bims-nenemi Biomed News
on Neuroinflammation, neurodegeneration and mitochondria
Issue of 2023‒03‒26
fourteen papers selected by
Marco Tigano
Thomas Jefferson University
  1. Mitochondrial damage activates the NLRP10 inflammasome.
  2. p53 regulates the mitochondrial immune checkpoint.
  3. Pharmacologic Activation of an Integrated Stress Response Kinase Promotes Mitochondrial Remodeling.
  4. Molecular mechanisms of mitochondrial DNA release and activation of the cGAS-STING pathway.
  5. Leaked genomic and mitochondrial DNA contribute to the host response to noroviruses in a STING-dependent manner.
  6. A quantitative fluorescence-based approach to study mitochondrial protein import.
  7. An unknown essential function of tRNA splicing endonuclease is linked to the integrated stress response and intron debranching.
  8. Mitochondrial haplotype and mito-nuclear matching drive somatic mutation and selection throughout aging.
  9. A defect in mitochondrial protein translation influences mitonuclear communication in the heart.
  10. Engineered allostery in light-regulated LOV-Turbo enables precise spatiotemporal control of proximity labeling in living cells.
  11. Structural basis of mitochondrial membrane bending by the I-II-III2-IV2 supercomplex.
  12. Hypertrophic cardiomyopathy as the initial presentation of mitochondrial disease in an infant born to a diabetic mother.
  13. NSUN3-mediated mitochondrial tRNA 5-formylcytidine modification is essential for embryonic development and respiratory complexes in mice.
  14. Loss of fatty acid degradation by astrocytic mitochondria triggers neuroinflammation and neurodegeneration.
  1. Nat Immunol. 2023 Mar 20.
    Mitochondrial damage activates the NLRP10 inflammasome.
    Tomasz Próchnicki, Matilde B Vasconcelos, Kim S Robinson, Matthew S J Mangan, Dennis De Graaf, Kateryna Shkarina, Marta Lovotti, Lena Standke, Romina Kaiser, Rainer Stahl, Fraser G Duthie, Maximilian Rothe, Kateryna Antonova, Lea-Marie Jenster, Zhi Heng Lau, Sarah Rösing, Nora Mirza, Clarissa Gottschild, Dagmar Wachten, Claudia Günther, Thomas A Kufer, Florian I Schmidt, Franklin L Zhong, Eicke Latz.
      Upon detecting pathogens or cell stress, several NOD-like receptors (NLRs) form inflammasome complexes with the adapter ASC and caspase-1, inducing gasdermin D (GSDMD)-dependent cell death and maturation and release of IL-1β and IL-18. The triggers and activation mechanisms of several inflammasome-forming sensors are not well understood. Here we show that mitochondrial damage activates the NLRP10 inflammasome, leading to ASC speck formation and caspase-1-dependent cytokine release. While the AIM2 inflammasome can also sense mitochondrial demise by detecting mitochondrial DNA (mtDNA) in the cytosol, NLRP10 monitors mitochondrial integrity in an mtDNA-independent manner, suggesting the recognition of distinct molecular entities displayed by the damaged organelles. NLRP10 is highly expressed in differentiated human keratinocytes, in which it can also assemble an inflammasome. Our study shows that this inflammasome surveils mitochondrial integrity. These findings might also lead to a better understanding of mitochondria-linked inflammatory diseases.
    DOI:  https://doi.org/10.1038/s41590-023-01451-y
  2. Trends Immunol. 2023 Mar 16. pii: S1471-4906(23)00045-5. [Epub ahead of print]
    p53 regulates the mitochondrial immune checkpoint.
    Claire Vanpouille-Box, Lorenzo Galluzzi.
      Mitochondrial outer membrane permeabilization (MOMP) is crucial for the cytosolic accumulation of mitochondrial DNA (mtDNA) species that are required to jumpstart innate and adaptive immunity. Recent data reported by Ghosh et al. suggest that tumor protein p53 regulates MOMP-dependent type I interferon (IFN) production, not only via MOMP-promoting effects, but also by directing mtDNA-degrading exonucleases to proteasomal processing.
    Keywords:  BAX; BCL2; DNA-damage response; TRIM24; apoptosis
    DOI:  https://doi.org/10.1016/j.it.2023.03.001
  3. bioRxiv. 2023 Mar 12. pii: 2023.03.11.532186. [Epub ahead of print]
    Pharmacologic Activation of an Integrated Stress Response Kinase Promotes Mitochondrial Remodeling.
    Valerie Perea, Kelsey R Baron, Vivian Dolina, Giovanni Aviles, Jessica D Rosarda, Xiaoyan Guo, Martin Kampmann, R Luke Wiseman.
      The integrated stress response (ISR) is a network of eIF2 α kinases, comprising PERK, GCN2, HRI, and PKR, that induce translational and transcriptional signaling in response to diverse insults. The PERK ISR kinase regulates mitochondria in response to endoplasmic reticulum (ER) stress. Deficiencies in PERK signaling lead to mitochondrial dysfunction and contribute to the pathogenesis of numerous diseases. We define the potential for pharmacologic activators of other ISR kinases to rescue ISR signaling and promote mitochondrial adaptation in cells lacking PERK. We show that the HRI activator BtdCPU and the GCN2 activator halofuginone activate ISR signaling and restore ER stress sensitivity in Perk- deficient cells. However, these compounds differentially impact mitochondria. BtdCPU induces mitochondrial depolarization, leading to mitochondrial fragmentation and ISR activation through the OMA1-DELE1-HRI signaling axis. In contrast, halofuginone promotes mitochondrial elongation and altered mitochondrial respiration, mimicking the regulation induced by PERK. This shows halofuginone can compensate for deficiencies in PERK activity and promote adaptive mitochondrial remodeling, highlighting the potential for pharmacologic ISR activation to mitigate mitochondrial dysfunction and motivating the pursuit of highly-selective ISR activators.
    DOI:  https://doi.org/10.1101/2023.03.11.532186
  4. Exp Mol Med. 2023 Mar 24.
    Molecular mechanisms of mitochondrial DNA release and activation of the cGAS-STING pathway.
    Jeonghan Kim, Ho-Shik Kim, Jay H Chung.
      In addition to constituting the genetic material of an organism, DNA is a tracer for the recognition of foreign pathogens and a trigger of the innate immune system. cGAS functions as a sensor of double-stranded DNA fragments and initiates an immune response via the adaptor protein STING. The cGAS-STING pathway not only defends cells against various DNA-containing pathogens but also modulates many pathological processes caused by the immune response to the ectopic localization of self-DNA, such as cytosolic mitochondrial DNA (mtDNA) and extranuclear chromatin. In addition, macrophages can cause inflammation by forming a class of protein complexes called inflammasomes, and the activation of the NLRP3 inflammasome requires the release of oxidized mtDNA. In innate immunity related to inflammasomes, mtDNA release is mediated by macropores that are formed on the outer membrane of mitochondria via VDAC oligomerization. These macropores are specifically formed in response to mitochondrial stress and tissue damage, and the inhibition of VDAC oligomerization mitigates this inflammatory response. The rapidly expanding area of research on the mechanisms by which mtDNA is released and triggers inflammation has revealed new treatment strategies not only for inflammation but also, surprisingly, for neurodegenerative diseases such as amyotrophic lateral sclerosis.
    DOI:  https://doi.org/10.1038/s12276-023-00965-7
  5. Cell Rep. 2023 Mar 20. pii: S2211-1247(23)00190-0. [Epub ahead of print]42(3): 112179
    Leaked genomic and mitochondrial DNA contribute to the host response to noroviruses in a STING-dependent manner.
    Aminu S Jahun, Frederic Sorgeloos, Yasmin Chaudhry, Sabastine E Arthur, Myra Hosmillo, Iliana Georgana, Rhys Izuagbe, Ian G Goodfellow.
      The cGAS-STING pathway is central to the interferon response against DNA viruses. However, recent studies are increasingly demonstrating its role in the restriction of some RNA viruses. Here, we show that the cGAS-STING pathway also contributes to the interferon response against noroviruses, currently the commonest causes of infectious gastroenteritis worldwide. We show a significant reduction in interferon-β induction and a corresponding increase in viral replication in norovirus-infected cells after deletion of STING, cGAS, or IFI16. Further, we find that immunostimulatory host genome-derived DNA and mitochondrial DNA accumulate in the cytosol of norovirus-infected cells. Lastly, overexpression of the viral NS4 protein is sufficient to drive the accumulation of cytosolic DNA. Together, our data find a role for cGAS, IFI16, and STING in the restriction of noroviruses and show the utility of host genomic DNA as a damage-associated molecular pattern in cells infected with an RNA virus.
    Keywords:  CP: Immunology; CP: Molecular biology; DNA leakage; IFI16; NS4; STING; VF1; cGAS; cytosolic DNA; genomic DNA; interferon response; mitochondrial DNA; norovirus; p204
    DOI:  https://doi.org/10.1016/j.celrep.2023.112179
  6. EMBO Rep. 2023 Mar 20. e55760
    A quantitative fluorescence-based approach to study mitochondrial protein import.
    Naintara Jain, Ridhima Gomkale, Olaf Bernhard, Peter Rehling, Luis Daniel Cruz-Zaragoza.
      Mitochondria play central roles in cellular energy production and metabolism. Most proteins required to carry out these functions are synthesized in the cytosol and imported into mitochondria. A growing number of metabolic disorders arising from mitochondrial dysfunction can be traced to errors in mitochondrial protein import. The mechanisms underlying the import of precursor proteins are commonly studied using radioactively labeled precursor proteins imported into purified mitochondria. Here, we establish a fluorescence-based import assay to analyze protein import into mitochondria. We show that fluorescently labeled precursors enable import analysis with similar sensitivity to those using radioactive precursors, yet they provide the advantage of quantifying import with picomole resolution. We adapted the import assay to a 96-well plate format allowing for fast analysis in a screening-compatible format. Moreover, we show that fluorescently labeled precursors can be used to monitor the assembly of the F1 F0 ATP synthase in purified mitochondria. Thus, we provide a sensitive fluorescence-based import assay that enables quantitative and fast import analysis.
    Keywords:  fluorescent precursor; in vitro import; mitochondria; presequence pathway; protein import
    DOI:  https://doi.org/10.15252/embr.202255760
  7. Genetics. 2023 Mar 21. pii: iyad044. [Epub ahead of print]
    An unknown essential function of tRNA splicing endonuclease is linked to the integrated stress response and intron debranching.
    Jennifer E Hurtig, Ambro van Hoof.
      tRNA splicing endonuclease (TSEN) has a well-characterized role in tRNA splicing, but also other functions. For yeast TSEN, these other functions include degradation of a subset of mRNAs that encode mitochondrial proteins and an unknown essential function. In this study, we use yeast genetics to characterize the unknown tRNA-independent function(s) of TSEN. Using a high-copy suppressor screen we found that sen2 mutants can be suppressed by overexpression of SEN54. This effect was seen both for tRNA-dependent and tRNA-independent functions indicating SEN54 is a general suppressor of sen2, likely through structural stabilization. A spontaneous suppressor screen identified mutations in the intron-debranching enzyme, Dbr1, as tRNA-splicing independent suppressors. Transcriptome analysis showed sen2 mutation activates the Gcn4 stress response. These Gcn4 target transcripts decreased considerably in the sen2 dbr1 double mutant. We propose that Dbr1 and TSEN may compete for a shared substrate, which TSEN normally processes into an essential RNA, while Dbr1 initiates its degradation. These data provide further insight into the essential function(s) of TSEN. Importantly, single amino acid mutations in TSEN cause the generally fatal neuronal disease pontocerebellar hypoplasia (PCH). The mechanism by which defects in TSEN cause this disease is unknown and our results reveal new possible mechanisms.
    Keywords:  intron debranching; pontocerrebellar hypoplasia; tRNA splicing endonuclease
    DOI:  https://doi.org/10.1093/genetics/iyad044
  8. bioRxiv. 2023 Mar 08. pii: 2023.03.06.531392. [Epub ahead of print]
    Mitochondrial haplotype and mito-nuclear matching drive somatic mutation and selection throughout aging.
    Isabel M Serrano, Misa Hirose, Clint Valentine, Sharie Austin, Elizabeth Schmidt, Gabriel Pratt, Lindsey Williams, Jesse Salk, Saleh Ibrahim, Peter H Sudmant.
      Mitochondrial genomes co-evolve with the nuclear genome over evolutionary timescales and are shaped by selection in the female germline. Here, we investigate how mismatching between nuclear and mitochondrial ancestry impacts the somatic evolution of the mt-genome in different tissues throughout aging. We used ultra-sensitive Duplex Sequencing to profile ∼2.5 million mt-genomes across five mitochondrial haplotypes and three tissues in young and aged mice, cataloging ∼1.2 million mitochondrial somatic mutations. We identify haplotype-specific mutational patterns and several mutational hotspots, including at the Light Strand Origin of Replication, which consistently exhibits the highest mutation frequency. We show that rodents exhibit a distinct mitochondrial somatic mutational spectrum compared to primates with a surfeit of reactive oxygen species-associated G>T/C>A mutations and that somatic mutations in protein coding genes exhibit strong signatures of positive selection. Lastly, we identify an extensive enrichment in somatic reversion mutations that "re-align" mito-nuclear ancestry within an organism's lifespan. Together, our findings demonstrate that mitochondrial genomes are a dynamically evolving subcellular population shaped by somatic mutation and selection throughout organismal lifetimes.
    DOI:  https://doi.org/10.1101/2023.03.06.531392
  9. Nat Commun. 2023 Mar 22. 14(1): 1595
    A defect in mitochondrial protein translation influences mitonuclear communication in the heart.
    Feng Gao, Tian Liang, Yao Wei Lu, Xuyang Fu, Xiaoxuan Dong, Linbin Pu, Tingting Hong, Yuxia Zhou, Yu Zhang, Ning Liu, Feng Zhang, Jianming Liu, Andrea P Malizia, Hong Yu, Wei Zhu, Douglas B Cowan, Hong Chen, Xinyang Hu, John D Mably, Jian'an Wang, Da-Zhi Wang, Jinghai Chen.
      The regulation of the informational flow from the mitochondria to the nucleus (mitonuclear communication) is not fully characterized in the heart. We have determined that mitochondrial ribosomal protein S5 (MRPS5/uS5m) can regulate cardiac function and key pathways to coordinate this process during cardiac stress. We demonstrate that loss of Mrps5 in the developing heart leads to cardiac defects and embryonic lethality while postnatal loss induces cardiac hypertrophy and heart failure. The structure and function of mitochondria is disrupted in Mrps5 mutant cardiomyocytes, impairing mitochondrial protein translation and OXPHOS. We identify Klf15 as a Mrps5 downstream target and demonstrate that exogenous Klf15 is able to rescue the overt defects and re-balance the cardiac metabolome. We further show that Mrps5 represses Klf15 expression through c-myc, together with the metabolite L-phenylalanine. This critical role for Mrps5 in cardiac metabolism and mitonuclear communication highlights its potential as a target for heart failure therapies.
    DOI:  https://doi.org/10.1038/s41467-023-37291-5
  10. bioRxiv. 2023 Mar 09. pii: 2023.03.09.531939. [Epub ahead of print]
    Engineered allostery in light-regulated LOV-Turbo enables precise spatiotemporal control of proximity labeling in living cells.
    Song-Yi Lee, Joleen S Cheah, Boxuan Zhao, Charles Xu, Heegwang Roh, Christina K Kim, Kelvin F Cho, Namrata D Udeshi, Steven A Carr, Alice Y Ting.
      The incorporation of light-responsive domains into engineered proteins has enabled control of protein localization, interactions, and function with light. We integrated optogenetic control into proximity labeling (PL), a cornerstone technique for high-resolution proteomic mapping of organelles and interactomes in living cells. Through structure-guided screening and directed evolution, we installed the light-sensitive LOV domain into the PL enzyme TurboID to rapidly and reversibly control its labeling activity with low-power blue light. "LOV-Turbo" works in multiple contexts and dramatically reduces background in biotin-rich environments such as neurons. We used LOV-Turbo for pulse-chase labeling to discover proteins that traffick between endoplasmic reticulum, nuclear, and mitochondrial compartments under cellular stress. We also showed that instead of external light, LOV-Turbo can be activated by BRET from luciferase, enabling interaction-dependent PL. Overall, LOV-Turbo increases the spatial and temporal precision of PL, expanding the scope of experimental questions that can be addressed with PL.
    DOI:  https://doi.org/10.1101/2023.03.09.531939
  11. Nature. 2023 Mar 22.
    Structural basis of mitochondrial membrane bending by the I-II-III2-IV2 supercomplex.
    Alexander Mühleip, Rasmus Kock Flygaard, Rozbeh Baradaran, Outi Haapanen, Thomas Gruhl, Victor Tobiasson, Amandine Maréchal, Vivek Sharma, Alexey Amunts.
      Mitochondrial energy conversion requires an intricate architecture of the inner mitochondrial membrane1. Here we show that a supercomplex containing all four respiratory chain components contributes to membrane curvature induction in ciliates. We report cryo-electron microscopy and cryo-tomography structures of the supercomplex that comprises 150 different proteins and 311 bound lipids, forming a stable 5.8-MDa assembly. Owing to subunit acquisition and extension, complex I associates with a complex IV dimer, generating a wedge-shaped gap that serves as a binding site for complex II. Together with a tilted complex III dimer association, it results in a curved membrane region. Using molecular dynamics simulations, we demonstrate that the divergent supercomplex actively contributes to the membrane curvature induction and tubulation of cristae. Our findings highlight how the evolution of protein subunits of respiratory complexes has led to the I-II-III2-IV2 supercomplex that contributes to the shaping of the bioenergetic membrane, thereby enabling its functional specialization.
    DOI:  https://doi.org/10.1038/s41586-023-05817-y
  12. Cardiol Young. 2023 Mar 23. 1-3
    Hypertrophic cardiomyopathy as the initial presentation of mitochondrial disease in an infant born to a diabetic mother.
    Jun Chul Byun, Hee Joung Choi.
      In contrast to hypertrophic cardiomyopathy caused by maternal diabetes, neonatal mitochondrial cardiomyopathy is rare and has a poor prognosis. We report an infant born to a mother with maternal diabetes with persistent ventricular hypertrophy, who was diagnosed with mitochondrial disease associated with m.3243A>G mutation in a mitochondrial tRNA leucine 1 gene. The hypertrophic cardiomyopathy was his initial and only clinical presentation.
    Keywords:  Hypertrophic cardiomyopathy; MT-TL1 mutation; infant of a diabetic mother; mitochondrial cardiomyopathy
    DOI:  https://doi.org/10.1017/S1047951123000392
  13. Commun Biol. 2023 Mar 22. 6(1): 307
    NSUN3-mediated mitochondrial tRNA 5-formylcytidine modification is essential for embryonic development and respiratory complexes in mice.
    Yoshitaka Murakami, Fan-Yan Wei, Yoshimi Kawamura, Haruki Horiguchi, Tsuyoshi Kadomatsu, Keishi Miyata, Kyoko Miura, Yuichi Oike, Yukio Ando, Mitsuharu Ueda, Kazuhito Tomizawa, Takeshi Chujo.
      In mammalian mitochondria, translation of the AUA codon is supported by 5-formylcytidine (f5C) modification in the mitochondrial methionine tRNA anticodon. The 5-formylation is initiated by NSUN3 methylase. Human NSUN3 mutations are associated with mitochondrial diseases. Here we show that Nsun3 is essential for embryonic development in mice with whole-body Nsun3 knockout embryos dying between E10.5 and E12.5. To determine the functions of NSUN3 in adult tissue, we generated heart-specific Nsun3 knockout (Nsun3HKO) mice. Nsun3HKO heart mitochondria were enlarged and contained fragmented cristae. Nsun3HKO resulted in enhanced heart contraction and age-associated mild heart enlargement. In the Nsun3HKO hearts, mitochondrial mRNAs that encode respiratory complex subunits were not down regulated, but the enzymatic activities of the respiratory complexes decreased, especially in older mice. Our study emphasizes that mitochondrial tRNA anticodon modification is essential for mammalian embryonic development and shows that tissue-specific loss of a single mitochondrial tRNA modification can induce tissue aberration that worsens in later adulthood.
    DOI:  https://doi.org/10.1038/s42003-023-04680-x
  14. Nat Metab. 2023 Mar 23.
    Loss of fatty acid degradation by astrocytic mitochondria triggers neuroinflammation and neurodegeneration.
    Yashi Mi, Guoyuan Qi, Francesca Vitali, Yuan Shang, Adam C Raikes, Tian Wang, Yan Jin, Roberta D Brinton, Haiwei Gu, Fei Yin.
      Astrocytes provide key neuronal support, and their phenotypic transformation is implicated in neurodegenerative diseases. Metabolically, astrocytes possess low mitochondrial oxidative phosphorylation (OxPhos) activity, but its pathophysiological role in neurodegeneration remains unclear. Here, we show that the brain critically depends on astrocytic OxPhos to degrade fatty acids (FAs) and maintain lipid homeostasis. Aberrant astrocytic OxPhos induces lipid droplet (LD) accumulation followed by neurodegeneration that recapitulates key features of Alzheimer's disease (AD), including synaptic loss, neuroinflammation, demyelination and cognitive impairment. Mechanistically, when FA load overwhelms astrocytic OxPhos capacity, elevated acetyl-CoA levels induce astrocyte reactivity by enhancing STAT3 acetylation and activation. Intercellularly, lipid-laden reactive astrocytes stimulate neuronal FA oxidation and oxidative stress, activate microglia through IL-3 signalling, and inhibit the biosynthesis of FAs and phospholipids required for myelin replenishment. Along with LD accumulation and impaired FA degradation manifested in an AD mouse model, we reveal a lipid-centric, AD-resembling mechanism by which astrocytic mitochondrial dysfunction progressively induces neuroinflammation and neurodegeneration.
    DOI:  https://doi.org/10.1038/s42255-023-00756-4
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