bims-nenemi 2023-06-18 papers

bims-nenemi

Biomed News

on Neuroinflammation, neurodegeneration and mitochondria

Issue of 2023–06–18
twelve papers selected by
Marco Tigano, Thomas Jefferson University

A mitochondrial iron-responsive pathway regulated by DELE1.
Mitochondrial DNA induces nucleus pulposus cell pyroptosis via the TLR9-NF-κB-NLRP3 axis.
RIG-I recognizes metabolite-capped RNAs as signaling ligands.
Time-resolved proteomic analyses of senescence highlight metabolic rewiring of mitochondria.
Mitochondrial outer membrane permeabilization and inner membrane permeabilization in regulating apoptosis and inflammation.
Hexokinase dissociation from mitochondria promotes oligomerization of VDAC that facilitates NLRP3 inflammasome assembly and activation.
Mitochondrial control of innate immune responses.
Nuclear translocation of an aminoacyl-tRNA synthetase may mediate a chronic "integrated stress response".
Reversing the mitochondrial hex that bewitches NLRP3.
Inner mitochondrial membrane fission protein, MTP18, serves as a mitophagy receptor to prevent apoptosis in oral cancer.
Retrotransposon LINE-1 bodies in the cytoplasm of piRNA-deficient mouse spermatocytes: Ribonucleoproteins overcoming the integrated stress response.
Whole-genome CRISPR screen identifies RAVER1 as a key regulator of RIPK1-mediated inflammatory cell death, PANoptosis.

Mol Cell. 2023 Jun 15. pii: S1097-2765(23)00413-6. [Epub ahead of print]83(12): 2059-2076.e6

A mitochondrial iron-responsive pathway regulated by DELE1.

Yusuke Sekine, Ryan Houston, Eva-Maria Eckl, Evelyn Fessler, Derek P Narendra, Lucas T Jae, Shiori Sekine.

  The heme-regulated kinase HRI is activated under heme/iron deficient conditions; however, the underlying molecular mechanism is incompletely understood. Here, we show that iron-deficiency-induced HRI activation requires the mitochondrial protein DELE1. Notably, mitochondrial import of DELE1 and its subsequent protein stability are regulated by iron availability. Under steady-state conditions, DELE1 is degraded by the mitochondrial matrix-resident protease LONP1 soon after mitochondrial import. Upon iron chelation, DELE1 import is arrested, thereby stabilizing DELE1 on the mitochondrial surface to activate the HRI-mediated integrated stress response (ISR). Ablation of this DELE1-HRI-ISR pathway in an erythroid cell model enhances cell death under iron-limited conditions, suggesting a cell-protective role for this pathway in iron-demanding cell lineages. Our findings highlight mitochondrial import regulation of DELE1 as the core component of a previously unrecognized mitochondrial iron responsive pathway that elicits stress signaling following perturbation of iron homeostasis.

Keywords:  DELE1; HRI; LONP1; erythroid cells; integrated stress response; iron; mitochondria; mitochondrial import; mitochondrial proteostasis

DOI:  https://doi.org/10.1016/j.molcel.2023.05.031
J Transl Med. 2023 Jun 15. 21(1): 389

Mitochondrial DNA induces nucleus pulposus cell pyroptosis via the TLR9-NF-κB-NLRP3 axis.

Peng Lu, Huayong Zheng, Hao Meng, Chuan Liu, Lianhong Duan, Jianzheng Zhang, Zhicheng Zhang, Jie Gao, Yang Zhang, Tiansheng Sun.

   BACKGROUND: Nucleus pulposus cell (NPC) death and progressive reduction play important roles in intervertebral disc degeneration (IVDD). As part of a damage-associated molecular pattern, mitochondrial DNA (mtDNA) can be recognized by TLR9 and triggers the expression of NF-κB and NLRP3 inflammasomes, inducing pyroptosis and inflammatory response. However, whether mtDNA induces NPC pyroptosis via the TLR9-NF-κB-NLRP3 axis and promotes IVDD remains uncertain.
METHODS: We constructed an in vitro NPC oxidative stress injury model to clarify the mechanism of mtDNA release, TLR9-NF-κB signaling pathway activation, and NPC injury. We further verified the mechanism of action underlying the inhibition of mtDNA release or TLR9 activation in NPC injury in vitro. We then constructed a rat punctured IVDD model to understand the mechanism inhibiting mtDNA release and TLR9 activation in IVDD.
RESULTS: We used human NP specimen assays to show that the expression levels of TLR9, NF-κB, and NLRP3 inflammasomes correlated with the degree of IVDD. We demonstrated that mtDNA mediated TLR9-NF-κB-NLRP3 axis activation in oxidative stress-induced human NPC pyroptosis in vitro. Oxidative stress can damage the mitochondria of NPCs, causing the opening of the mitochondrial permeability transition pores (mPTP) and leading to the release of mtDNA into the cytosol. Furthermore, inhibition of mPTP opening or TLR9 activation blocked TLR9-NF-κB-NLRP3 axis activation and thereby mediated NPC pyroptosis and IVDD.
CONCLUSION: mtDNA plays a key role in mediating NPC pyroptosis and IVDD via the TLR9-NF-κB-NLRP3 axis. Our findings provide new potential targets for IVDD.

Keywords:  Intervertebral disc degeneration; NF-κB; NLRP3 inflammasome; Nucleus pulposus cells; Pyroptosis; TLR9; mtDNA

DOI:  https://doi.org/10.1186/s12967-023-04266-5
Nucleic Acids Res. 2023 Jun 16. pii: gkad518. [Epub ahead of print]

RIG-I recognizes metabolite-capped RNAs as signaling ligands.

Brandon D Schweibenz, Mihai Solotchi, Pranita Hanpude, Swapnil C Devarkar, Smita S Patel.

The innate immune receptor RIG-I recognizes 5'-triphosphate double-stranded RNAs (5' PPP dsRNA) as pathogenic RNAs. Such RNA-ends are present in viral genomes and replication intermediates, and they activate the RIG-I signaling pathway to produce a potent interferon response essential for viral clearance. Endogenous mRNAs cap the 5' PPP-end with m7G and methylate the 2'-O-ribose to evade RIG-I, preventing aberrant immune responses deleterious to the cell. Recent studies have identified RNAs in cells capped with metabolites such as NAD+, FAD and dephosphoCoA. Whether RIG-I recognizes these metabolite-capped RNAs has not been investigated. Here, we describe a strategy to make metabolite-capped RNAs free from 5' PPP dsRNA contamination, using in vitro transcription initiated with metabolites. Mechanistic studies show that metabolite-capped RNAs have a high affinity for RIG-I, stimulating the ATPase activity at comparable levels to 5' PPP dsRNA. Cellular signaling assays show that the metabolite-capped RNAs potently stimulate the innate antiviral immune response. This demonstrates that RIG-I can tolerate diphosphate-linked, capped RNAs with bulky groups at the 5' RNA end. This novel class of RNAs that stimulate RIG-I signaling may have cellular roles in activating the interferon response and may be exploited with proper functionalities for RIG-I-related RNA therapeutics.

DOI: https://doi.org/10.1093/nar/gkad518
Life Sci Alliance. 2023 Sep;pii: e202302127. [Epub ahead of print]6(9):

Time-resolved proteomic analyses of senescence highlight metabolic rewiring of mitochondria.

Jun Yong Kim, Ilian Atanassov, Frederik Dethloff, Lara Kroczek, Thomas Langer.

Mitochondrial dysfunction and cellular senescence are hallmarks of aging. However, the relationship between these two phenomena remains incompletely understood. In this study, we investigated the rewiring of mitochondria upon development of the senescent state in human IMR90 fibroblasts. Determining the bioenergetic activities and abundance of mitochondria, we demonstrate that senescent cells accumulate mitochondria with reduced OXPHOS activity, resulting in an overall increase of mitochondrial activities in senescent cells. Time-resolved proteomic analyses revealed extensive reprogramming of the mitochondrial proteome upon senescence development and allowed the identification of metabolic pathways that are rewired with different kinetics upon establishment of the senescent state. Among the early responding pathways, the degradation of branched-chain amino acid was increased, whereas the one carbon folate metabolism was decreased. Late-responding pathways include lipid metabolism and mitochondrial translation. These signatures were confirmed by metabolic flux analyses, highlighting metabolic rewiring as a central feature of mitochondria in cellular senescence. Together, our data provide a comprehensive view on the changes in mitochondrial proteome in senescent cells and reveal how the mitochondrial metabolism is rewired in senescent cells.

DOI: https://doi.org/10.26508/lsa.202302127
J Theor Biol. 2023 Jun 14. pii: S0022-5193(23)00155-8. [Epub ahead of print] 111558

Mitochondrial outer membrane permeabilization and inner membrane permeabilization in regulating apoptosis and inflammation.

Hong Qi, Yu-Song Yin, Zhi-Yong Yin, Xiang Li, Jian-Wei Shuai.

  Recent studies delineate an intimate crosstalk between apoptosis and inflammation. However, the dynamic mechanism linking them by mitochondrial membrane permeabilization remains elusive. Here, we construct a mathematical model consisting of four functional modules. Bifurcation analysis reveals that bistability stems from Bcl-2 family member interaction and time series shows that the time difference between Cyt c and mtDNA release is around 30 minutes, which are consistent with previous works. The model predicts that Bax aggregation kinetic determines cells to undergo apoptosis or inflammation, and that modulating the inhibitory effect of caspase 3 on IFN-β production allows the concurrent occurrence of apoptosis and inflammation. This work provides a theoretical framework for exploring the mechanism of mitochondrial membrane permeabilization in controlling cell fate.

Keywords:  Apoptosis; Dynamic mechanism; Inflammation; Mitochondrial inner membrane permeabilization; Mitochondrial outer membrane permeabilization

DOI:  https://doi.org/10.1016/j.jtbi.2023.111558
Sci Immunol. 2023 Jun 23. 8(84): eade7652

Hexokinase dissociation from mitochondria promotes oligomerization of VDAC that facilitates NLRP3 inflammasome assembly and activation.

Sung Hoon Baik, V Krishnan Ramanujan, Courtney Becker, Sarah Fett, David M Underhill, Andrea J Wolf.

NLRP3 inflammasome activation is a highly regulated process for controlling secretion of the potent inflammatory cytokines IL-1β and IL-18 that are essential during bacterial infection, sterile inflammation, and disease, including colitis, diabetes, Alzheimer's disease, and atherosclerosis. Diverse stimuli activate the NLRP3 inflammasome, and unifying upstream signals has been challenging to identify. Here, we report that a common upstream step in NLRP3 inflammasome activation is the dissociation of the glycolytic enzyme hexokinase 2 from the voltage-dependent anion channel (VDAC) in the outer membrane of mitochondria. Hexokinase 2 dissociation from VDAC triggers activation of inositol triphosphate receptors, leading to release of calcium from the ER, which is taken up by mitochondria. This influx of calcium into mitochondria leads to oligomerization of VDAC, which is known to form a macromolecule-sized pore in the outer membranes of mitochondria that allows proteins and mitochondrial DNA (mtDNA), often associated with apoptosis and inflammation, respectively, to exit the mitochondria. We observe that VDAC oligomers aggregate with NLRP3 during initial assembly of the multiprotein oligomeric NLRP3 inflammasome complex. We also find that mtDNA is necessary for NLRP3 association with VDAC oligomers. These data, together with other recent work, help to paint a more complete picture of the pathway leading to NLRP3 inflammasome activation.

DOI: https://doi.org/10.1126/sciimmunol.ade7652
Front Immunol. 2023 ;14 1166214

Mitochondrial control of innate immune responses.

Shasha Chen, Zhiyong Liao, Pinglong Xu.

  Mitochondria are versatile organelles and essential components of numerous biological processes such as energy metabolism, signal transduction, and cell fate determination. In recent years, their critical roles in innate immunity have come to the forefront, highlighting impacts on pathogenic defense, tissue homeostasis, and degenerative diseases. This review offers an in-depth and comprehensive examination of the multifaceted mechanisms underlying the interactions between mitochondria and innate immune responses. We will delve into the roles of healthy mitochondria as platforms for signalosome assembly, the release of mitochondrial components as signaling messengers, and the regulation of signaling via mitophagy, particularly to cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) signaling and inflammasomes. Furthermore, the review will explore the impacts of mitochondrial proteins and metabolites on modulating innate immune responses, the polarization of innate immune cells, and their implications on infectious and inflammatory diseases.

Keywords:  MAVS; cGAS-STING; inflammasome; innate immunity; mitochondria; mitochondrial metabolism; mitophagy; mtDNA

DOI:  https://doi.org/10.3389/fimmu.2023.1166214
Cell Rep. 2023 Jun 13. pii: S2211-1247(23)00643-5. [Epub ahead of print]42(6): 112632

Nuclear translocation of an aminoacyl-tRNA synthetase may mediate a chronic "integrated stress response".

Julia A Jones, Na Wei, Haissi Cui, Yi Shi, Guangsen Fu, Navin Rauniyar, Ryan Shapiro, Yosuke Morodomi, Nadine Berenst, Calin Dan Dumitru, Sachiko Kanaji, John R Yates, Taisuke Kanaji, Xiang-Lei Yang.

  Various stress conditions are signaled through phosphorylation of translation initiation factor eukaryotic initiation factor 2α (eIF2α) to inhibit global translation while selectively activating transcription factor ATF4 to aid cell survival and recovery. However, this integrated stress response is acute and cannot resolve lasting stress. Here, we report that tyrosyl-tRNA synthetase (TyrRS), a member of the aminoacyl-tRNA synthetase family that responds to diverse stress conditions through cytosol-nucleus translocation to activate stress-response genes, also inhibits global translation. However, it occurs at a later stage than eIF2α/ATF4 and mammalian target of rapamycin (mTOR) responses. Excluding TyrRS from the nucleus over-activates translation and increases apoptosis in cells under prolonged oxidative stress. Nuclear TyrRS transcriptionally represses translation genes by recruiting TRIM28 and/or NuRD complex. We propose that TyrRS, possibly along with other family members, can sense a variety of stress signals through intrinsic properties of this enzyme and strategically located nuclear localization signal and integrate them by nucleus translocation to effect protective responses against chronic stress.

Keywords:  CP: Cell biology; CP: Molecular biology; aminoacyl-tRNA synthetase; cell survival; oxidative stress; stress response; transcriptional regulation; translation inhibition

DOI:  https://doi.org/10.1016/j.celrep.2023.112632
Sci Immunol. 2023 Jun 23. 8(84): eadh2967

Reversing the mitochondrial hex that bewitches NLRP3.

Manasa Mellacheruvu, Grace M E P Lawrence, Stefan Emming, Kate Schroder.

Hexokinase dissociation from mitochondria triggers calcium-induced oligomerization of VDAC within the outer mitochondrial membrane, leading to NLRP3 recruitment and inflammasome signaling (see related Research Article by Baik et al.).

DOI: https://doi.org/10.1126/sciimmunol.adh2967
J Cell Sci. 2023 Jun 14. pii: jcs.259986. [Epub ahead of print]

Inner mitochondrial membrane fission protein, MTP18, serves as a mitophagy receptor to prevent apoptosis in oral cancer.

Debasna P Panigrahi, Prakash P Praharaj, Bishnu P Behera, Srimanta Patra, Shankargouda Patil, Birija Sankar Patro, Sujit K Bhutia.

  MTP18, an inner mitochondrial membrane protein, plays a vital role in maintaining mitochondrial morphology. Furthermore, MTP18 induces mitochondrial fission with subsequent mitophagy, functioning as a mitophagy receptor that targets dysfunctional mitochondria into autophagosomes for elimination. Interestingly, MTP18 interacts with LC3 through its LC3 interacting region (LIR) to induce mitochondrial autophagy. Mutation in the LIR motif (mLIR) inhibits that interaction, thus suppressing mitophagy. Moreover, Parkin/PINK1 deficiency abrogates mitophagy in MTP18-overexpressing FaDu cells. Upon exposure to CCCP, MTP18[mLIR]-FaDu cells show decreased TOM20 expression without affecting COX IV expression. Conversely, loss of Parkin/PINK1 results in inhibition of TOM20 and COX IV degradation in MTP18[mLIR]-FaDu cells exposed to CCCP, establishing Parkin-mediated proteasomal degradation of outer mitochondrial membrane as essential for effective mitophagy. We found that MTP18 provides a survival advantage to oral cancer cells exposed to cellular stress and that inhibition of MTP18-dependent mitophagy induced cell death in oral cancer cells. The findings demonstrate that MTP18 is a novel mitophagy receptor and that MTP18-dependent mitophagy has pathophysiologic implications for oral cancer progression, indicating inhibition of MTP18-mitophagy could thus be a promising cancer therapy strategy.

Keywords:  Apoptosis; MTP18; Mitochondrial fission; Mitophagy; Parkin

DOI:  https://doi.org/10.1242/jcs.259986
PLoS Genet. 2023 Jun 12. 19(6): e1010797

Retrotransposon LINE-1 bodies in the cytoplasm of piRNA-deficient mouse spermatocytes: Ribonucleoproteins overcoming the integrated stress response.

Chiara De Luca, Anuj Gupta, Alex Bortvin.

Transposable elements (TE) are mobile DNA sequences whose excessive proliferation endangers the host. Although animals have evolved robust TE-targeting defenses, including Piwi-interacting (pi)RNAs, retrotransposon LINE-1 (L1) still thrives in humans and mice. To gain insights into L1 endurance, we characterized L1 Bodies (LBs) and ORF1p complexes in germ cells of piRNA-deficient Maelstrom null mice. We report that ORF1p interacts with TE RNAs, genic mRNAs, and stress granule proteins, consistent with earlier studies. We also show that ORF1p associates with the CCR4-NOT deadenylation complex and PRKRA, a Protein Kinase R factor. Despite ORF1p interactions with these negative regulators of RNA expression, the stability and translation of LB-localized mRNAs remain unchanged. To scrutinize these findings, we studied the effects of PRKRA on L1 in cultured cells and showed that it elevates ORF1p levels and L1 retrotransposition. These results suggest that ORF1p-driven condensates promote L1 propagation, without affecting the metabolism of endogenous RNAs.

DOI: https://doi.org/10.1371/journal.pgen.1010797
iScience. 2023 Jun 16. 26(6): 106938

Whole-genome CRISPR screen identifies RAVER1 as a key regulator of RIPK1-mediated inflammatory cell death, PANoptosis.

R K Subbarao Malireddi, Ratnakar R Bynigeri, Raghvendra Mall, Eswar Kumar Nadendla, Jon P Connelly, Shondra M Pruett-Miller, Thirumala-Devi Kanneganti.

  Transforming growth factor-β-activated kinase 1 (TAK1) is a central regulator of innate immunity, cell death, inflammation, and cellular homeostasis. Therefore, many pathogens carry TAK1 inhibitors (TAK1i). As a host strategy to counteract this, inhibition or deletion of TAK1 induces spontaneous inflammatory cell death, PANoptosis, through the RIPK1-PANoptosome complex, containing the NLRP3 inflammasome and caspase-8/FADD/RIPK3 as integral components; however, PANoptosis also promotes pathological inflammation. Therefore, understanding molecular mechanisms that regulate TAK1i-induced cell death is essential. Here, we report a genome-wide CRISPR screen in macrophages that identified TAK1i-induced cell death regulators, including polypyrimidine tract-binding (PTB) protein 1 (PTBP1), a known regulator of RIPK1, and a previously unknown regulator RAVER1. RAVER1 blocked alternative splicing of Ripk1, and its genetic depletion inhibited TAK1i-induced, RIPK1-mediated inflammasome activation and PANoptosis. Overall, our CRISPR screen identified several positive regulators of PANoptosis. Moreover, our study highlights the utility of genome-wide CRISPR-Cas9 screens in myeloid cells for comprehensive characterization of complex cell death pathways to discover therapeutic targets.

Keywords:  Biological sciences; Cell biology; Immunology; Molecular biology

DOI:  https://doi.org/10.1016/j.isci.2023.106938