bims-nenemi Biomed News
on Neuroinflammation, neurodegeneration and mitochondria
Issue of 2022–03–27
23 papers selected by
Marco Tigano, Thomas Jefferson University
  1. Nuclear-Mitochondrial Interactions.
  2. Loss of Sam50 in hepatocytes induces cardiolipin-dependent mitochondrial membrane remodeling to trigger mtDNA release and liver injury.
  3. Biallelic Variants in ENDOG Associated with Mitochondrial Myopathy and Multiple mtDNA Deletions.
  4. Mitochondrial Protein Homeostasis and Cardiomyopathy.
  5. Temporal control of the integrated stress response by a stochastic molecular switch.
  6. FMRP protects the lung from xenobiotic stress by facilitating the Integrated Stress Response.
  7. Clueless/CLUH regulates mitochondrial fission by promoting recruitment of Drp1 to mitochondria.
  8. Dusp26 phosphatase regulates mitochondrial respiration and oxidative stress and protects neuronal cell death.
  9. Preprint Highlight: ER-lysosome lipid transfer protein VPS13C/PARK23 prevents aberrant mtDNA- dependent STING signaling.
  10. Mitochondrial Phenotypes in Genetically Diverse Neurodegenerative Diseases and Their Response to Mitofusin Activation.
  11. Adenosine Monophosphate Activated Protein Kinase (AMPK) enhances chemotherapy response in Acute Myeloid Leukemia (AML).
  12. Ejection of damaged mitochondria and their removal by macrophages ensure efficient thermogenesis in brown adipose tissue.
  13. Neurons Release Injured Mitochondria as "Help-Me" Signaling After Ischemic Stroke.
  14. Telomerase RNA TERC and the PI3K-AKT pathway form a positive feedback loop to regulate cell proliferation independent of telomerase activity.
  15. Mitochondria Related Cell Death Modalities and Disease.
  16. CRISPR activation screen identifies BCL-2 proteins and B3GNT2 as drivers of cancer resistance to T cell-mediated cytotoxicity.
  17. PRMT5 regulates ATF4 transcript splicing and oxidative stress response.
  18. Mitochondrial ATP synthase c-subunit leak channel triggers cell death upon loss of its F1 subcomplex.
  19. A light-gated transcriptional recorder for detecting cell-cell contacts.
  20. Succinate Is a Natural Suppressor of Antiviral Immune Response by Targeting MAVS.
  21. Retinoic acid signaling mediates peripheral cone photoreceptor survival in a mouse model of retina degeneration.
  22. Editorial: The Genetic and Epigenetic Bases of Cellular Response to Ionizing Radiation.
  23. Chemotherapy Resistance: Role of Mitochondrial and Autophagic Components.
  1. Biomolecules. 2022 Mar 10. pii: 427. [Epub ahead of print]12(3):
    Nuclear-Mitochondrial Interactions.
    Brittni R Walker, Carlos T Moraes.
      Mitochondria, the cell's major energy producers, also act as signaling hubs, interacting with other organelles both directly and indirectly. Despite having its own circular genome, the majority of mitochondrial proteins are encoded by nuclear DNA. To respond to changes in cell physiology, the mitochondria must send signals to the nucleus, which can, in turn, upregulate gene expression to alter metabolism or initiate a stress response. This is known as retrograde signaling. A variety of stimuli and pathways fall under the retrograde signaling umbrella. Mitochondrial dysfunction has already been shown to have severe implications for human health. Disruption of retrograde signaling, whether directly associated with mitochondrial dysfunction or cellular environmental changes, may also contribute to pathological deficits. In this review, we discuss known signaling pathways between the mitochondria and the nucleus, examine the possibility of direct contacts, and identify pathological consequences of an altered relationship.
    Keywords:  MAMs; integrated stress response; mitochondria; nucleus; retrograde signaling
    DOI:  https://doi.org/10.3390/biom12030427
  2. Hepatology. 2022 Mar 21.
    Loss of Sam50 in hepatocytes induces cardiolipin-dependent mitochondrial membrane remodeling to trigger mtDNA release and liver injury.
    Li Chen, Jun Dong, Siyang Liao, Siyou Wang, Zhida Wu, Meiling Zuo, Bing Liu, Chaojun Yan, Yong Chen, He He, Qingtao Meng, Zhiyin Song.
      Sam50, a key component of the sorting and assembly machinery (SAM) complex, is also involved in bridging mitochondrial outer- and inner-membrane contacts. However, the physiological and pathological functions of Sam50 remain largely unknown. Here, we show that Sam50 interacts with MICOS and ATAD3 to form the Sam50-MICOS-ATAD3-mtDNA axis, which maintains mtDNA stability. Loss of Sam50 causes mtDNA aggregation. Furthermore, Sam50 cooperates with Mic60 to bind to cardiolipin, maintaining the integrity of mitochondrial membranes. Sam50 depletion leads to cardiolipin externalization, which causes mitochondrial outer- and inner-membrane (including crista membrane) remodeling, triggering Bax mitochondrial recruitment, mtDNA aggregation and release. Physiologically, acetaminophen (APAP, an effective antipyretic and analgesic)-caused Sam50 reduction or Sam50 liver-specific knockout induces mtDNA release, leading to activation of the cGAS-STING pathway and liver inflammation in mice. Moreover, exogenous expression of Sam50 remarkably attenuates APAP-induced liver hepatoxicity. Thus, our findings uncover the critical role of Sam50 in maintaining mitochondrial membrane integrity and mtDNA stability in hepatocytes, and reveal that Sam50 depletion-induced cardiolipin externalization is a new signal of mtDNA release and controls mtDNA-dependent innate immunity.
    Keywords:  Sam50; acetaminophen; cGAS-STING; cardiolipin; mtDNA release
    DOI:  https://doi.org/10.1002/hep.32471
  3. Cells. 2022 Mar 12. pii: 974. [Epub ahead of print]11(6):
    Biallelic Variants in ENDOG Associated with Mitochondrial Myopathy and Multiple mtDNA Deletions.
    Alessia Nasca, Andrea Legati, Megi Meneri, Melisa Emel Ermert, Chiara Frascarelli, Nadia Zanetti, Manuela Garbellini, Giacomo Pietro Comi, Alessia Catania, Costanza Lamperti, Dario Ronchi, Daniele Ghezzi.
      Endonuclease G (ENDOG) is a nuclear-encoded mitochondrial-localized nuclease. Although its precise biological function remains unclear, its proximity to mitochondrial DNA (mtDNA) makes it an excellent candidate to participate in mtDNA replication, metabolism and maintenance. Indeed, several roles for ENDOG have been hypothesized, including maturation of RNA primers during mtDNA replication, splicing of polycistronic transcripts and mtDNA repair. To date, ENDOG has been deemed as a determinant of cardiac hypertrophy, but no pathogenic variants or genetically defined patients linked to this gene have been described. Here, we report biallelic ENDOG variants identified by NGS in a patient with progressive external ophthalmoplegia, mitochondrial myopathy and multiple mtDNA deletions in muscle. The absence of the ENDOG protein in the patient's muscle and fibroblasts indicates that the identified variants are pathogenic. The presence of multiple mtDNA deletions supports the role of ENDOG in mtDNA maintenance; moreover, the patient's clinical presentation is very similar to mitochondrial diseases caused by mutations in other genes involved in mtDNA homeostasis. Although the patient's fibroblasts did not present multiple mtDNA deletions or delay in the replication process, interestingly, we detected an accumulation of low-level heteroplasmy mtDNA point mutations compared with age-matched controls. This may indicate a possible role of ENDOG in mtDNA replication or repair. Our report provides evidence of the association of ENDOG variants with mitochondrial myopathy.
    Keywords:  ENDOG; endonuclease G; mitochondrial DNA; mitochondrial myopathy; multiple mtDNA deletions
    DOI:  https://doi.org/10.3390/cells11060974
  4. Int J Mol Sci. 2022 Mar 20. pii: 3353. [Epub ahead of print]23(6):
    Mitochondrial Protein Homeostasis and Cardiomyopathy.
    Emily Wachoski-Dark, Tian Zhao, Aneal Khan, Timothy E Shutt, Steven C Greenway.
      Human mitochondrial disorders impact tissues with high energetic demands and can be associated with cardiac muscle disease (cardiomyopathy) and early mortality. However, the mechanistic link between mitochondrial disease and the development of cardiomyopathy is frequently unclear. In addition, there is often marked phenotypic heterogeneity between patients, even between those with the same genetic variant, which is also not well understood. Several of the mitochondrial cardiomyopathies are related to defects in the maintenance of mitochondrial protein homeostasis, or proteostasis. This essential process involves the importing, sorting, folding and degradation of preproteins into fully functional mature structures inside mitochondria. Disrupted mitochondrial proteostasis interferes with mitochondrial energetics and ATP production, which can directly impact cardiac function. An inability to maintain proteostasis can result in mitochondrial dysfunction and subsequent mitophagy or even apoptosis. We review the known mitochondrial diseases that have been associated with cardiomyopathy and which arise from mutations in genes that are important for mitochondrial proteostasis. Genes discussed include DnaJ heat shock protein family member C19 (DNAJC19), mitochondrial import inner membrane translocase subunit TIM16 (MAGMAS), translocase of the inner mitochondrial membrane 50 (TIMM50), mitochondrial intermediate peptidase (MIPEP), X-prolyl-aminopeptidase 3 (XPNPEP3), HtraA serine peptidase 2 (HTRA2), caseinolytic mitochondrial peptidase chaperone subunit B (CLPB) and heat shock 60-kD protein 1 (HSPD1). The identification and description of disorders with a shared mechanism of disease may provide further insights into the disease process and assist with the identification of potential therapeutics.
    Keywords:  cardiomyopathy; integrated stress response; mitochondria; protein homeostasis; protein import; unfolded protein response
    DOI:  https://doi.org/10.3390/ijms23063353
  5. Sci Adv. 2022 Mar 25. 8(12): eabk2022
    Temporal control of the integrated stress response by a stochastic molecular switch.
    Philipp Klein, Stefan M Kallenberger, Hanna Roth, Karsten Roth, Thi Bach Nga Ly-Hartig, Vera Magg, Janez Aleš, Soheil Rastgou Talemi, Yu Qiang, Steffen Wolf, Olga Oleksiuk, Roma Kurilov, Barbara Di Ventura, Ralf Bartenschlager, Roland Eils, Karl Rohr, Fred A Hamprecht, Thomas Höfer, Oliver T Fackler, Georg Stoecklin, Alessia Ruggieri.
      Stress granules (SGs) are formed in the cytosol as an acute response to environmental cues and activation of the integrated stress response (ISR), a central signaling pathway controlling protein synthesis. Using chronic virus infection as stress model, we previously uncovered a unique temporal control of the ISR resulting in recurrent phases of SG assembly and disassembly. Here, we elucidate the molecular network generating this fluctuating stress response by integrating quantitative experiments with mathematical modeling and find that the ISR operates as a stochastic switch. Key elements controlling this switch are the cooperative activation of the stress-sensing kinase PKR, the ultrasensitive response of SG formation to the phosphorylation of the translation initiation factor eIF2α, and negative feedback via GADD34, a stress-induced subunit of protein phosphatase 1. We identify GADD34 messenger RNA levels as the molecular memory of the ISR that plays a central role in cell adaptation to acute and chronic stress.
    DOI:  https://doi.org/10.1126/sciadv.abk2022
  6. J Cell Sci. 2022 Mar 23. pii: jcs.258652. [Epub ahead of print]
    FMRP protects the lung from xenobiotic stress by facilitating the Integrated Stress Response.
    Deblina Sain Basu, Rital Bhavsar, Imtiyaz Gulami, Saraswati Chavda, Sai Manoz Lingamallu, Ravi Muddashetty, Chandrakanth Veeranna, Sumantra Chattarji, Rajesh Thimmulappa, Aditi Bhattacharya, Arjun Guha.
      Stress response pathways protect the lung from the damaging effects of environmental toxicants. Here we investigate the role of the Fragile X Mental Retardation Protein (FMRP), a multifunctional protein implicated in stress responses, in the lung. We report that FMRP is expressed in murine and human lungs, in the airways and more broadly. Analysis of airway stress responses in mice and in a murine cell line ex vivo, using the well-established Naphthalene (Nap) injury model, reveals that FMRP-deficient cells exhibit increased expression of markers of oxidative and genotoxic stress and increased cell death. Further inquiry shows that FMRP-deficient cells fail to actuate the Integrated Stress Response Pathway (ISR) and upregulate the transcription factor ATF4. Knockdown of ATF4 expression phenocopies the loss of FMRP. We extend our analysis of the role of FMRP to human bronchial BEAS-2B cells, using a 9, 10-Phenanthrenequinone air pollutant model, to find FMRP-deficient BEAS-2B also fail to actuate the ISR and exhibit greater susceptibility. Taken together, our data suggest that FMRP has a conserved role in protecting the airways by facilitating the ISR.
    Keywords:   FMR1 ; FMRP; Integrated Stress Response; Lung; Stress Response
    DOI:  https://doi.org/10.1242/jcs.258652
  7. Nat Commun. 2022 Mar 24. 13(1): 1582
    Clueless/CLUH regulates mitochondrial fission by promoting recruitment of Drp1 to mitochondria.
    Huan Yang, Caroline Sibilla, Raymond Liu, Jina Yun, Bruce A Hay, Craig Blackstone, David C Chan, Robert J Harvey, Ming Guo.
      Mitochondrial fission is critically important for controlling mitochondrial morphology, function, quality and transport. Drp1 is the master regulator driving mitochondrial fission, but exactly how Drp1 is regulated remains unclear. Here, we identified Drosophila Clueless and its mammalian orthologue CLUH as key regulators of Drp1. As with loss of drp1, depletion of clueless or CLUH results in mitochondrial elongation, while as with drp1 overexpression, clueless or CLUH overexpression leads to mitochondrial fragmentation. Importantly, drp1 overexpression rescues adult lethality, tissue disintegration and mitochondrial defects of clueless null mutants in Drosophila. Mechanistically, Clueless and CLUH promote recruitment of Drp1 to mitochondria from the cytosol. This involves CLUH binding to mRNAs encoding Drp1 receptors MiD49 and Mff, and regulation of their translation. Our findings identify a crucial role of Clueless and CLUH in controlling mitochondrial fission through regulation of Drp1.
    DOI:  https://doi.org/10.1038/s41467-022-29071-4
  8. Cell Mol Life Sci. 2022 Mar 21. 79(4): 198
    Dusp26 phosphatase regulates mitochondrial respiration and oxidative stress and protects neuronal cell death.
    Binnur Eroglu, Xiongjie Jin, Sadiki Deane, Bahadır Öztürk, Owen A Ross, Demetrius Moskophidis, Nahid F Mivechi.
      The dual specificity protein phosphatases (Dusps) control dephosphorylation of mitogen-activated protein kinases (MAPKs) as well as other substrates. Here, we report that Dusp26, which is highly expressed in neuroblastoma cells and primary neurons is targeted to the mitochondrial outer membrane via its NH2-terminal mitochondrial targeting sequence. Loss of Dusp26 has a significant impact on mitochondrial function that is associated with increased levels of reactive oxygen species (ROS), reduction in ATP generation, reduction in mitochondria motility and release of mitochondrial HtrA2 protease into the cytoplasm. The mitochondrial dysregulation in dusp26-deficient neuroblastoma cells leads to the inhibition of cell proliferation and cell death. In vivo, Dusp26 is highly expressed in neurons in different brain regions, including cortex and midbrain (MB). Ablation of Dusp26 in mouse model leads to dopaminergic (DA) neuronal cell loss in the substantia nigra par compacta (SNpc), inflammatory response in MB and striatum, and phenotypes that are normally associated with Neurodegenerative diseases. Consistent with the data from our mouse model, Dusp26 expressing cells are significantly reduced in the SNpc of Parkinson's Disease patients. The underlying mechanism of DA neuronal death is that loss of Dusp26 in neurons increases mitochondrial ROS and concurrent activation of MAPK/p38 signaling pathway and inflammatory response. Our results suggest that regulation of mitochondrial-associated protein phosphorylation is essential for the maintenance of mitochondrial homeostasis and dysregulation of this process may contribute to the initiation and development of neurodegenerative diseases.
    Keywords:  Dopaminergic neurons; Dusp26; LRRK2; Mouse model; Neurodegeneration; p38
    DOI:  https://doi.org/10.1007/s00018-022-04162-z
  9. Mol Biol Cell. 2022 Apr 01. 33(4): mbcP22021003
    Preprint Highlight: ER-lysosome lipid transfer protein VPS13C/PARK23 prevents aberrant mtDNA- dependent STING signaling.
    Luis Bonet-Ponce.
      
    DOI:  https://doi.org/10.1091/mbc.P22-02-1003
  10. Cells. 2022 Mar 21. pii: 1053. [Epub ahead of print]11(6):
    Mitochondrial Phenotypes in Genetically Diverse Neurodegenerative Diseases and Their Response to Mitofusin Activation.
    Xiawei Dang, Emily K Walton, Barbara Zablocka, Robert H Baloh, Michael E Shy, Gerald W Dorn.
      Mitochondrial fusion is essential to mitochondrial fitness and cellular health. Neurons of patients with genetic neurodegenerative diseases often exhibit mitochondrial fragmentation, reflecting an imbalance in mitochondrial fusion and fission (mitochondrial dysdynamism). Charcot-Marie-Tooth (CMT) disease type 2A is the prototypical disorder of impaired mitochondrial fusion caused by mutations in the fusion protein mitofusin (MFN)2. Yet, cultured CMT2A patient fibroblast mitochondria are often reported as morphologically normal. Metabolic stress might evoke pathological mitochondrial phenotypes in cultured patient fibroblasts, providing a platform for the pre-clinical individualized evaluation of investigational therapeutics. Here, substitution of galactose for glucose in culture media was used to redirect CMT2A patient fibroblasts (MFN2 T105M, R274W, H361Y, R364W) from glycolytic metabolism to mitochondrial oxidative phosphorylation, which provoked characteristic mitochondrial fragmentation and depolarization and induced a distinct transcriptional signature. Pharmacological MFN activation of metabolically reprogrammed fibroblasts partially reversed the mitochondrial abnormalities in CMT2A and CMT1 and a subset of Parkinson's and Alzheimer's disease patients, implicating addressable mitochondrial dysdynamism in these illnesses.
    Keywords:  mitochondrial dynamics; mitofusin; neurodegenerative diseases
    DOI:  https://doi.org/10.3390/cells11061053
  11. Cancer Lett. 2022 Mar 20. pii: S0304-3835(22)00142-2. [Epub ahead of print]535 215659
    Adenosine Monophosphate Activated Protein Kinase (AMPK) enhances chemotherapy response in Acute Myeloid Leukemia (AML).
    Lais Ghiraldeli, Rebecca Anderson, Kristin Pladna, Timothy S Pardee.
      Adenosine monophosphate activated protein kinase (AMPK) is a master regulator of cell metabolism and is involved in cancer as both a tumor suppressor and a source of resistance to metabolic stress. The role of AMPK in response to chemotherapy has been examined in solid tumor models but remains unclear in acute myeloid leukemia (AML). To determine the role of AMPK in chemotherapy response, AML cell lines were generated lacking AMPK activity. AMPK knock out cells demonstrated significant resistance to cytarabine and doxorubicin both in vitro and in vivo. Mitochondrial mass and function were unchanged in AMPK knockout cells. Mechanistically, AMPK knock out cells demonstrated a diminished DNA damage response with significantly lower γH2AX foci, p53 and p21 induction as well as decreased apoptosis following chemotherapy exposure. Most importantly, TCGA datasets revealed that patients expressing low levels of the PRKAA1 subunit of AMPK had significantly shorter survival. Finally, AML cells were sensitized to chemotherapy with the addition of the AMPK activator AICAR. These data demonstrate that AMPK sensitizes AML cells to chemotherapy and suggests a contribution of the cellular metabolic state to cell fate decisions ultimately affecting therapy response.
    DOI:  https://doi.org/10.1016/j.canlet.2022.215659
  12. Cell Metab. 2022 Mar 15. pii: S1550-4131(22)00088-2. [Epub ahead of print]
    Ejection of damaged mitochondria and their removal by macrophages ensure efficient thermogenesis in brown adipose tissue.
    Marco Rosina, Veronica Ceci, Riccardo Turchi, Li Chuan, Nicholas Borcherding, Francesca Sciarretta, María Sánchez-Díaz, Flavia Tortolici, Keaton Karlinsey, Valerio Chiurchiù, Claudia Fuoco, Rocky Giwa, Rachael L Field, Matteo Audano, Simona Arena, Alessandro Palma, Federica Riccio, Farnaz Shamsi, Giovanni Renzone, Martina Verri, Anna Crescenzi, Salvatore Rizza, Fiorella Faienza, Giuseppe Filomeni, Sander Kooijman, Stefano Rufini, Antoine A F de Vries, Andrea Scaloni, Nico Mitro, Yu-Hua Tseng, Andrés Hidalgo, Beiyan Zhou, Jonathan R Brestoff, Katia Aquilano, Daniele Lettieri-Barbato.
      Recent findings have demonstrated that mitochondria can be transferred between cells to control metabolic homeostasis. Although the mitochondria of brown adipocytes comprise a large component of the cell volume and undergo reorganization to sustain thermogenesis, it remains unclear whether an intercellular mitochondrial transfer occurs in brown adipose tissue (BAT) and regulates adaptive thermogenesis. Herein, we demonstrated that thermogenically stressed brown adipocytes release extracellular vesicles (EVs) that contain oxidatively damaged mitochondrial parts to avoid failure of the thermogenic program. When re-uptaken by parental brown adipocytes, mitochondria-derived EVs reduced peroxisome proliferator-activated receptor-γ signaling and the levels of mitochondrial proteins, including UCP1. Their removal via the phagocytic activity of BAT-resident macrophages is instrumental in preserving BAT physiology. Depletion of macrophages in vivo causes the abnormal accumulation of extracellular mitochondrial vesicles in BAT, impairing the thermogenic response to cold exposure. These findings reveal a homeostatic role of tissue-resident macrophages in the mitochondrial quality control of BAT.
    Keywords:  adipose tissue; brown adipocytes; extracellular vesicles; homeostasis; immunometabolism; macrophages; mitochondria; mitochondrial quality control; thermogenesis
    DOI:  https://doi.org/10.1016/j.cmet.2022.02.016
  13. Front Aging Neurosci. 2022 ;14 785761
    Neurons Release Injured Mitochondria as "Help-Me" Signaling After Ischemic Stroke.
    Li Gao, Fan Liu, Pin-Pin Hou, Anatol Manaenko, Zhi-Peng Xiao, Fei Wang, Tian-Le Xu, Qin Hu.
      Mitochondrial dysfunction has been regarded as one of the major contributors of ischemic neuronal death after stroke. Recently, intercellular mitochondrial transfer between different cell types has been widely studied and suggested as a potential therapeutic approach. However, whether mitochondria are involved in the neuron-glia cross-talk following ischemic stroke and the underlying mechanisms have not been explored yet. In this study, we demonstrated that under physiological condition, neurons release few mitochondria into the extracellular space, and the mitochondrial release increased when subjected to the challenges of acidosis, hydrogen peroxide (H2O2), N-methyl-D-aspartate (NMDA), or glutamate. Acidosis reduced the mitochondrial basal respiration and lowered the membrane potential in primary-cultured mouse cortical neurons. These defective mitochondria were prone to be expelled to the extracellular space by the injured neurons, and were engulfed by adjacent astrocytes, leading to increased astrocytic expressions of mitochondrial Rho GTPase 1 (Miro 1) and mitochondrial transcription factor A (TFAM) at mRNA level. In mice subjected to transient focal cerebral ischemia, the number of defective mitochondria in the cerebrospinal fluid increased. Our results suggested that the neuron-derived mitochondria may serve as a "help-me" signaling and mediate the neuron-astrocyte cross-talk following ischemic stroke. Promoting the intercellular mitochondrial transfer by accelerating the neuronal releasing or astrocytic engulfing might be a potential and attractive therapeutic strategy for the treatment of ischemic stroke in the future.
    Keywords:  ischemic stroke; metabolic stress; mitochondrial biogenesis; mitochondrial release; neuron-glial crosstalk
    DOI:  https://doi.org/10.3389/fnagi.2022.785761
  14. Nucleic Acids Res. 2022 Mar 22. pii: gkac179. [Epub ahead of print]
    Telomerase RNA TERC and the PI3K-AKT pathway form a positive feedback loop to regulate cell proliferation independent of telomerase activity.
    Shu Wu, Yuanlong Ge, Kaixuan Lin, Qianqian Liu, Haoxian Zhou, Qian Hu, Yong Zhao, Weifeng He, Zhenyu Ju.
      The core catalytic unit of telomerase comprises telomerase reverse transcriptase (TERT) and telomerase RNA (TERC). Unlike TERT, which is predominantly expressed in cancer and stem cells, TERC is ubiquitously expressed in normal somatic cells without telomerase activity. However, the functions of TERC in these telomerase-negative cells remain elusive. Here, we reported positive feedback regulation between TERC and the PI3K-AKT pathway that controlled cell proliferation independent of telomerase activity in human fibroblasts. Mechanistically, we revealed that TERC activated the transcription of target genes from the PI3K-AKT pathway, such as PDPK1, by targeting their promoters. Overexpression of PDPK1 partially rescued the deficiency of AKT activation caused by TERC depletion. Furthermore, we found that FOXO1, a transcription factor negatively regulated by the PI3K-AKT pathway, bound to TERC promoter and suppressed its expression. Intriguingly, TERC-induced activation of the PI3K-AKT pathway also played a critical role in the proliferation of activated CD4+ T cells. Collectively, our findings identify a novel function of TERC that regulates the PI3K-AKT pathway via positive feedback to elevate cell proliferation independent of telomerase activity and provide a potential strategy to promote CD4+ T cells expansion that is responsible for enhancing adaptive immune reactions to defend against pathogens and tumor cells.
    DOI:  https://doi.org/10.1093/nar/gkac179
  15. Front Cell Dev Biol. 2022 ;10 832356
    Mitochondria Related Cell Death Modalities and Disease.
    Chuwen Tian, Yifan Liu, Zhuoshu Li, Ping Zhu, Mingyi Zhao.
      Mitochondria are well known as the centre of energy metabolism in eukaryotic cells. However, they can not only generate ATP through the tricarboxylic acid cycle and oxidative phosphorylation but also control the mode of cell death through various mechanisms, especially regulated cell death (RCD), such as apoptosis, mitophagy, NETosis, pyroptosis, necroptosis, entosis, parthanatos, ferroptosis, alkaliptosis, autosis, clockophagy and oxeiptosis. These mitochondria-associated modes of cell death can lead to a variety of diseases. During cell growth, these modes of cell death are programmed, meaning that they can be induced or predicted. Mitochondria-based treatments have been shown to be effective in many trials. Therefore, mitochondria have great potential for the treatment of many diseases. In this review, we discuss how mitochondria are involved in modes of cell death, as well as basic research and the latest clinical progress in related fields. We also detail a variety of organ system diseases related to mitochondria, including nervous system diseases, cardiovascular diseases, digestive system diseases, respiratory diseases, endocrine diseases, urinary system diseases and cancer. We highlight the role that mitochondria play in these diseases and suggest possible therapeutic directions as well as pressing issues that need to be addressed today. Because of the key role of mitochondria in cell death, a comprehensive understanding of mitochondria can help provide more effective strategies for clinical treatment.
    Keywords:  ferroptosis; mitochondria; mitochondrial diseases; parthanatos; regulated cell death
    DOI:  https://doi.org/10.3389/fcell.2022.832356
  16. Nat Commun. 2022 Mar 25. 13(1): 1606
    CRISPR activation screen identifies BCL-2 proteins and B3GNT2 as drivers of cancer resistance to T cell-mediated cytotoxicity.
    Julia Joung, Paul C Kirchgatterer, Ankita Singh, Jang H Cho, Suchita P Nety, Rebecca C Larson, Rhiannon K Macrae, Rebecca Deasy, Yuen-Yi Tseng, Marcela V Maus, Feng Zhang.
      The cellular processes that govern tumor resistance to immunotherapy remain poorly understood. To gain insight into these processes, here we perform a genome-scale CRISPR activation screen for genes that enable human melanoma cells to evade cytotoxic T cell killing. Overexpression of four top candidate genes (CD274 (PD-L1), MCL1, JUNB, and B3GNT2) conferred resistance in diverse cancer cell types and mouse xenografts. By investigating the resistance mechanisms, we find that MCL1 and JUNB modulate the mitochondrial apoptosis pathway. JUNB encodes a transcription factor that downregulates FasL and TRAIL receptors, upregulates the MCL1 relative BCL2A1, and activates the NF-κB pathway. B3GNT2 encodes a poly-N-acetyllactosamine synthase that targets >10 ligands and receptors to disrupt interactions between tumor and T cells and reduce T cell activation. Inhibition of candidate genes sensitized tumor models to T cell cytotoxicity. Our results demonstrate that systematic gain-of-function screening can elucidate resistance pathways and identify potential targets for cancer immunotherapy.
    DOI:  https://doi.org/10.1038/s41467-022-29205-8
  17. Redox Biol. 2022 Mar 11. pii: S2213-2317(22)00054-4. [Epub ahead of print]51 102282
    PRMT5 regulates ATF4 transcript splicing and oxidative stress response.
    Magdalena M Szewczyk, Genna M Luciani, Victoria Vu, Alex Murison, David Dilworth, Samir H Barghout, Mathieu Lupien, Cheryl H Arrowsmith, Mark D Minden, Dalia Barsyte-Lovejoy.
      Protein methyltransferase 5 (PRMT5) symmetrically dimethylates arginine residues leading to regulation of transcription and splicing programs. Although PRMT5 has emerged as an attractive oncology target, the molecular determinants of PRMT5 dependency in cancer remain incompletely understood. Our transcriptomic analysis identified PRMT5 regulation of the activating transcription factor 4 (ATF4) pathway in acute myelogenous leukemia (AML). PRMT5 inhibition resulted in the expression of unstable, intron-retaining ATF4 mRNA that is detained in the nucleus. Concurrently, the decrease in the spliced cytoplasmic transcript of ATF4 led to lower levels of ATF4 protein and downregulation of ATF4 target genes. Upon loss of functional PRMT5, cells with low ATF4 displayed increased oxidative stress, growth arrest, and cellular senescence. Interestingly, leukemia cells with EVI1 oncogene overexpression demonstrated dependence on PRMT5 function. EVI1 and ATF4 regulated gene signatures were inversely correlated. We show that EVI1-high AML cells have reduced ATF4 levels, elevated baseline reactive oxygen species and increased sensitivity to PRMT5 inhibition. Thus, EVI1-high cells demonstrate dependence on PRMT5 function and regulation of oxidative stress response. Overall, our findings identify the PRMT5-ATF4 axis to be safeguarding the cellular redox balance that is especially important in high oxidative stress states, such as those that occur with EVI1 overexpression.
    Keywords:  ATF4; EVI1; Epigenetics; Intron retention; Oxidative stress; PRMT5; Splicing
    DOI:  https://doi.org/10.1016/j.redox.2022.102282
  18. Cell Death Differ. 2022 Mar 23.
    Mitochondrial ATP synthase c-subunit leak channel triggers cell death upon loss of its F1 subcomplex.
    Nelli Mnatsakanyan, Han-A Park, Jing Wu, Xiang He, Marc C Llaguno, Maria Latta, Paige Miranda, Besnik Murtishi, Morven Graham, Joachim Weber, Richard J Levy, Evgeny V Pavlov, Elizabeth A Jonas.
      Mitochondrial ATP synthase is vital not only for cellular energy production but also for energy dissipation and cell death. ATP synthase c-ring was suggested to house the leak channel of mitochondrial permeability transition (mPT), which activates during excitotoxic ischemic insult. In this present study, we purified human c-ring from both eukaryotic and prokaryotic hosts to biophysically characterize its channel activity. We show that purified c-ring forms a large multi-conductance, voltage-gated ion channel that is inhibited by the addition of ATP synthase F1 subcomplex. In contrast, dissociation of F1 from FO occurs during excitotoxic neuronal death suggesting that the F1 constitutes the gate of the channel. mPT is known to dissipate the osmotic gradient across the inner membrane during cell death. We show that ATP synthase c-subunit knock down (KD) prevents the osmotic change in response to high calcium and eliminates large conductance, Ca2+ and CsA sensitive channel activity of mPT. These findings elucidate the gating mechanism of the ATP synthase c-subunit leak channel (ACLC) and suggest how ACLC opening is regulated by cell stress in a CypD-dependent manner.
    DOI:  https://doi.org/10.1038/s41418-022-00972-7
  19. Elife. 2022 Mar 21. pii: e70881. [Epub ahead of print]11
    A light-gated transcriptional recorder for detecting cell-cell contacts.
    Kelvin F Cho, Shawn M Gillespie, Nicholas A Kalogriopoulos, Michael A Quezada, Martin Jacko, Michelle Monje, Alice Y Ting.
      Technologies for detecting cell-cell contacts are powerful tools for studying a wide range of biological processes, from neuronal signaling to cancer-immune interactions within the tumor microenvironment. Here, we report TRACC (Transcriptional Readout Activated by Cell-cell Contacts), a GPCR-based transcriptional recorder of cellular contacts, which converts contact events into stable transgene expression. TRACC is derived from our previous protein-protein interaction recorders, SPARK (Kim et al., 2017) and SPARK2 (Kim et al., 2019), reported in this journal. TRACC incorporates light gating via the light-oxygen-voltage-sensing (LOV) domain, which provides user-defined temporal control of tool activation and reduces background. We show that TRACC detects cell-cell contacts with high specificity and sensitivity in mammalian cell culture and that it can be used to interrogate interactions between neurons and glioma, a form of brain cancer.
    Keywords:  cell biology; cell contacts; none; synthetic biology; transcriptional reporter
    DOI:  https://doi.org/10.7554/eLife.70881
  20. Front Immunol. 2022 ;13 816378
    Succinate Is a Natural Suppressor of Antiviral Immune Response by Targeting MAVS.
    Yue Xiao, Xinyi Chen, Zhun Wang, Jiazheng Quan, Xibao Zhao, Haimei Tang, Han Wu, Qianqian Di, Zherui Wu, Weilin Chen.
      Succinate is at the crossroads of multiple metabolic pathways and plays a role in several immune responses acting as an inflammation signal. However, whether succinate regulates antiviral immune response remains unclear. Here, we found that the production of succinate was reduced in RAW264.7 cells during vesicular stomatitis virus (VSV) infection. Using diethyl succinate to pretreat the mouse peritoneal macrophages and RAW264.7 cells before VSV infection, the production of interferon-β (IFN-β), chemokine (C-X-C motif) ligand 10 (CXCL-10), and IFN-stimulated genes 15 (ISG15) was significantly decreased, following which the VSV replication in diethyl succinate-pretreated cells was obviously increased. Moreover, succinate decreased the expression of IFN-β in serum, lung, and spleen derived from the VSV-infected mice. The overall survival rate in the VSV-infected mice with diethyl succinate pretreatment was also remarkably downregulated. Furthermore, we identified that succinate inhibited the activation of MAVS-TBK1-IRF3 signaling by suppressing the formation of MAVS aggregates. Our findings provide previously unrecognized roles of succinate in antiviral immune response and establish a novel link between metabolism and innate immune response.
    Keywords:  MAVS; VSV; antiviral immune response; metabolism; succinate
    DOI:  https://doi.org/10.3389/fimmu.2022.816378
  21. Elife. 2022 Mar 22. pii: e76389. [Epub ahead of print]11
    Retinoic acid signaling mediates peripheral cone photoreceptor survival in a mouse model of retina degeneration.
    Ryoji Amamoto, Grace K Wallick, Constance L Cepko.
      Retinitis Pigmentosa (RP) is a progressive, debilitating visual disorder caused by mutations in a diverse set of genes. In both humans with RP and mouse models of RP, rod photoreceptor dysfunction leads to loss of night vision, and is followed by secondary cone photoreceptor dysfunction and degeneration, leading to loss of daylight color vision. A strategy to prevent secondary cone death could provide a general RP therapy to preserve daylight color vision regardless of the underlying mutation. In mouse models of RP, cones in the peripheral retina survive long-term, despite complete rod loss. The mechanism for such peripheral cone survival had not been explored. Here, we found that active retinoic acid (RA) signaling in peripheral Muller glia is necessary for the abnormally long survival of these peripheral cones. RA depletion by conditional knockout of RA synthesis enzymes, or overexpression of an RA degradation enzyme, abrogated the extended survival of peripheral cones. Conversely, constitutive activation of RA signaling in the central retina promoted long-term cone survival. These results indicate that RA signaling mediates the prolonged peripheral cone survival in the rd1 mouse model of retinal degeneration, and provide a basis for a generic strategy for cone survival in the many diseases that lead to loss of cone-mediated vision.
    Keywords:  cones; degeneration; developmental biology; mouse; neuroscience; photoreceptor; retina; retinitis pigmentosa
    DOI:  https://doi.org/10.7554/eLife.76389
  22. Front Genet. 2022 ;13 857168
    Editorial: The Genetic and Epigenetic Bases of Cellular Response to Ionizing Radiation.
    Ki Moon Seong, Giovanni Cenci.
      
    Keywords:  cellular response; epigenetic changes; genetic alteration; ionizing radiation; reactive oxy gen species
    DOI:  https://doi.org/10.3389/fgene.2022.857168
  23. Cancers (Basel). 2022 Mar 12. pii: 1462. [Epub ahead of print]14(6):
    Chemotherapy Resistance: Role of Mitochondrial and Autophagic Components.
    Entaz Bahar, Sun-Young Han, Ji-Ye Kim, Hyonok Yoon.
      Cancer chemotherapy resistance is one of the most critical obstacles in cancer therapy. One of the well-known mechanisms of chemotherapy resistance is the change in the mitochondrial death pathways which occur when cells are under stressful situations, such as chemotherapy. Mitophagy, or mitochondrial selective autophagy, is critical for cell quality control because it can efficiently break down, remove, and recycle defective or damaged mitochondria. As cancer cells use mitophagy to rapidly sweep away damaged mitochondria in order to mediate their own drug resistance, it influences the efficacy of tumor chemotherapy as well as the degree of drug resistance. Yet despite the importance of mitochondria and mitophagy in chemotherapy resistance, little is known about the precise mechanisms involved. As a consequence, identifying potential therapeutic targets by analyzing the signal pathways that govern mitophagy has become a vital research goal. In this paper, we review recent advances in mitochondrial research, mitophagy control mechanisms, and their implications for our understanding of chemotherapy resistance.
    Keywords:  chemotherapy resistance; mitochondria; mitophagy
    DOI:  https://doi.org/10.3390/cancers14061462
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