bims-nenemi Biomed News
on Neuroinflammation, neurodegeneration and mitochondria
Issue of 2022–08–28
seventeen papers selected by
Marco Tigano, Thomas Jefferson University
  1. PT-112 Induces Mitochondrial Stress and Immunogenic Cell Death, Targeting Tumor Cells with Mitochondrial Deficiencies.
  2. Aberrant RNA processing contributes to the pathogenesis of mitochondrial diseases in trans-mitochondrial mouse model carrying mitochondrial tRNALeu(UUR) with a pathogenic A2748G mutation.
  3. ER, Mitochondria, and ISR Regulation by mt-HSP70 and ATF5 upon Procollagen Misfolding in Osteoblasts.
  4. Premature aging is associated with higher levels of 8-oxoguanine and increased DNA damage in the Polg mutator mouse.
  5. Leaky mitochondria.
  6. The Role of Mitochondrial Mutations in Chronification of Inflammation: Hypothesis and Overview of Own Data.
  7. Common methods in mitochondrial research (Review).
  8. Mitofusin 2 mutation drives cell proliferation in Charcot-Marie-Tooth 2A fibroblasts.
  9. Zeb1 sustains hematopoietic stem cell functions by suppressing mitofusin-2-mediated mitochondrial fusion.
  10. The protein arginine methyltransferase PRMT9 attenuates MAVS activation through arginine methylation.
  11. Macrophage Polarization Mediated by Mitochondrial Dysfunction Induces Adipose Tissue Inflammation in Obesity.
  12. DNA damage induces STING mediated IL-6-STAT3 survival pathway in triple-negative breast cancer cells and decreased survival of breast cancer patients.
  13. Nicotinamide mitigates radiation injury in submandibular gland by protecting mitochondrial structure and functions.
  14. scRNA-seq reveals ATPIF1 activity in control of T cell antitumor activity.
  15. NAD+ metabolism drives astrocyte proinflammatory reprogramming in central nervous system autoimmunity.
  16. Integrating cell morphology with gene expression and chemical structure to aid mitochondrial toxicity detection.
  17. Microglial Activation and Oxidative Stress in PM2.5-Induced Neurodegenerative Disorders.
  1. Cancers (Basel). 2022 Aug 09. pii: 3851. [Epub ahead of print]14(16):
    PT-112 Induces Mitochondrial Stress and Immunogenic Cell Death, Targeting Tumor Cells with Mitochondrial Deficiencies.
    Ruth Soler-Agesta, Joaquín Marco-Brualla, Martha Minjárez-Sáenz, Christina Y Yim, Marta Martínez-Júlvez, Matthew R Price, Raquel Moreno-Loshuertos, Tyler D Ames, José Jimeno, Alberto Anel.
      PT-112 is a novel pyrophosphate-platinum conjugate, with clinical activity reported in advanced pretreated solid tumors. While PT-112 has been shown to induce robust immunogenic cell death (ICD) in vivo but only minimally bind DNA, the molecular mechanism underlying PT-112 target disruption in cancer cells is still under elucidation. The murine L929 in vitro system was used to test whether differential metabolic status alters PT-112's effects, including cell cytotoxicity. The results showed that tumor cells presenting mutations in mitochondrial DNA (mtDNA) (L929dt and L929dt cybrid cells) and reliant on glycolysis for survival were more sensitive to cell death induced by PT-112 compared to the parental and cybrid cells with an intact oxidative phosphorylation (OXPHOS) pathway (L929 and dtL929 cybrid cells). The type of cell death induced by PT-112 did not follow the classical apoptotic pathway: the general caspase inhibitor Z-VAD-fmk did not inhibit PT-112-induced cell death, alone or in combination with the necroptosis inhibitor necrostatin-1. Interestingly, PT-112 initiated autophagy in all cell lines, though this process was not complete. Autophagy is known to be associated with an integrated stress response in cancer cells and with subsequent ICD. PT-112 also induced a massive accumulation of mitochondrial reactive oxygen species, as well as changes in mitochondrial polarization-only in the sensitive cells harboring mitochondrial dysfunction-along with calreticulin cell-surface exposure consistent with ICD. PT-112 substantially reduced the amount of mitochondrial CoQ10 in L929 cells, while the basal CoQ10 levels were below our detection limits in L929dt cells, suggesting a potential relationship between a low basal level of CoQ10 and PT-112 sensitivity. Finally, the expression of HIF-1α was much higher in cells sensitive to PT-112 compared to cells with an intact OXPHOS pathway, suggesting potential clinical applications.
    Keywords:  CoQ10; HIF-1α; ICD; PT-112; cancer cell death; immunogenic cell death; mitochondrial ROS
    DOI:  https://doi.org/10.3390/cancers14163851
  2. Nucleic Acids Res. 2022 Aug 24. pii: gkac699. [Epub ahead of print]
    Aberrant RNA processing contributes to the pathogenesis of mitochondrial diseases in trans-mitochondrial mouse model carrying mitochondrial tRNALeu(UUR) with a pathogenic A2748G mutation.
    Haruna Tani, Kaori Ishikawa, Hiroaki Tamashiro, Emi Ogasawara, Takehiro Yasukawa, Shigeru Matsuda, Akinori Shimizu, Dongchon Kang, Jun-Ichi Hayashi, Fan-Yan Wei, Kazuto Nakada.
      Mitochondrial tRNAs are indispensable for the intra-mitochondrial translation of genes related to respiratory subunits, and mutations in mitochondrial tRNA genes have been identified in various disease patients. However, the molecular mechanism underlying pathogenesis remains unclear due to the lack of animal models. Here, we established a mouse model, designated 'mito-mice tRNALeu(UUR)2748', that carries a pathogenic A2748G mutation in the tRNALeu(UUR) gene of mitochondrial DNA (mtDNA). The A2748G mutation is orthologous to the human A3302G mutation found in patients with mitochondrial diseases and diabetes. A2748G mtDNA was maternally inherited, equally distributed among tissues in individual mice, and its abundance did not change with age. At the molecular level, A2748G mutation is associated with aberrant processing of precursor mRNA containing tRNALeu(UUR) and mt-ND1, leading to a marked decrease in the steady-levels of ND1 protein and Complex I activity in tissues. Mito-mice tRNALeu(UUR)2748 with ≥50% A2748G mtDNA exhibited age-dependent metabolic defects including hyperglycemia, insulin insensitivity, and hepatic steatosis, resembling symptoms of patients carrying the A3302G mutation. This work demonstrates a valuable mouse model with an inheritable pathological A2748G mutation in mt-tRNALeu(UUR) that shows metabolic syndrome-like phenotypes at high heteroplasmy level. Furthermore, our findings provide molecular basis for understanding A3302G mutation-mediated mitochondrial disorders.
    DOI:  https://doi.org/10.1093/nar/gkac699
  3. Adv Sci (Weinh). 2022 Aug 21. e2201273
    ER, Mitochondria, and ISR Regulation by mt-HSP70 and ATF5 upon Procollagen Misfolding in Osteoblasts.
    Laura Gorrell, Elena Makareeva, Shakib Omari, Satoru Otsuru, Sergey Leikin.
      Cellular response to protein misfolding underlies multiple diseases. Collagens are the most abundant vertebrate proteins, yet little is known about cellular response to misfolding of their procollagen precursors. Osteoblasts (OBs)-the cells that make bone-produce so much procollagen that it accounts for up to 40% of mRNAs in the cell, which is why bone bears the brunt of mutations causing procollagen misfolding in osteogenesis imperfecta (OI). The present study of a G610C mouse model of OI by multiple transcriptomic techniques provides first solid clues to how OBs respond to misfolded procollagen accumulation in the endoplasmic reticulum (ER) and how this response affects OB function. Surprisingly, misfolded procollagen escapes the quality control in the ER lumen and indirectly triggers the integrated stress response (ISR) through other cell compartments. In G610C OBs, the ISR is regulated by mitochondrial HSP70 (mt-HSP70) and ATF5 instead of their BIP and ATF4 paralogues, which normally activate and regulate ISR to secretory protein misfolding in the ER. The involvement of mt-HSP70 and ATF5 together with other transcriptomic findings suggest that mitochondria might initiate the ISR upon disruption of ER-mitochondria connections or might respond to the ISR activated by a yet unknown sensor.
    Keywords:  ATF5; HSPA9/mt-Hsp70/GRP75; cell stress; collagen; osteoblast; osteogenesis imperfecta
    DOI:  https://doi.org/10.1002/advs.202201273
  4. Aging Cell. 2022 Aug 22. e13669
    Premature aging is associated with higher levels of 8-oxoguanine and increased DNA damage in the Polg mutator mouse.
    Tenghui Yu, Jesse Slone, Wensheng Liu, Ryan Barnes, Patricia L Opresko, Landon Wark, Sabine Mai, Steve Horvath, Taosheng Huang.
      Mitochondrial dysfunction plays an important role in the aging process. However, the mechanism by which this dysfunction causes aging is not fully understood. The accumulation of mutations in the mitochondrial genome (or "mtDNA") has been proposed as a contributor. One compelling piece of evidence in support of this hypothesis comes from the PolgD257A/D257A mutator mouse (Polgmut/mut ). These mice express an error-prone mitochondrial DNA polymerase that results in the accumulation of mtDNA mutations, accelerated aging, and premature death. In this paper, we have used the Polgmut/mut model to investigate whether the age-related biological effects observed in these mice are triggered by oxidative damage to the DNA that compromises the integrity of the genome. Our results show that mutator mouse has significantly higher levels of 8-oxoguanine (8-oxoGua) that are correlated with increased nuclear DNA (nDNA) strand breakage and oxidative nDNA damage, shorter average telomere length, and reduced mtDNA integrity. Based on these results, we propose a model whereby the increased level of reactive oxygen species (ROS) associated with the accumulation of mtDNA mutations in Polgmut/mut mice results in higher levels of 8-oxoGua, which in turn lead to compromised DNA integrity and accelerated aging via increased DNA fragmentation and telomere shortening. These results suggest that mitochondrial play a central role in aging and may guide future research to develop potential therapeutics for mitigating aging process.
    Keywords:  8-oxoguanine; aging; mitochondria; oxidative stress; telomeres
    DOI:  https://doi.org/10.1111/acel.13669
  5. Nat Immunol. 2022 Aug 23.
    Leaky mitochondria.
    Nick Bernard.
      
    DOI:  https://doi.org/10.1038/s41590-022-01305-z
  6. Life (Basel). 2022 Jul 29. pii: 1153. [Epub ahead of print]12(8):
    The Role of Mitochondrial Mutations in Chronification of Inflammation: Hypothesis and Overview of Own Data.
    Alexander N Orekhov, Nikita G Nikiforov, Andrey V Omelchenko, Vasily V Sinyov, Igor A Sobenin, Andrey Y Vinokurov, Varvara A Orekhova.
      Chronic human diseases, especially age-related disorders, are often associated with chronic inflammation. It is currently not entirely clear what factors are responsible for the sterile inflammatory process becoming chronic in affected tissues. This process implies impairment of the normal resolution of the inflammatory response, when pro-inflammatory cytokine production ceases and tissue repair process begins. The important role of the mitochondria in the correct functioning of innate immune cells is currently well recognized, with mitochondrial signals being an important component of the inflammatory response regulation. In this work, we propose a hypothesis according to which mitochondrial DNA (mtDNA) mutations may play a key role in rendering certain cells prone to prolonged pro-inflammatory activation, therefore contributing to chronification of inflammation. The affected cells become sites of constant pro-inflammatory stimulation. The study of the distribution of atherosclerotic lesions on the surface of the arterial wall samples obtained from deceased patients revealed a focal distribution of lesions corresponding to the distribution of cells with altered morphology that are affected by mtDNA mutations. These observations support the proposed hypothesis and encourage further studies.
    Keywords:  atherosclerosis; inflammation; mitophagy; mtDNA mutation
    DOI:  https://doi.org/10.3390/life12081153
  7. Int J Mol Med. 2022 Oct;pii: 126. [Epub ahead of print]50(4):
    Common methods in mitochondrial research (Review).
    Yiyuan Yin, Haitao Shen.
      Mitochondrial abnormalities are primarily seen in morphology, structure and function. They can cause damage to organs, including the heart, brain and muscle, by various mechanisms, such as oxidative stress, abnormal energy metabolism, or genetic mutations. Identifying and detecting pathophysiological alterations in mitochondria is the principal means of studying mitochondrial abnormalities. The present study reviewed methods in mitochondrial research and focused on three aspects: Mitochondrial extraction and purification, morphology and structure and function. In addition to classical methods, such as electron microscopy and mitochondrial membrane potential monitoring, newly developed methods, such as mitochondrial ultrastructural determination, mtDNA mutation assays, metabolomics and analyses of regulatory mechanisms, have also been utilized in recent years. These approaches enable the accurate detection of mitochondrial abnormalities and provide guidance for the diagnosis and treatment of related diseases.
    Keywords:  mitochondria; mitochondrial DNA; mitochondrial diseases; mitochondrial dysfunction; mitochondrial morphology
    DOI:  https://doi.org/10.3892/ijmm.2022.5182
  8. Hum Mol Genet. 2022 Aug 22. pii: ddac201. [Epub ahead of print]
    Mitofusin 2 mutation drives cell proliferation in Charcot-Marie-Tooth 2A fibroblasts.
    Paola Zanfardino, Giovanna Longo, Alessandro Amati, Federica Morani, Ernesto Picardi, Francesco Girolamo, Mariella Pafundi, Sharon N Cox, Caterina Manzari, Apollonia Tullo, Stefano Doccini, Filippo M Santorelli, Vittoria Petruzzella.
      Dominant mutations in ubiquitously expressed Mitofusin 2 gene (MFN2) cause Charcot-Marie-Tooth type 2A (CMT2A; OMIM 609260), an inherited sensory-motor neuropathy that affects peripheral nerve axons. Mitofusin 2 protein has been found to take part in mitochondrial fusion, mitochondria-endoplasmic reticulum tethering, mitochondrial trafficking along axons, mitochondrial quality control, and various types of cancer, in which MFN2 has been indicated as a tumor suppressor gene. Discordant data on the mitochondrial altered phenotypes in patient-derived fibroblasts harboring MFN2 mutations and in animal models have been reported. We addressed some of these issues by focusing on mitochondria behavior during autophagy and mitophagy in fibroblasts derived from a CMT2AMFN2 patient with an MFN2650G > T/C217F mutation in the GTPase domain. This study investigated mitochondrial dynamics, respiratory capacity, and autophagy/mitophagy, to tackle the multifaceted MFN2 contribution to CMT2A pathogenesis. We found that MFN2 mutated fibroblasts showed impairment of mitochondrial morphology, bioenergetics capacity, and impairment of the early stages of autophagy, but not mitophagy. Unexpectedly, transcriptomic analysis of mutated fibroblasts highlighted marked differentially expressed pathways related to cell population proliferation and extracellular matrix organization. We consistently found the activation of mTORC2/AKT signaling and accelerated proliferation in the CMT2AMFN2 fibroblasts. In conclusion, our evidence indicates that MFN2 mutation can positively drive cell proliferation in CMT2AMFN2 fibroblasts.
    DOI:  https://doi.org/10.1093/hmg/ddac201
  9. Cell Death Dis. 2022 Aug 25. 13(8): 735
    Zeb1 sustains hematopoietic stem cell functions by suppressing mitofusin-2-mediated mitochondrial fusion.
    Kai Zhang, Huifang Zhao, Yaru Sheng, Xinyu Chen, Penghui Xu, Jinming Wang, Zhongzhong Ji, Yuman He, Wei-Qiang Gao, Helen He Zhu.
      Metabolic status is essential in maintaining normal functions of hematopoietic stem cells (HSCs). However, how the dynamic of the mitochondrion, as a central organelle in metabolism, is molecularly regulated to orchestrate metabolism and HSC stemness remains to be elucidated. Here, we focus on the role of Zeb1, a well-characterized epithelial-to-mesenchymal transition (EMT) inducer which has been demonstrated to confer stem-cell-like characteristics in multiple cancer types in stemness regulation of HSCs. Using a Zeb1-tdTomato reporter mouse model, we find that Zeb1+Lin-Sca-1+c-Kit+ cells (Zeb1+-LSKs) represent a subset of functional long-term HSCs. Zeb1+LSKs exhibit a reduced reactive oxygen species (ROS) level, low mitochondrial mass, low mitochondrial membrane potential (MMP), and particularly small, round fragmented mitochondria. Of note, ectopic expression of Zeb1 leads to a fragmented mitochondrial morphology with a low mitochondrial metabolic status in EML cells. In addition, Zeb1-knockout (Zeb1-KO) LSKs from fetal liver display an exhausted stem-cell activity. Zeb1 deficiency results in elongated and tubulated mitochondria with increased mitochondrial mass, elevated MMP, and higher ROS production. Mechanistically, Zeb1 acts as a transcriptional suppressor on the key mitochondrial-fusion protein Mitofusin-2 (encoded by Mfn2). We highlight an important role of Zeb1 in the regulation of mitochondrial morphology in HSC and the metabolic control of HSC stemness by repressing Mfn2-mediated mitochondrial fusion.
    DOI:  https://doi.org/10.1038/s41419-022-05194-w
  10. Nat Commun. 2022 Aug 26. 13(1): 5016
    The protein arginine methyltransferase PRMT9 attenuates MAVS activation through arginine methylation.
    Xuemei Bai, Chao Sui, Feng Liu, Tian Chen, Lei Zhang, Yi Zheng, Bingyu Liu, Chengjiang Gao.
      The signaling adaptor MAVS forms prion-like aggregates to activate the innate antiviral immune response after viral infection. However, spontaneous aggregation of MAVS can lead to autoimmune diseases. The molecular mechanism that prevents MAVS from spontaneous aggregation in resting cells has been enigmatic. Here we report that protein arginine methyltransferase 9 targets MAVS directly and catalyzes the arginine methylation of MAVS at the Arg41 and Arg43. In the resting state, this modification inhibits MAVS aggregation and autoactivation of MAVS. Upon virus infection, PRMT9 dissociates from the mitochondria, leading to the aggregation and activation of MAVS. Our study implicates a form of post-translational modification on MAVS, which can keep MAVS inactive in physiological conditions to maintain innate immune homeostasis.
    DOI:  https://doi.org/10.1038/s41467-022-32628-y
  11. Int J Mol Sci. 2022 Aug 17. pii: 9252. [Epub ahead of print]23(16):
    Macrophage Polarization Mediated by Mitochondrial Dysfunction Induces Adipose Tissue Inflammation in Obesity.
    Long Xu, Xiaoyu Yan, Yuanxin Zhao, Jian Wang, Buhan Liu, Sihang Yu, Jiaying Fu, Yanan Liu, Jing Su.
      Obesity is one of the prominent global health issues, contributing to the growing prevalence of insulin resistance and type 2 diabetes. Chronic inflammation in adipose tissue is considered as a key risk factor for the development of insulin resistance and type 2 diabetes in obese individuals. Macrophages are the most abundant immune cells in adipose tissue and play an important role in adipose tissue inflammation. Mitochondria are critical for regulating macrophage polarization, differentiation, and survival. Changes to mitochondrial metabolism and physiology induced by extracellular signals may underlie the corresponding state of macrophage activation. Macrophage mitochondrial dysfunction is a key mediator of obesity-induced macrophage inflammatory response and subsequent systemic insulin resistance. Mitochondrial dysfunction drives the activation of the NLRP3 inflammasome, which induces the release of IL-1β. IL-1β leads to decreased insulin sensitivity of insulin target cells via paracrine signaling or infiltration into the systemic circulation. In this review, we discuss the new findings on how obesity induces macrophage mitochondrial dysfunction and how mitochondrial dysfunction induces NLRP3 inflammasome activation. We also summarize therapeutic approaches targeting mitochondria for the treatment of diabetes.
    Keywords:  NLRP3 inflammasome; adipose tissue inflammation; insulin resistance; mitochondrial dysfunction; obesity
    DOI:  https://doi.org/10.3390/ijms23169252
  12. Apoptosis. 2022 Aug 26.
    DNA damage induces STING mediated IL-6-STAT3 survival pathway in triple-negative breast cancer cells and decreased survival of breast cancer patients.
    Hitesh Vasiyani, Minal Mane, Khushboo Rana, Anjali Shinde, Milton Roy, Jyoti Singh, Dhruv Gohel, Fatema Currim, Ratika Srivastava, Rajesh Singh.
      Triple-negative breast cancer is aggressive and metastatic breast cancer type and shows immune evasion, drug resistance, relapse and poor survival. Anti-cancer therapy like ionizing radiation and chemotherapeutic drug majorly induces DNA damage hence, alteration in DNA damage repair and downstream pathways may contribute to tumor cell survival. DNA damage during chemotherapy is sensed by cyclic GMP-AMP synthase(cGAS)-stimulator of interferon genes (STING), which determines the anti-tumor immune response by modulating the expression of programmed cell death ligand-1 (PD-L1), immune suppressor, in the tumor microenvironment. Triple-negative breast cancer cells are cGAS-STING positive and modulation of this pathway during DNA damage response for survival and immune escape mechanism is not well understood. Here we demonstrate that doxorubicin-mediated DNA damage induces STING mediated NF-κB activation in triple-negative as compared to ER/PR positive breast cancer cells. STING-mediated NF-κB induces the expression of IL-6 in triple-negative breast cancer cells and activates pSTAT3, which enhances cell survival and PD-L1 expression. Doxorubicin and STAT3 inhibitor act synergistically and inhibit cell survival and clonogenicity in triple-negative breast cancer cells. Knockdown of STING in triple-negative breast cancer cells enhances CD8 mediated immune cell death of breast cancer cells. The combinatorial treatment of triple-negative breast cells with doxorubicin and STAT3 inhibitor reduces PD-L1 expression and activates immune cell-mediated cancer cell death. Further STING and IL-6 levels show a positive correlation in breast cancer patients and poor survival outcomes. The study here strongly suggests that STING mediated activation of NF-κB enhances IL-6 mediated STAT3 in triple-negative breast cancer cells which induces cell survival and immune-suppressive mechanism.
    Keywords:  Drug resistance; IL-6; Immune escape; PD-L1; STAT3; STING
    DOI:  https://doi.org/10.1007/s10495-022-01763-8
  13. J Oral Pathol Med. 2022 Aug 23.
    Nicotinamide mitigates radiation injury in submandibular gland by protecting mitochondrial structure and functions.
    Xin Yue Wang, Ke Jian Liu, Fu Yin Zhang, Bin Xiang.
       BACKGROUND: Radiation damage to salivary gland (SG) is inevitable in head and neck cancer patients receiving radiotherapy. Safe and effective treatments for protecting SGs from radiation are still unavailable. Mitochondrial damage is a critical mechanism in irradiated SG, however, treatment targeting mitochondria has not received much attention. Nicotinamide (NAM) is a key component of the mitochondrial metabolism. Here, we investigated the effects and underlying mechanisms of NAM on protecting irradiated submandibular gland (SMG).
    METHODS: SMG cells and tissues were randomly divided into four groups: control, NAM alone, radiation alone, and radiation with NAM pretreatment. Cell viability was detected by PrestoBlue™ cell viability reagent. Histopathological alterations were observed with HE staining. Pilocarpine-stimulated saliva was measured from Wharton's duct. Cell apoptosis was determined by flow cytometry and TUNEL assay. Nicotinamide phosphoribosyl transferase (NAMPT) was examined with immunofluorescence. The levels of nicotinamide adenine dinucleotide (NAD), mitochondrial membrane potential (MMP) and ATP were measured with the relevant kits. The mitochondrial ultrastructure was observed under transmission electron microscopy.
    RESULTS: NAM significantly mitigated radiation damage both in vitro and in vivo. Also, NAM improved saliva secretion and reduced radiation-induced apoptosis in irradiated SMGs. Moreover, NAM improved NAMPT and the levels of NAD/ATP and MMP, all of which were decreased by radiation in SMG cells. Importantly, NAM protected the mitochondrial ultrastructure from radiation.
    CONCLUSION: These findings demonstrate that NAM alleviates radiation damage in SMG by replenishing NAD and maintaining mitochondrial function and ultrastructure, suggesting that NAM could be used as a prospective radioprotectant for preventing radiation sialadenitis.
    Keywords:  NAD; mitochondrion; nicotinamide; radiation; submandibular gland
    DOI:  https://doi.org/10.1111/jop.13347
  14. Oncoimmunology. 2022 ;11(1): 2114740
    scRNA-seq reveals ATPIF1 activity in control of T cell antitumor activity.
    Genshen Zhong, Qi Wang, Ying Wang, Ying Guo, Meiqi Xu, Yaya Guan, Xiaoying Zhang, Minna Wu, Zhishan Xu, Weidong Zhao, Hongkai Lian, Hui Wang, Jianping Ye.
      ATP synthase inhibitory factor 1 (ATPIF1) is a mitochondrial protein with an activity in inhibition of F1Fo-ATP synthase. ATPIF1 activity remains unknown in the control of immune activity of T cells. In this study, we identified ATPIF1 activity in the induction of CD8+ T cell function in tumor models through genetic approaches. ATPIF1 gene inactivation impaired the immune activities of CD8+ T cells leading to quick tumor growth (B16 melanoma and Lewis lung cancer) in ATPIF1-KO mice. The KO T cells exhibited a reduced activity in proliferation and IFN-γ secretion with metabolic reprogramming of increased glycolysis and decreased oxidative phosphorylation (OXPHOS) after activation. T cell exhaustion was increased in the tumor infiltrating leukocytes (TILs) of KO mice as revealed by the single-cell RNA sequencing (scRNA-seq) and confirmed by flow cytometry. In contrast, ATPIF1 overexpression in T cells increased expression of IFN-γ and Granzyme B, subset of central memory T cells in CAR-T cells, and survival rate of NALM-6 tumor-bearing mice. These data demonstrate that ATPIF1 deficiency led to tumor immune deficiency through induction of T cell exhaustion. ATPIF1 overexpression enhanced the T cell tumor immunity. Therefore, ATPIF1 is a potential molecular target in the modulation of antitumor immunity of CD8+ T cells in cancer immunotherapy. Induction of ATPIF1 activity may promote CAR-T activity in cancer therapy.
    Keywords:  ATPIF1; CD19 CAR-T; CD8+ T cells; single cell RNA sequencing
    DOI:  https://doi.org/10.1080/2162402X.2022.2114740
  15. Proc Natl Acad Sci U S A. 2022 Aug 30. 119(35): e2211310119
    NAD+ metabolism drives astrocyte proinflammatory reprogramming in central nervous system autoimmunity.
    Tom Meyer, Dor Shimon, Sawsan Youssef, Gal Yankovitz, Adi Tessler, Tom Chernobylsky, Anat Gaoni-Yogev, Rita Perelroizen, Noga Budick-Harmelin, Lawrence Steinman, Lior Mayo.
      Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS). Astrocytes are the most abundant glial cells in the CNS, and their dysfunction contributes to the pathogenesis of MS and its animal model, experimental autoimmune encephalomyelitis (EAE). Recent advances highlight the pivotal role of cellular metabolism in programming immune responses. However, the underlying immunometabolic mechanisms that drive astrocyte pathogenicity remain elusive. Nicotinamide adenine dinucleotide (NAD+) is a vital coenzyme involved in cellular redox reactions and a substrate for NAD+-dependent enzymes. Cellular NAD+ levels are dynamically controlled by synthesis and degradation, and dysregulation of this balance has been associated with inflammation and disease. Here, we demonstrate that cell-autonomous generation of NAD+ via the salvage pathway regulates astrocyte immune function. Inhibition of nicotinamide phosphoribosyltransferase (NAMPT), a key enzyme in the salvage pathway, results in depletion of NAD+, inhibits oxidative phosphorylation, and limits astrocyte inflammatory potential. We identified CD38 as the main NADase up-regulated in reactive mouse and human astrocytes in models of neuroinflammation and MS. Genetic or pharmacological blockade of astrocyte CD38 activity augmented NAD+ levels, suppressed proinflammatory transcriptional reprogramming, impaired chemotactic potential to inflammatory monocytes, and ameliorated EAE. We found that CD38 activity is mediated via calcineurin/NFAT signaling in mouse and human reactive astrocytes. Thus, NAMPT-NAD+-CD38 circuitry in astrocytes controls their ability to meet their energy demands and drives the expression of proinflammatory transcriptional modules, contributing to CNS pathology in EAE and, potentially, MS. Our results identify candidate therapeutic targets in MS.
    Keywords:  Nicotinamide adenine dinucleotide; astrocyte; multiple sclerosis; neuroinflammation; tryptophan catabolism
    DOI:  https://doi.org/10.1073/pnas.2211310119
  16. Commun Biol. 2022 Aug 23. 5(1): 858
    Integrating cell morphology with gene expression and chemical structure to aid mitochondrial toxicity detection.
    Srijit Seal, Jordi Carreras-Puigvert, Maria-Anna Trapotsi, Hongbin Yang, Ola Spjuth, Andreas Bender.
      Mitochondrial toxicity is an important safety endpoint in drug discovery. Models based solely on chemical structure for predicting mitochondrial toxicity are currently limited in accuracy and applicability domain to the chemical space of the training compounds. In this work, we aimed to utilize both -omics and chemical data to push beyond the state-of-the-art. We combined Cell Painting and Gene Expression data with chemical structural information from Morgan fingerprints for 382 chemical perturbants tested in the Tox21 mitochondrial membrane depolarization assay. We observed that mitochondrial toxicants differ from non-toxic compounds in morphological space and identified compound clusters having similar mechanisms of mitochondrial toxicity, thereby indicating that morphological space provides biological insights related to mechanisms of action of this endpoint. We further showed that models combining Cell Painting, Gene Expression features and Morgan fingerprints improved model performance on an external test set of 244 compounds by 60% (in terms of F1 score) and improved extrapolation to new chemical space. The performance of our combined models was comparable with dedicated in vitro assays for mitochondrial toxicity. Our results suggest that combining chemical descriptors with biological readouts enhances the detection of mitochondrial toxicants, with practical implications in drug discovery.
    DOI:  https://doi.org/10.1038/s42003-022-03763-5
  17. Antioxidants (Basel). 2022 Jul 29. pii: 1482. [Epub ahead of print]11(8):
    Microglial Activation and Oxidative Stress in PM2.5-Induced Neurodegenerative Disorders.
    Jie Song, Keyang Han, Ya Wang, Rongrong Qu, Yuan Liu, Shaolan Wang, Yinbiao Wang, Zhen An, Juan Li, Hui Wu, Weidong Wu.
      Fine particulate matter (PM2.5) pollution remains a prominent environmental problem worldwide, posing great threats to human health. The adverse effects of PM2.5 on the respiratory and cardiovascular systems have been extensively studied, while its detrimental effects on the central nervous system (CNS), specifically neurodegenerative disorders, are less investigated. Neurodegenerative disorders are characterized by reduced neurogenesis, activated microglia, and neuroinflammation. A variety of studies involving postmortem examinations, epidemiological investigations, animal experiments, and in vitro cell models have shown that PM2.5 exposure results in neuroinflammation, oxidative stress, mitochondrial dysfunction, neuronal apoptosis, and ultimately neurodegenerative disorders, which are strongly associated with the activation of microglia. Microglia are the major innate immune cells of the brain, surveilling and maintaining the homeostasis of CNS. Upon activation by environmental and endogenous insults, such as PM exposure, microglia can enter an overactivated state that is featured by amoeboid morphology, the over-production of reactive oxygen species, and pro-inflammatory mediators. This review summarizes the evidence of microglial activation and oxidative stress and neurodegenerative disorders following PM2.5 exposure. Moreover, the possible mechanisms underlying PM2.5-induced microglial activation and neurodegenerative disorders are discussed. This knowledge provides certain clues for the development of therapies that may slow or halt the progression of neurodegenerative disorders induced by ambient PM.
    Keywords:  PM2.5; microglia; neurodegeneration; neuroinflammation; oxidative stress
    DOI:  https://doi.org/10.3390/antiox11081482
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