bims-nenemi 2024-02-11 papers

bims-nenemi

Biomed News

on Neuroinflammation, neurodegeneration and mitochondria

Issue of 2024–02–11
fourteen papers selected by
Marco Tigano, Thomas Jefferson University

Mitochondrial DNA replication stress triggers a pro-inflammatory endosomal pathway of nucleoid disposal.
Mitochondrial outer membrane integrity regulates a ubiquitin-dependent and NF-κB-mediated inflammatory response.
Regulation of proteostasis and innate immunity via mitochondria-nuclear communication.
Itaconate impairs immune control of Plasmodium by enhancing mtDNA-mediated PD-L1 expression in monocyte-derived dendritic cells.
mtDNA extramitochondrial replication mediates mitochondrial defect effects.
Epidermal ZBP1 stabilizes mitochondrial Z-DNA to drive UV-induced IFN signaling in autoimmune photosensitivity.
Mitochondrial DNA mutation enhances sensitivity to immunotherapy in melanoma.
Deficient tRNA posttranscription modification dysregulated the mitochondrial quality controls and apoptosis.
Significant Variations in Double-Stranded RNA Levels in Cultured Skin Cells.
The NS1 protein of influenza B virus binds 5'-triphosphorylated dsRNA to suppress RIG-I activation and the host antiviral response.
Relaxation of mitochondrial hyperfusion in the diabetic retina via N6-furfuryladenosine confers neuroprotection regardless of glycaemic status.
MT-TN mutations lead to progressive mitochondrial encephalopathy and promotes mitophagy.
Genome-wide CRISPR screen reveals the synthetic lethality between BCL2L1 inhibition and radiotherapy.
Detection of senescence using machine learning algorithms based on nuclear features.

Nat Cell Biol. 2024 Feb 08.

Mitochondrial DNA replication stress triggers a pro-inflammatory endosomal pathway of nucleoid disposal.

Laura E Newman, Sammy Weiser Novak, Gladys R Rojas, Nimesha Tadepalle, Cara R Schiavon, Danielle A Grotjahn, Christina G Towers, Marie-Ève Tremblay, Matthew P Donnelly, Sagnika Ghosh, Michaela Medina, Sienna Rocha, Ricardo Rodriguez-Enriquez, Joshua A Chevez, Ian Lemersal, Uri Manor, Gerald S Shadel.

Mitochondrial DNA (mtDNA) encodes essential subunits of the oxidative phosphorylation system, but is also a major damage-associated molecular pattern (DAMP) that engages innate immune sensors when released into the cytoplasm, outside of cells or into circulation. As a DAMP, mtDNA not only contributes to anti-viral resistance, but also causes pathogenic inflammation in many disease contexts. Cells experiencing mtDNA stress caused by depletion of the mtDNA-packaging protein, transcription factor A, mitochondrial (TFAM) or during herpes simplex virus-1 infection exhibit elongated mitochondria, enlargement of nucleoids (mtDNA-protein complexes) and activation of cGAS-STING innate immune signalling via mtDNA released into the cytoplasm. However, the relationship among aberrant mitochondria and nucleoid dynamics, mtDNA release and cGAS-STING activation remains unclear. Here we show that, under a variety of mtDNA replication stress conditions and during herpes simplex virus-1 infection, enlarged nucleoids that remain bound to TFAM exit mitochondria. Enlarged nucleoids arise from mtDNA experiencing replication stress, which causes nucleoid clustering via a block in mitochondrial fission at a stage when endoplasmic reticulum actin polymerization would normally commence, defining a fission checkpoint that ensures mtDNA has completed replication and is competent for segregation into daughter mitochondria. Chronic engagement of this checkpoint results in enlarged nucleoids trafficking into early and then late endosomes for disposal. Endosomal rupture during transit through this endosomal pathway ultimately causes mtDNA-mediated cGAS-STING activation. Thus, we propose that replication-incompetent nucleoids are selectively eliminated by an adaptive mitochondria-endosomal quality control pathway that is prone to innate immune system activation, which might represent a therapeutic target to prevent mtDNA-mediated inflammation during viral infection and other pathogenic states.

DOI: https://doi.org/10.1038/s41556-023-01343-1
EMBO J. 2024 Feb 09.

Mitochondrial outer membrane integrity regulates a ubiquitin-dependent and NF-κB-mediated inflammatory response.

Esmee Vringer, Rosalie Heilig, Joel S Riley, Annabel Black, Catherine Cloix, George Skalka, Alfredo E Montes-Gómez, Aurore Aguado, Sergio Lilla, Henning Walczak, Mads Gyrd-Hansen, Daniel J Murphy, Danny T Huang, Sara Zanivan, Stephen Wg Tait.

  Mitochondrial outer membrane permeabilisation (MOMP) is often essential for apoptosis, by enabling cytochrome c release that leads to caspase activation and rapid cell death. Recently, MOMP has been shown to be inherently pro-inflammatory with emerging cellular roles, including its ability to elicit anti-tumour immunity. Nonetheless, how MOMP triggers inflammation and how the cell regulates this remains poorly defined. We find that upon MOMP, many proteins localised either to inner or outer mitochondrial membranes are ubiquitylated in a promiscuous manner. This extensive ubiquitylation serves to recruit the essential adaptor molecule NEMO, leading to the activation of pro-inflammatory NF-κB signalling. We show that disruption of mitochondrial outer membrane integrity through different means leads to the engagement of a similar pro-inflammatory signalling platform. Therefore, mitochondrial integrity directly controls inflammation, such that permeabilised mitochondria initiate NF-κB signalling.

Keywords:  Cell Death; Inflammation; Mitochondria; NF-κB; Ubiquitin

DOI:  https://doi.org/10.1038/s44318-024-00044-1
J Cell Biol. 2024 Mar 04. pii: e202310005. [Epub ahead of print]223(3):

Regulation of proteostasis and innate immunity via mitochondria-nuclear communication.

Sookyung Kim, Theresa R Ramalho, Cole M Haynes.

Mitochondria are perhaps best known as the "powerhouse of the cell" for their role in ATP production required for numerous cellular activities. Mitochondria have emerged as an important signaling organelle. Here, we first focus on signaling pathways mediated by mitochondria-nuclear communication that promote protein homeostasis (proteostasis). We examine the mitochondrial unfolded protein response (UPRmt) in C. elegans, which is regulated by a transcription factor harboring both a mitochondrial- and nuclear-targeting sequence, the integrated stress response in mammals, as well as the regulation of chromatin by mitochondrial metabolites. In the second section, we explore the role of mitochondria-to-nuclear communication in the regulation of innate immunity and inflammation. Perhaps related to their prokaryotic origin, mitochondria harbor molecules also found in viruses and bacteria. If these molecules accumulate in the cytosol, they elicit the same innate immune responses as viral or bacterial infection.

DOI: https://doi.org/10.1083/jcb.202310005
Cell Metab. 2024 Jan 30. pii: S1550-4131(24)00008-1. [Epub ahead of print]

Itaconate impairs immune control of Plasmodium by enhancing mtDNA-mediated PD-L1 expression in monocyte-derived dendritic cells.

Theresa Ramalho, Patricia A Assis, Ogooluwa Ojelabi, Lin Tan, Brener Carvalho, Luiz Gardinassi, Osvaldo Campos, Philip L Lorenzi, Katherine A Fitzgerald, Cole Haynes, Douglas T Golenbock, Ricardo T Gazzinelli.

  Severe forms of malaria are associated with systemic inflammation and host metabolism disorders; however, the interplay between these outcomes is poorly understood. Using a Plasmodium chabaudi model of malaria, we demonstrate that interferon (IFN) γ boosts glycolysis in splenic monocyte-derived dendritic cells (MODCs), leading to itaconate accumulation and disruption in the TCA cycle. Increased itaconate levels reduce mitochondrial functionality, which associates with organellar nucleic acid release and MODC restraint. We hypothesize that dysfunctional mitochondria release degraded DNA into the cytosol. Once mitochondrial DNA is sensitized, the activation of IRF3 and IRF7 promotes the expression of IFN-stimulated genes and checkpoint markers. Indeed, depletion of the STING-IRF3/IRF7 axis reduces PD-L1 expression, enabling activation of CD8+ T cells that control parasite proliferation. In summary, mitochondrial disruption caused by itaconate in MODCs leads to a suppressive effect in CD8+ T cells, which enhances parasitemia. We provide evidence that ACOD1 and itaconate are potential targets for adjunct antimalarial therapy.

Keywords:  PD-1; PD-L1; Plasmodium chabaudi; TCA cycle; cGAS-STING; immuno checkpoint markers; inate immunity; itaconate; itaconic acid; lymphocytes; malaria; metabolism; methylenesuccinic acid; mitochondria; mitochondrial DNA; monocyte-derived dendritic cells; mtDNA

DOI:  https://doi.org/10.1016/j.cmet.2024.01.008
iScience. 2024 Feb 16. 27(2): 108970

mtDNA extramitochondrial replication mediates mitochondrial defect effects.

Zhaoliang Shan, Shengnan Li, Yuxue Gao, Chunhua Jian, Xiuxiu Ti, Hui Zuo, Ying Wang, Guochun Zhao, Yan Wang, Qing Zhang.

  A high ratio of severe mitochondrial defects causes multiple human mitochondrial diseases. However, until now, the in vivo rescue signal of such mitochondrial defect effects has not been clear. Here, we built fly mitochondrial defect models by knocking down the essential mitochondrial genes dMterf4 and dMrps23. Following genome-wide RNAi screens, we found that knockdown of Med8/Tfb4/mtSSB/PolG2/mtDNA-helicase rescued dMterf4/dMrps23 RNAi-mediated mitochondrial defect effects. Extremely surprisingly, they drove mtDNA replication outside mitochondria through the Med8/Tfb4-mtSSB/PolG2/mtDNA-helicase axis to amplify cytosolic mtDNA, leading to activation of the cGAS-Sting-like IMD pathway to partially mediate dMterf4/dMrps23 RNAi-triggered effects. Moreover, we found that the Med8/Tfb4-mtSSB/PolG2/mtDNA-helicase axis also mediated other fly mitochondrial gene defect-triggered dysfunctions and Drosophila aging. Overall, our study demarcates the Med8/Tfb4-mtSSB/PolG2/mtDNA-helicase axis as a candidate mechanism to mediate mitochondrial defect effects through driving mtDNA extramitochondrial replication; dysfunction of this axis might be used for potential treatments for many mitochondrial and age-related diseases.

Keywords:  Biological sciences; Molecular biology; Molecular genetics; Molecular interaction

DOI:  https://doi.org/10.1016/j.isci.2024.108970
bioRxiv. 2024 Jan 26. pii: 2024.01.23.576771. [Epub ahead of print]

Epidermal ZBP1 stabilizes mitochondrial Z-DNA to drive UV-induced IFN signaling in autoimmune photosensitivity.

Benjamin Klein, Mack B Reynolds, Bin Xu, Mehrnaz Gharaee-Kermani, Yiqing Gao, Celine C Berthier, Svenja Henning, Shannon N Loftus, Kelsey E McNeely, Amanda M Victory, Craig Dobry, Grace A Hile, Feiyang Ma, Jessica L Turnier, Johann E Gudjonsson, Mary X O'Riordan, J Michelle Kahlenberg.

Photosensitivity is observed in numerous autoimmune diseases and drives poor quality of life and disease flares. Elevated epidermal type I interferon (IFN) production primes for photosensitivity and enhanced inflammation, but the substrates that sustain and amplify this cycle remain undefined. Here, we show that IFN-induced Z-DNA binding protein 1 (ZBP1) stabilizes ultraviolet (UV)B-induced cytosolic Z-DNA derived from oxidized mitochondrial DNA. ZBP1 is significantly upregulated in the epidermis of adult and pediatric patients with autoimmune photosensitivity. Strikingly, lupus keratinocytes accumulate extensive cytosolic Z-DNA after UVB, and transfection of keratinocytes with Z-DNA results in stronger IFN production through cGAS-STING activation compared to B-DNA. ZBP1 knockdown abrogates UV-induced IFN responses, whereas overexpression results in a lupus-like phenotype with spontaneous Z-DNA accumulation and IFN production. Our results highlight Z-DNA and ZBP1 as critical mediators for UVB-induced inflammation and uncover how type I IFNs prime for cutaneous inflammation in photosensitivity. One Sentence Summary: ZBP1 and mitochondrial Z-DNA drive autoimmune photosensitivity via cGAS-STING activation.

DOI: https://doi.org/10.1101/2024.01.23.576771
Nat Cancer. 2024 Feb 09.

Mitochondrial DNA mutation enhances sensitivity to immunotherapy in melanoma.

DOI: https://doi.org/10.1038/s43018-023-00722-9
iScience. 2024 Feb 16. 27(2): 108883

Deficient tRNA posttranscription modification dysregulated the mitochondrial quality controls and apoptosis.

Yunfan He, Gao Zhu, Xincheng Li, Mi Zhou, Min-Xin Guan.

  Mitochondria are dynamic organelles in cellular metabolism and physiology. Mitochondrial DNA (mtDNA) mutations are associated with a broad spectrum of clinical abnormalities. However, mechanisms underlying mtDNA mutations regulate intracellular signaling related to the mitochondrial and cellular integrity are less explored. Here, we demonstrated that mt-tRNAMet 4435A>G mutation-induced nucleotide modification deficiency dysregulated the expression of nuclear genes involved in cytosolic proteins involved in oxidative phosphorylation system (OXPHOS) and impaired the assemble and integrity of OXPHOS complexes. These dysfunctions caused mitochondrial dynamic imbalance, thereby increasing fission and decreasing fusion. Excessive fission impaired the process of autophagy including initiation phase, formation, and maturation of autophagosome. Strikingly, the m.4435A>G mutation upregulated the PARKIN dependent mitophagy pathways but downregulated the ubiquitination-independent mitophagy. These alterations promoted intrinsic apoptotic process for the removal of damaged cells. Our findings provide new insights into mechanism underlying deficient tRNA posttranscription modification regulated intracellular signaling related to the mitochondrial and cellular integrity.

Keywords:  Cell biology; Molecular physiology; Properties of biomolecules

DOI:  https://doi.org/10.1016/j.isci.2024.108883
Cells. 2024 Jan 25. pii: 226. [Epub ahead of print]13(3):

Significant Variations in Double-Stranded RNA Levels in Cultured Skin Cells.

Shaymaa Sadeq, Suwalak Chitcharoen, Surar Al-Hashimi, Somruthai Rattanaburi, John Casement, Andreas Werner.

  Endogenous double-stranded RNA has emerged as a potent stimulator of innate immunity. Under physiological conditions, endogenous dsRNA is maintained in the cell nucleus or the mitochondria; however, if protective mechanisms are breached, it leaches into the cytoplasm and triggers immune signaling pathways. Ectopic activation of innate immune pathways is associated with various diseases and senescence and can trigger apoptosis. Hereby, the level of cytoplasmic dsRNA is crucial. We have enriched dsRNA from two melanoma cell lines and primary dermal fibroblasts, including a competing probe, and analyzed the dsRNA transcriptome using RNA sequencing. There was a striking difference in read counts between the cell lines and the primary cells, and the effect was confirmed by northern blotting and immunocytochemistry. Both mitochondria (10-20%) and nuclear transcription (80-90%) contributed significantly to the dsRNA transcriptome. The mitochondrial contribution was lower in the cancer cells compared to fibroblasts. The expression of different transposable element families was comparable, suggesting a general up-regulation of transposable element expression rather than stimulation of a specific sub-family. Sequencing of the input control revealed minor differences in dsRNA processing pathways with an upregulation of oligoadenylate synthase and RNP125 that negatively regulates the dsRNA sensors RIG1 and MDA5. Moreover, RT-qPCR, Western blotting, and immunocytochemistry confirmed the relatively minor adaptations to the hugely different dsRNA levels. As a consequence, these transformed cell lines are potentially less tolerant to interventions that increase the formation of endogenous dsRNA.

Keywords:  J2 antibody; RNA sequencing; double-stranded RNA; innate immunity; pattern recognition receptor

DOI:  https://doi.org/10.3390/cells13030226
bioRxiv. 2024 Jan 24. pii: 2023.09.25.559316. [Epub ahead of print]

The NS1 protein of influenza B virus binds 5'-triphosphorylated dsRNA to suppress RIG-I activation and the host antiviral response.

Ryan Woltz, Brandon Schweibenz, Susan E Tsutakawa, Chen Zhao, LiChung Ma, Ben Shurina, Gregory L Hura, Rachael John, Sergey Vorobiev, Gvt Swapna, Mihai Solotchi, John A Tainer, Robert M Krug, Smita S Patel, Gaetano T Montelione.

Influenza A and B viruses overcome the host antiviral response to cause a contagious and often severe human respiratory disease. Here, integrative structural biology and biochemistry studies on non- structural protein 1 of influenza B virus (NS1B) reveal a previously unrecognized viral mechanism for innate immune evasion. Conserved basic groups of its C-terminal domain (NS1B-CTD) bind 5'- triphosphorylated double-stranded RNA (5'ppp-dsRNA), the primary pathogen-associated feature that activates the host retinoic acid-inducible gene I protein (RIG-I) to initiate interferon synthesis and the cellular antiviral response. Like RIG-I, NS1B-CTD preferentially binds blunt-end 5'ppp-dsRNA. NS1B-CTD also competes with RIG-I for binding 5'ppp-dsRNA, and thus suppresses activation of RIG-I's ATPase activity. Although the NS1B N-terminal domain also binds dsRNA, it utilizes a different binding mode and lacks 5'ppp-dsRNA end preferences. In cells infected with wild-type influenza B virus, RIG-I activation is inhibited. In contrast, RIG-I activation and the resulting phosphorylation of transcription factor IRF-3 are not inhibited in cells infected with a mutant virus encoding NS1B with a R208A substitution it its CTD that eliminates its 5'ppp-dsRNA binding activity. These results reveal a novel mechanism in which NS1B binds 5'ppp-dsRNA to inhibit the RIG-I antiviral response during influenza B virus infection, and open the door to new avenues for antiviral drug discovery.

DOI: https://doi.org/10.1101/2023.09.25.559316
Nat Commun. 2024 Feb 06. 15(1): 1124

Relaxation of mitochondrial hyperfusion in the diabetic retina via N6-furfuryladenosine confers neuroprotection regardless of glycaemic status.

Aidan Anderson, Nada Alfahad, Dulani Wimalachandra, Kaouthar Bouzinab, Paula Rudzinska, Heather Wood, Isabel Fazey, Heping Xu, Timothy J Lyons, Nicholas M Barnes, Parth Narendran, Janet M Lord, Saaeha Rauz, Ian G Ganley, Tim M Curtis, Graham R Wallace, Jose R Hombrebueno.

The recovery of mitochondrial quality control (MQC) may bring innovative solutions for neuroprotection, while imposing a significant challenge given the need of holistic approaches to restore mitochondrial dynamics (fusion/fission) and turnover (mitophagy and biogenesis). In diabetic retinopathy, this is compounded by our lack of understanding of human retinal neurodegeneration, but also how MQC processes interact during disease progression. Here, we show that mitochondria hyperfusion is characteristic of retinal neurodegeneration in human and murine diabetes, blunting the homeostatic turnover of mitochondria and causing metabolic and neuro-inflammatory stress. By mimicking this mitochondrial remodelling in vitro, we ascertain that N6-furfuryladenosine enhances mitochondrial turnover and bioenergetics by relaxing hyperfusion in a controlled fashion. Oral administration of N6-furfuryladenosine enhances mitochondrial turnover in the diabetic mouse retina (Ins2Akita males), improving clinical correlates and conferring neuroprotection regardless of glycaemic status. Our findings provide translational insights for neuroprotection in the diabetic retina through the holistic recovery of MQC.

DOI: https://doi.org/10.1038/s41467-024-45387-9
Biochim Biophys Acta Mol Basis Dis. 2024 Feb 05. pii: S0925-4439(24)00028-0. [Epub ahead of print]1870(4): 167043

MT-TN mutations lead to progressive mitochondrial encephalopathy and promotes mitophagy.

Haolin Duan, Cunhui Pan, Tenghui Wu, Jing Peng, Li Yang.

  Mitochondrial encephalopathy is a neurological disorder caused by impaired mitochondrial function and energy production. One of the genetic causes of this condition is the mutation of MT-TN, a gene that encodes the mitochondrial transfer RNA (tRNA) for asparagine. MT-TN mutations affect the stability and structure of the tRNA, resulting in reduced protein synthesis and complex enzymatic deficiency of the mitochondrial respiratory chain. Our patient cohort manifests with epileptic encephalopathy, ataxia, hypotonia, and bilateral basal ganglia calcification, which differs from previously reported cases. MT-TN mutation deficiency leads to decreased basal and maximal oxygen consumption rates, disrupted spare respiratory capacity, declined mitochondrial membrane potential, and impaired ATP production. Moreover, MT-TN mutations promote mitophagy, a process of selective degradation of damaged mitochondria by autophagy. Excessive mitophagy further leads to mitochondrial biogensis as a compensatory mechanism. In this study, we provided evidence of pathogenicity for two MT-TN mutations, m.5688 T > C and m.G5691A, explored the molecular mechanisms, and summarized the clinical manifestations of MT-TN mutations. Our study expanded the genotype and phenotypic spectrum and provided new insight into mt-tRNA (Asn)-associated mitochondrial encephalopathy.

Keywords:  Epilepsy; MT-TN; Mitochondrial encephalopathy; Mitophagy

DOI:  https://doi.org/10.1016/j.bbadis.2024.167043
Life Sci Alliance. 2024 Apr;pii: e202302353. [Epub ahead of print]7(4):

Genome-wide CRISPR screen reveals the synthetic lethality between BCL2L1 inhibition and radiotherapy.

Ling Yin, Xiaoding Hu, Guangsheng Pei, Mengfan Tang, You Zhou, Huimin Zhang, Min Huang, Siting Li, Jie Zhang, Citu Citu, Zhongming Zhao, Bisrat G Debeb, Xu Feng, Junjie Chen.

Radiation therapy (RT) is one of the most commonly used anticancer therapies. However, the landscape of cellular response to irradiation, especially to a single high-dose irradiation, remains largely unknown. In this study, we performed a whole-genome CRISPR loss-of-function screen and revealed temporal inherent and acquired responses to RT. Specifically, we found that loss of the IL1R1 pathway led to cellular resistance to RT. This is in part because of the involvement of radiation-induced IL1R1-dependent transcriptional regulation, which relies on the NF-κB pathway. Moreover, the mitochondrial anti-apoptotic pathway, particularly the BCL2L1 gene, is crucially important for cell survival after radiation. BCL2L1 inhibition combined with RT dramatically impeded tumor growth in several breast cancer cell lines and syngeneic models. Taken together, our results suggest that the combination of an apoptosis inhibitor such as a BCL2L1 inhibitor with RT may represent a promising anticancer strategy for solid cancers including breast cancer.

DOI: https://doi.org/10.26508/lsa.202302353
Nat Commun. 2024 Feb 03. 15(1): 1041

Detection of senescence using machine learning algorithms based on nuclear features.

Imanol Duran, Joaquim Pombo, Bin Sun, Suchira Gallage, Hiromi Kudo, Domhnall McHugh, Laura Bousset, Jose Efren Barragan Avila, Roberta Forlano, Pinelopi Manousou, Mathias Heikenwalder, Dominic J Withers, Santiago Vernia, Robert D Goldin, Jesús Gil.

Cellular senescence is a stress response with broad pathophysiological implications. Senotherapies can induce senescence to treat cancer or eliminate senescent cells to ameliorate ageing and age-related pathologies. However, the success of senotherapies is limited by the lack of reliable ways to identify senescence. Here, we use nuclear morphology features of senescent cells to devise machine-learning classifiers that accurately predict senescence induced by diverse stressors in different cell types and tissues. As a proof-of-principle, we use these senescence classifiers to characterise senolytics and to screen for drugs that selectively induce senescence in cancer cells but not normal cells. Moreover, a tissue senescence score served to assess the efficacy of senolytic drugs and identified senescence in mouse models of liver cancer initiation, ageing, and fibrosis, and in patients with fatty liver disease. Thus, senescence classifiers can help to detect pathophysiological senescence and to discover and validate potential senotherapies.

DOI: https://doi.org/10.1038/s41467-024-45421-w