytokines. Others have reported that miR-146a-5p overexpression is associated with β cell apoptosis and impaired insulin secretion. However, the molecular mechanisms mediating these effects remain elusive. To investigate the role of miR-146a-5p in β cell function, we developed stable MIN6 cell lines to either overexpress or inhibit the expression of miR-146a-5p. Monoclonal cell populations were treated with pro-inflammatory cytokines (IL-1β, IFNγ, and TNFα) to model T1D in vitro . We found that overexpression of miR-146a-5p increased cell death under conditions of inflammatory stress, whereas inhibition of miR-146a-5p reversed these effects. Additionally, inhibition of miR-146a-5p increased mitochondrial DNA copy number, respiration rate, and ATP production. Further, RNA sequencing data showed enrichment of pathways related to insulin secretion, apoptosis, and mitochondrial function when the expression levels of miR-146a-5p were altered. Finally, a temporal increase in miR-146a-5p expression levels and a decrease in mitochondria function markers was observed in islets derived from NOD mice. Collectively, these data suggest that miR-146a-5p may promote β cell dysfunction and death during inflammatory stress by suppressing mitochondrial function.

DOI: https://doi.org/10.1101/2024.03.18.585543
bioRxiv. 2024 Mar 14. pii: 2024.03.14.585107. [Epub ahead of print]

YTHDC1 cooperates with the THO complex to prevent RNA damage-induced DNA breaks.

Ning Tsao, Jennifer Olabode, Rebecca Rodell, Hua Sun, Joshua R Brickner, Miaw-Sheue Tsai, Elizabeth A Pollina, Chun-Kan Chen, Nima Mosammaparast.

Certain environmental toxins are nucleic acid damaging agents, as are many chemotherapeutics used for cancer therapy. These agents induce various adducts in DNA as well as RNA. Indeed, most of the nucleic acid adducts (>90%) formed due to these chemicals, such as alkylating agents, occur in RNA 1 . However, compared to the well-studied mechanisms for DNA alkylation repair, the biological consequences of RNA damage are largely unexplored. Here, we demonstrate that RNA damage can directly result in loss of genome integrity. Specifically, we show that a human YTH domain-containing protein, YTHDC1, regulates alkylation damage responses in association with the THO complex (THOC) 2 . In addition to its established binding to N 6-methyladenosine (m6A)-containing RNAs, YTHDC1 binds to N 1-methyladenosine (m1A)-containing RNAs upon alkylation. In the absence of YTHDC1, alkylation damage results in increased alkylation damage sensitivity and DNA breaks. Such phenotypes are fully attributable to RNA damage, since an RNA-specific dealkylase can rescue these phenotypes. These R NA d amage-induced DNA b reaks (RDIBs) depend on R-loop formation, which in turn are processed by factors involved in transcription-coupled nucleotide excision repair. Strikingly, in the absence of YTHDC1 or THOC, an RNA m1A methyltransferase targeted to the nucleus is sufficient to induce DNA breaks. Our results uncover a unique role for YTHDC1-THOC in base damage responses by preventing RDIBs, providing definitive evidence for how damaged RNAs can impact genomic integrity.

DOI: https://doi.org/10.1101/2024.03.14.585107
J Biochem. 2024 Apr 02. pii: mvae032. [Epub ahead of print]

Intracellular acidification and glycolysis modulate inflammatory pathway in senescent cells.

Satoshi Kawakami, Yoshikazu Johmura, Makoto Nakanishi.

  Senescent cells accumulate in various organs with aging, and its accumulation induces chronic inflammation and age-related physiological dysfunctions. Several remodeling of intracellular environments has been identified in senescent cells, including enlargement of cell / nuclear size and intracellular acidification. Although these alterations of intracellular environments were reported to be involved in unique characteristics of senescent cells, the contribution of intracellular acidification to senescence-associated cellular phenotypes is poorly understood. Here, we identified that upregulation of TXNIP and its paralog ARRDC4 as a hallmark of intracellular acidification in addition to KGA-type GLS1. These genes were also upregulated in response to senescence-associated intracellular acidification. Neutralization of the intracellular acidic environment ameliorated not only senescence-related upregulation of TXNIP, ARRDC4, and KGA, but also inflammation-related genes, possibly through suppression of PDK-dependent anaerobic glycolysis. Furthermore, we found that expression of the intracellular acidification-induced genes, TXNIP and ARRDC4, correlated with inflammatory gene expression in heterogeneous senescent cell population in vitro and even in vivo, implying that the contribution of intracellular pH to senescence-associated cellular features, such as SASP.

Keywords:  SASP; glycolysis; intracellular acidification; senescence

DOI:  https://doi.org/10.1093/jb/mvae032