bims-nenemi 2022-12-18 papers

bims-nenemi

Biomed News

on Neuroinflammation, neurodegeneration and mitochondria

Issue of 2022‒12‒18
thirteen papers selected by
Marco Tigano
Thomas Jefferson University

A rapid RIG-I signaling relay mediates efficient antiviral response.
Intraneuronal tau aggregation induces the integrated stress response in astrocytes.
An AAA-ATPase links mitochondrial division with DNA nucleoids.
Genetic basis of enhanced stress resistance in long-lived mutants highlights key role of innate immunity in determining longevity.
TFAM's Contributions to mtDNA Replication and OXPHOS Biogenesis Are Genetically Separable.
Divergent Molecular and Cellular Responses to Low and High-Dose Ionizing Radiation.
SHF confers radioresistance in colorectal cancer by the regulation of mitochondrial DNA copy number.
Investigating mitochondrial fission, fusion, and autophagy in retinal pigment epithelium from donors with age-related macular degeneration.
Trophoblastic mitochondrial DNA induces endothelial dysfunction and NLRP3 inflammasome activation: Implications for preeclampsia.
Distinct signaling signatures drive compensatory proliferation via S-phase acceleration.
FASTK family of genes linked to cancer.
An increase in mitochondrial TOM activates apoptosis to drive retinal neurodegeneration.
RNA granule-clustered mitochondrial aminoacyl-tRNA synthetases form multiple complexes with the potential to fine-tune tRNA aminoacylation.

Mol Cell. 2022 Dec 06. pii: S1097-2765(22)01131-5. [Epub ahead of print]

A rapid RIG-I signaling relay mediates efficient antiviral response.

Daniel T Thoresen, Drew Galls, Benjamin Götte, Wenshuai Wang, Anna M Pyle.

  RIG-I is essential for host defense against viral pathogens, as it triggers the release of type I interferons upon encounter with viral RNA molecules. In this study, we show that RIG-I is rapidly and efficiently activated by small quantities of incoming viral RNA and that it relies exclusively on the constitutively expressed resident pool of RIG-I receptors for a strong antiviral response. Live-cell imaging of RIG-I following stimulation with viral or synthetic dsRNA reveals that RIG-I signaling occurs without mass aggregation at the mitochondrial membrane. By contrast, interferon-induced RIG-I protein becomes embedded in cytosolic aggregates that are functionally unrelated to signaling. These findings suggest that endogenous RIG-I efficiently recognizes viral RNA and rapidly relays an antiviral signal to MAVS via a transient signaling complex and that cellular aggregates of RIG-I have a function that is distinct from signaling.

Keywords:  RIG-I; antiviral response; innate immunity; type I interferon response

DOI:  https://doi.org/10.1016/j.molcel.2022.11.018
J Mol Cell Biol. 2022 Dec 15. pii: mjac071. [Epub ahead of print]

Intraneuronal tau aggregation induces the integrated stress response in astrocytes.

Kevin L Batenburg, Nael N Kasri, Vivi M Heine, Wiep Scheper.

  Progressive aggregation of tau protein in neurons is associated with neurodegeneration in tauopathies. Cell non-autonomous disease mechanisms in astrocytes may be important drivers of the disease process but remain largely elusive. Here, we studied cell type-specific responses to intraneuronal tau aggregation prior to neurodegeneration. To this end, we developed a fully human co-culture model of seed-independent intraneuronal tau pathology, which shows no neuron- and synapse loss. Using high-content microscopy, we show that intraneuronal tau aggregation induces oxidative stress accompanied by activation of the integrated stress response specifically in astrocytes. This requires the direct co-culture with neurons and is not related to neurodegeneration or extracellular tau levels. Tau-directed antisense therapy reduced intraneuronal tau levels and aggregation and prevented the cell non-autonomous responses in astrocytes. These data identify the astrocytic integrated stress response as a novel disease mechanism activated by intraneuronal tau aggregation. In addition, our data provide the first evidence for the efficacy of tau-directed antisense therapy to target cell autonomous and cell non-autonomous disease pathways in a fully human model of tau pathology.

Keywords:  antisense oligonucleotides; astrocytes; hiPSC-derived neurons; integrated stress response; oxidative stress; tau aggregation

DOI:  https://doi.org/10.1093/jmcb/mjac071
Proc Natl Acad Sci U S A. 2022 Dec 20. 119(51): e2217949119

An AAA-ATPase links mitochondrial division with DNA nucleoids.

Nelson Yeung, Miho Iijima, Hiromi Sesaki.

DOI: https://doi.org/10.1073/pnas.2217949119
Aging Cell. 2022 Dec 13. e13740

Genetic basis of enhanced stress resistance in long-lived mutants highlights key role of innate immunity in determining longevity.

Sonja K Soo, Annika Traa, Zenith D Rudich, Alibek Moldakozhayev, Meeta Mistry, Jeremy M Van Raamsdonk.

  Mutations that extend lifespan are associated with enhanced resistance to stress. To better understand the molecular mechanisms underlying this relationship, we directly compared lifespan extension, resistance to external stressors, and gene expression in a panel of nine long-lived Caenorhabditis elegans mutants from different pathways of lifespan extension. All of the examined long-lived mutants exhibited increased resistance to one or more types of stress. Resistance to each of the examined types of stress had a significant, positive correlation with lifespan, with bacterial pathogen resistance showing the strongest relationship. Analysis of transcriptional changes indicated that all of the examined long-lived mutants showed a significant upregulation of multiple stress response pathways. Interestingly, there was a very significant overlap between genes highly correlated with stress resistance and genes highly correlated with longevity, suggesting that the same genetic pathways drive both phenotypes. This was especially true for genes correlated with bacterial pathogen resistance, which showed an 84% overlap with genes correlated with lifespan. To further explore the relationship between innate immunity and longevity, we disrupted the p38-mediated innate immune signaling pathway in each of the long-lived mutants and found that this pathway is required for lifespan extension in eight of nine mutants. Overall, our results demonstrate a strong correlation between stress resistance and longevity that results from the high degree of overlap in genes contributing to each phenotype. Moreover, these findings demonstrate the importance of the innate immune system in lifespan determination and indicate that the same underlying genes drive both immunity and longevity.

Keywords:   C. elegans ; DAF-16/FOXO; SKN-1/NRF2; aging; genetics; innate immunity; lifespan; stress resistance

DOI:  https://doi.org/10.1111/acel.13740
Cells. 2022 Nov 24. pii: 3754. [Epub ahead of print]11(23):

TFAM's Contributions to mtDNA Replication and OXPHOS Biogenesis Are Genetically Separable.

Natalya Kozhukhar, Mikhail F Alexeyev.

  The ability of animal orthologs of human mitochondrial transcription factor A (hTFAM) to support the replication of human mitochondrial DNA (hmtDNA) does not follow a simple pattern of phylogenetic closeness or sequence similarity. In particular, TFAM from chickens (Gallus gallus, chTFAM), unlike TFAM from the "living fossil" fish coelacanth (Latimeria chalumnae), cannot support hmtDNA replication. Here, we implemented the recently developed GeneSwap approach for reverse genetic analysis of chTFAM to obtain insights into this apparent contradiction. By implementing limited "humanization" of chTFAM focused either on amino acid residues that make DNA contacts, or the ones with significant variances in side chains, we isolated two variants, Ch13 and Ch22. The former has a low mtDNA copy number (mtCN) but robust respiration. The converse is true of Ch22. Ch13 and Ch22 complement each other's deficiencies. Opposite directionalities of changes in mtCN and respiration were also observed in cells expressing frog TFAM. This led us to conclude that TFAM's contributions to mtDNA replication and respiratory chain biogenesis are genetically separable. We also present evidence that TFAM residues that make DNA contacts play the leading role in mtDNA replication. Finally, we present evidence for a novel mode of regulation of the respiratory chain biogenesis by regulating the supply of rRNA subunits.

Keywords:  GeneSwap approach; TFAM; mtDNA instability; mtDNA replication; mtDNA transcription

DOI:  https://doi.org/10.3390/cells11233754
Cells. 2022 Nov 27. pii: 3794. [Epub ahead of print]11(23):

Divergent Molecular and Cellular Responses to Low and High-Dose Ionizing Radiation.

Bharath Sampadi, Sylvia Vermeulen, Branislav Mišovic, Jan J Boei, Tanveer S Batth, Jer-Gung Chang, Michelle T Paulsen, Brian Magnuson, Joost Schimmel, Hanneke Kool, Cyriel S Olie, Bart Everts, Alfred C O Vertegaal, Jesper V Olsen, Mats Ljungman, Penny A Jeggo, Leon H F Mullenders, Harry Vrieling.

  Cancer risk after ionizing radiation (IR) is assumed to be linear with the dose; however, for low doses, definite evidence is lacking. Here, using temporal multi-omic systems analyses after a low (LD; 0.1 Gy) or a high (HD; 1 Gy) dose of X-rays, we show that, although the DNA damage response (DDR) displayed dose proportionality, many other molecular and cellular responses did not. Phosphoproteomics uncovered a novel mode of phospho-signaling via S12-PPP1R7, and large-scale dephosphorylation events that regulate mitotic exit control in undamaged cells and the G2/M checkpoint upon IR in a dose-dependent manner. The phosphoproteomics of irradiated DNA double-strand breaks (DSBs) repair-deficient cells unveiled extended phospho-signaling duration in either a dose-dependent (DDR signaling) or independent (mTOR-ERK-MAPK signaling) manner without affecting signal magnitude. Nascent transcriptomics revealed the transcriptional activation of genes involved in NRF2-regulated antioxidant defense, redox-sensitive ERK-MAPK signaling, glycolysis and mitochondrial function after LD, suggesting a prominent role for reactive oxygen species (ROS) in molecular and cellular responses to LD exposure, whereas DDR genes were prominently activated after HD. However, how and to what extent the observed dose-dependent differences in molecular and cellular responses may impact cancer development remain unclear, as the induction of chromosomal damage was found to be dose-proportional (10-200 mGy).

Keywords:  DNA damage response; antioxidant response; cell signaling; ionizing radiation; linear no-threshold; low dose; mitochondria; phosphoproteomics; reactive oxygen species; signal transduction

DOI:  https://doi.org/10.3390/cells11233794
Clin Exp Med. 2022 Dec 17.

SHF confers radioresistance in colorectal cancer by the regulation of mitochondrial DNA copy number.

Zhenyu Zhu, Meihua Gong, Weipeng Gong, Bishi Wang, Changhao Li, Qingsheng Hou, Hongliang Guo, Jie Chai, Jie Guan, Yanhan Jia.

  Altered mitochondrial function contributes greatly to pathogenesis and progression of colorectal cancer. In this study, we report a functional pool of Src homology 2 domain-containing F (SHF) in mitochondria controlling the response of colorectal cancer cells to radiation therapy. We found that elevated expression of SHF in cancer cells is essential for promoting mitochondrial function by increasing mitochondrial DNA copy number, thus reducing the sensitivity of colorectal cancer cells to radiation. Mechanistically, SHF binds to mitochondrial DNA and promotes POLG/SSBP1-mediated mitochondrial DNA synthesis. Importantly, SHF loss-mediated radiosensitization was phenocopied by depletion of mitochondrial DNA. Thus, our data demonstrate that mitochondrial SHF is an important regulator of radioresistance in colorectal cancer cells, identifying SHF as a promising therapeutic target to enhance radiotherapy efficacy in colorectal cancer.

Keywords:  Colorectal cancer; Mitochondrial DNA copy number; Mitochondrial function; Radioresistance; Radiosensitivity

DOI:  https://doi.org/10.1007/s10238-022-00969-z
Sci Rep. 2022 Dec 16. 12(1): 21725

Investigating mitochondrial fission, fusion, and autophagy in retinal pigment epithelium from donors with age-related macular degeneration.

Cody R Fisher, Adam A Shaaeli, Mara C Ebeling, Sandra R Montezuma, Deborah A Ferrington.

Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in developed countries, characterized by the death of retinal pigment epithelial (RPE) cells and photoreceptors. Previous studies report an accumulation of damaged and dysfunctional mitochondria in RPE of human donors with AMD. Understanding how damaged mitochondria accumulate in AMD is an important step in discovering disease mechanisms and identifying therapeutic targets. In this report, we assessed mitochondrial fission and fusion by quantifying proteins and measured mitochondrial autophagy (mitophagy) via protein analysis and advanced imaging techniques using mitochondrial targeted mKeima in primary human RPE from donors with or without AMD. We report disease-specific differences in mitochondrial proteins that regulate fission, fusion, and mitophagy that were present at baseline and with treatments to stimulate these pathways. Data suggest AMD RPE utilize receptor-mediated mitophagy as a compensatory mechanism for deficits in the ubiquitin-mediated mitophagy pathway. These changes in mitochondrial homeostasis could lead to the buildup of damaged and dysfunctional mitochondria observed in the RPE of AMD donors.

DOI: https://doi.org/10.1038/s41598-022-26012-5
Int Immunopharmacol. 2022 Dec 09. pii: S1567-5769(22)01008-6. [Epub ahead of print]114 109523

Trophoblastic mitochondrial DNA induces endothelial dysfunction and NLRP3 inflammasome activation: Implications for preeclampsia.

Zi Lv, Ding-Yi Lv, Jia-Yu Meng, Xiao-Yan Sha, Xue-Ya Qian, Yun-Shan Chen, Xiu-Yu Pan, Guang-Yuan Yu, Hui-Shu Liu.

  AIMS: Preeclampsia (PE) is characterised by systemic vascular endothelium dysfunction. Circulating trophoblastic secretions contribute to endothelial dysfunction, resulting in PE; however, the underlying mechanisms remain unclear. Herein, we aimed to determine the potential correlation between the release of trophoblastic mitochondrial deoxyribonucleic acid (DNA) (mtDNA) and endothelium damage in PE.MATERIALS AND METHODS: Umbilical cord sera and tissues from patients with PE were investigated for inflammasome activation. Following this, trophoblastic mitochondria were isolated from HTR-8/SVneo trophoblasts under 21 % oxygen (O2) or hypoxic conditions (1 % O2 for 48 h) for subsequent treatments. Primary human umbilical veinendothelial cells (HUVECs) were isolated from the human umbilical cord and then exposed to a vehicle (phosphate-buffered saline [PBS]), mtDNA, hypo-mtDNA, or hypo-mtDNA with INF39 (nucleotide oligomerisation domain-like receptor family pyrin domain containing 3 [NLRP3]-specific inhibitor) for 12 h before flow cytometry and immunoblotting. The effects of trophoblastic mtDNA on the endothelium were further analysed in vivo using enzyme-linked immunosorbent assay (ELISA) and vascular reactivity assay. The effects of mtDNA on vascular phenotypes were also tested on NLRP3 knockout mice.
RESULTS: Elevated interleukin (IL)-1β in PE sera was accompanied by NLRP3 inflammasome activation in cord tissues. In vitro and in vivo experiments revealed that the release of trophoblastic mtDNA could damage the endothelium via NLRP3 activation, resulting in the overexpression of NLRP3, caspase-1 p20, IL-1β p17, and gasdermin D (GSDMD); reduced endothelial nitric oxide synthase (eNOS) levels; and impaired vascular relaxation. Flow cytometric analysis confirmed that extensive cell death was induced by mtDNA, and simultaneously, a more pronounced pro-apoptotic effect was caused by hypoxia-treated trophoblastic mtDNA. The NLRP3 knockout or pharmacologic NLRP3 inhibition partially reversed tumour necrosis factor-α (TNF-α) and IL-1β levels and endothelium-dependent vasodilation in mice.
CONCLUSION: These findings demonstrate that trophoblastic mtDNA induced NLRP3/caspase-1/IL-1β signalling activation, eNOS-related endothelial injury, and vasodilation dysfunction in PE.

Keywords:  Endothelial dysfunction; Inflammation; Mitochondrial DNA; NLRP3 inflammasome; Preeclampsia

DOI:  https://doi.org/10.1016/j.intimp.2022.109523
PLoS Genet. 2022 Dec 15. 18(12): e1010516

Distinct signaling signatures drive compensatory proliferation via S-phase acceleration.

Carlo Crucianelli, Janhvi Jaiswal, Ananthakrishnan Vijayakumar Maya, Liyne Nogay, Andrea Cosolo, Isabelle Grass, Anne-Kathrin Classen.

Regeneration relies on cell proliferation to restore damaged tissues. Multiple signaling pathways activated by local or paracrine cues have been identified to promote regenerative proliferation. How different types of tissue damage may activate distinct signaling pathways and how these differences converge on regenerative proliferation is less well defined. To better understand how tissue damage and proliferative signals are integrated during regeneration, we investigate models of compensatory proliferation in Drosophila imaginal discs. We find that compensatory proliferation is associated with a unique cell cycle profile, which is characterized by short G1 and G2 phases and, surprisingly, by acceleration of the S-phase. S-phase acceleration can be induced by two distinct signaling signatures, aligning with inflammatory and non-inflammatory tissue damage. Specifically, non-autonomous activation of JAK/STAT and Myc in response to inflammatory damage, or local activation of Ras/ERK and Hippo/Yki in response to elevated cell death, promote accelerated nucleotide incorporation during S-phase. This previously unappreciated convergence of different damaging insults on the same regenerative cell cycle program reconciles previous conflicting observations on proliferative signaling in different tissue regeneration and tumor models.

DOI: https://doi.org/10.1371/journal.pgen.1010516
Bioinformation. 2022 ;18(3): 206-213

FASTK family of genes linked to cancer.

Abilasha Ramasubramanian, A Paramasivam, Pratibha Ramani.

  Fas Activated Serine/Threonine Kinase (FASTK) family is a protein family encoded in the nuclear genome that spans the mitochondria and executes numerous functions, and consists of FASTK, the founding member along with 5 homologous proteins FASTKD1-5. Up regulation of FASTK family members have not only been implicated in tumour progression and invasion but also in increased resistance to chemotherapy proven by their knockdown leading to increased sensitivity to drugs. Thus, this review reports the implication of FASTK proteins in cancer and hence provides a scope to emphasise the role of these proteins in Oral Cancer.

Keywords:  FAST; FASTK family; cancer; mitochondrial dysfunction

DOI:  https://doi.org/10.6026/97320630018206
Sci Rep. 2022 Dec 14. 12(1): 21634

An increase in mitochondrial TOM activates apoptosis to drive retinal neurodegeneration.

Agalya Periasamy, Naomi Mitchell, Olga Zaytseva, Arjun S Chahal, Jiamin Zhao, Peter M Colman, Leonie M Quinn, Jacqueline M Gulbis.

Intronic polymorphic TOMM40 variants increasing TOMM40 mRNA expression are strongly correlated to late onset Alzheimer's Disease. The gene product, hTomm40, encoded in the APOE gene cluster, is a core component of TOM, the translocase that imports nascent proteins across the mitochondrial outer membrane. We used Drosophila melanogaster eyes as an in vivo model to investigate the relationship between elevated Tom40 (the Drosophila homologue of hTomm40) expression and neurodegeneration. Here we provide evidence that an overabundance of Tom40 in mitochondria invokes caspase-dependent cell death in a dose-dependent manner, leading to degeneration of the primarily neuronal eye tissue. Degeneration is contingent on the availability of co-assembling TOM components, indicating that an increase in assembled TOM is the factor that triggers apoptosis and degeneration in a neural setting. Eye death is not contingent on inner membrane translocase components, suggesting it is unlikely to be a direct consequence of impaired import. Another effect of heightened Tom40 expression is upregulation and co-association of a mitochondrial oxidative stress biomarker, DmHsp22, implicated in extension of lifespan, providing new insight into the balance between cell survival and death. Activation of regulated death pathways, culminating in eye degeneration, suggests a possible causal route from TOMM40 polymorphisms to neurodegenerative disease.

DOI: https://doi.org/10.1038/s41598-022-23280-z
Nucleic Acids Res. 2022 Dec 12. pii: gkac1141. [Epub ahead of print]

RNA granule-clustered mitochondrial aminoacyl-tRNA synthetases form multiple complexes with the potential to fine-tune tRNA aminoacylation.

Gui-Xin Peng, Xue-Ling Mao, Yating Cao, Shi-Ying Yao, Qing-Run Li, Xin Chen, En-Duo Wang, Xiao-Long Zhou.

Mitochondrial RNA metabolism is suggested to occur in identified compartmentalized foci, i.e. mitochondrial RNA granules (MRGs). Mitochondrial aminoacyl-tRNA synthetases (mito aaRSs) catalyze tRNA charging and are key components in mitochondrial gene expression. Mutations of mito aaRSs are associated with various human disorders. However, the suborganelle distribution, interaction network and regulatory mechanism of mito aaRSs remain largely unknown. Here, we found that all mito aaRSs partly colocalize with MRG, and this colocalization is likely facilitated by tRNA-binding capacity. A fraction of human mitochondrial AlaRS (hmtAlaRS) and hmtSerRS formed a direct complex via interaction between catalytic domains in vivo. Aminoacylation activities of both hmtAlaRS and hmtSerRS were fine-tuned upon complex formation in vitro. We further established a full spectrum of interaction networks via immunoprecipitation and mass spectrometry for all mito aaRSs and discovered interactions between hmtSerRS and hmtAsnRS, between hmtSerRS and hmtTyrRS and between hmtThrRS and hmtArgRS. The activity of hmtTyrRS was also influenced by the presence of hmtSerRS. Notably, hmtSerRS utilized the same catalytic domain in mediating several interactions. Altogether, our results systematically analyzed the suborganelle localization and interaction network of mito aaRSs and discovered several mito aaRS-containing complexes, deepening our understanding of the functional and regulatory mechanisms of mito aaRSs.

DOI: https://doi.org/10.1093/nar/gkac1141