bims-nenemi 2023-07-30 papers

bims-nenemi

Biomed News

on Neuroinflammation, neurodegeneration and mitochondria

Issue of 2023‒07‒30
twelve papers selected by
Marco Tigano
Thomas Jefferson University

Cytosolic and mitochondrial translation elongation are coordinated through the molecular chaperone TRAP1 for the synthesis and import of mitochondrial proteins.
FUS Unveiled in Mitochondrial DNA Repair and Targeted Ligase-1 Expression Rescues Repair-Defects in FUS-Linked Neurodegeneration.
Low-Dose Non-Targeted Effects and Mitochondrial Control.
Monitoring integrated stress response in live Drosophila.
Two RNA-binding proteins mediate the sorting of miR223 from mitochondria into exosomes.
Mitochondrial sourcing of interferogenic ligands and an autoantigen in human obesity-associated metaflammation.
The lncRNA HOXA11os regulates mitochondrial function in myeloid cells to maintain intestinal homeostasis.
UBQLN2 and HSP70 participate in Parkin-mediated mitophagy by facilitating outer mitochondrial membrane rupture.
Lats2 deficiency protects the heart against myocardial infarction by reducing inflammation and inhibiting mitochondrial fission and STING/p65 signaling.
Mitochondria-related genes and metabolic profiles of innate and adaptive immune cells in primary Sjögren's syndrome.
Ionizing radiation triggers mitophagy to enhance DNA damage in cancer cells.
Characterization of RNA driven structural changes in full length RIG-I leading to its agonism or antagonism.

Genome Res. 2023 Jul 24. pii: gr.277755.123. [Epub ahead of print]

Cytosolic and mitochondrial translation elongation are coordinated through the molecular chaperone TRAP1 for the synthesis and import of mitochondrial proteins.

Rosario Avolio, Ilenia Agliarulo, Daniela Criscuolo, Daniela Sarnataro, Margherita Auriemma, Sabrina De Lella, Sara Pennacchio, Giovanni Calice, Martin Y Ng, Carlotta Giorgi, Paolo Pinton, Barry Cooperman, Matteo Landriscina, Franca Esposito, Danilo Swann Matassa.

A complex interplay between mRNA translation and cellular respiration has been recently unveiled, but its regulation in humans is poorly characterized in either health or disease. Cancer cells radically reshape both biosynthetic and bioenergetic pathways to sustain their aberrant growth rates. In this regard, we have shown that the molecular chaperone TRAP1 not only regulates the activity of respiratory complexes, behaving alternatively as an oncogene or a tumor suppressor, but also plays a concomitant moonlighting function in mRNA translation regulation. Herein we identify the molecular mechanisms involved, demonstrating that TRAP1: i) binds both mitochondrial and cytosolic ribosomes as well as translation elongation factors, ii) slows down translation elongation rate, and iii) favors localized translation in the proximity of mitochondria. We also provide evidence that TRAP1 is coexpressed in human tissues with the mitochondrial translational machinery, which is responsible for the synthesis of respiratory complex proteins. Altogether, our results show an unprecedented level of complexity in the regulation of cancer cell metabolism, strongly suggesting the existence of a tight feedback loop between protein synthesis and energy metabolism, based on the demonstration that a single molecular chaperone plays a role in both mitochondrial and cytosolic translation, as well as in mitochondrial respiration.

DOI: https://doi.org/10.1101/gr.277755.123
Res Sq. 2023 Jul 12. pii: rs.3.rs-3152718. [Epub ahead of print]

FUS Unveiled in Mitochondrial DNA Repair and Targeted Ligase-1 Expression Rescues Repair-Defects in FUS-Linked Neurodegeneration.

Muralidhar Hegde, Kodavati Manohar, Haibo Wang, Wenting Gao, Joy Mitra, Pavana Hegde, Vincent Provasek, Vikas Rao, Indira Vedula, Aijun Zhang, Sankar Mitra, Alan Tomkinson, Ludo Van Den Bosch, Dale Hamilton.

This study establishes the physiological role of Fused in Sarcoma (FUS) in mitochondrial DNA (mtDNA) repair and highlights its implications to the pathogenesis of FUS-associated neurodegenerative diseases such as Amyotrophic lateral sclerosis (ALS). Endogenous FUS interacts with and recruits mtDNA Ligase IIIα (mtLig3) to DNA damage sites within mitochondria, a relationship essential for maintaining mtDNA repair and integrity in healthy cells. Using ALS patient-derived FUS mutant cell lines, a transgenic mouse model, and human autopsy samples, we discovered that compromised FUS functionality hinders mtLig3's repair role, resulting in increased mtDNA damage and mutations. These alterations cause various manifestations of mitochondrial dysfunction, particularly under stress conditions relevant to disease pathology. Importantly, rectifying FUS mutations in patient-derived induced pluripotent cells (iPSCs) preserves mtDNA integrity. Similarly, targeted introduction of human DNA Ligase 1 restores repair mechanisms and mitochondrial activity in FUS mutant cells, suggesting a potential therapeutic approach. Our findings unveil FUS's critical role in mitochondrial health and mtDNA repair, offering valuable insights into the mechanisms underlying mitochondrial dysfunction in FUS-associated neurodegeneration.

DOI: https://doi.org/10.21203/rs.3.rs-3152718/v1
Int J Mol Sci. 2023 Jul 14. pii: 11460. [Epub ahead of print]24(14):

Low-Dose Non-Targeted Effects and Mitochondrial Control.

Dietrich Averbeck.

  Non-targeted effects (NTE) have been generally regarded as a low-dose ionizing radiation (IR) phenomenon. Recently, regarding long distant abscopal effects have also been observed at high doses of IR) relevant to antitumor radiation therapy. IR is inducing NTE involving intracellular and extracellular signaling, which may lead to short-ranging bystander effects and distant long-ranging extracellular signaling abscopal effects. Internal and "spontaneous" cellular stress is mostly due to metabolic oxidative stress involving mitochondrial energy production (ATP) through oxidative phosphorylation and/or anaerobic pathways accompanied by the leakage of O2- and other radicals from mitochondria during normal or increased cellular energy requirements or to mitochondrial dysfunction. Among external stressors, ionizing radiation (IR) has been shown to very rapidly perturb mitochondrial functions, leading to increased energy supply demands and to ROS/NOS production. Depending on the dose, this affects all types of cell constituents, including DNA, RNA, amino acids, proteins, and membranes, perturbing normal inner cell organization and function, and forcing cells to reorganize the intracellular metabolism and the network of organelles. The reorganization implies intracellular cytoplasmic-nuclear shuttling of important proteins, activation of autophagy, and mitophagy, as well as induction of cell cycle arrest, DNA repair, apoptosis, and senescence. It also includes reprogramming of mitochondrial metabolism as well as genetic and epigenetic control of the expression of genes and proteins in order to ensure cell and tissue survival. At low doses of IR, directly irradiated cells may already exert non-targeted effects (NTE) involving the release of molecular mediators, such as radicals, cytokines, DNA fragments, small RNAs, and proteins (sometimes in the form of extracellular vehicles or exosomes), which can induce damage of unirradiated neighboring bystander or distant (abscopal) cells as well as immune responses. Such non-targeted effects (NTE) are contributing to low-dose phenomena, such as hormesis, adaptive responses, low-dose hypersensitivity, and genomic instability, and they are also promoting suppression and/or activation of immune cells. All of these are parts of the main defense systems of cells and tissues, including IR-induced innate and adaptive immune responses. The present review is focused on the prominent role of mitochondria in these processes, which are determinants of cell survival and anti-tumor RT.

Keywords:  DNA damage response (DDR); ROS; adaptive response; apoptosis; bystander effects; cancer; genomic instability; hormesis; hyper-radiosensitivity (HRS); innate and adaptive immune responses; ionizing radiation; low-dose effects; mitochondria; non-targeted effects (NTEs); radiotherapy; signaling

DOI:  https://doi.org/10.3390/ijms241411460
bioRxiv. 2023 Jul 14. pii: 2023.07.13.548942. [Epub ahead of print]

Monitoring integrated stress response in live Drosophila.

Peter V Lidsky, Jing Yuan, Kseniya A Lashkevich, Sergey E Dmitriev, Raul Andino.

Cells exhibit stress responses to various environmental changes. Among these responses, the integrated stress response (ISR) plays a pivotal role as a crucial stress signaling pathway. While extensive ISR research has been conducted on cultured cells, our understanding of its implications in multicellular organisms remains limited, largely due to the constraints of current techniques that hinder our ability to track and manipulate the ISR in vivo. To overcome these limitations, we have successfully developed an internal ribosome entry site (IRES)-based fluorescent reporter system. This innovative reporter enables us to label Drosophila cells, within the context of a living organism, that exhibit eIF2 phosphorylation-dependent translational shutoff - a characteristic feature of the ISR and viral infections. Through this methodology, we have unveiled tissue- and cell-specific regulation of stress response in Drosophila flies and have even been able to detect stressed tissues in vivo during virus and bacterial infections. To further validate the specificity of our reporter, we have engineered ISR-null eIF2αS50A mutant flies for stress response analysis. Our results shed light on the tremendous potential of this technique for investigating a broad range of developmental, stress, and infection-related experimental conditions. Combining the reporter tool with ISR-null mutants establishes Drosophila as an exceptionally powerful model for studying the ISR in the context of multicellular organisms.

DOI: https://doi.org/10.1101/2023.07.13.548942
Elife. 2023 Jul 25. pii: e85878. [Epub ahead of print]12

Two RNA-binding proteins mediate the sorting of miR223 from mitochondria into exosomes.

Liang Ma, Jasleen Singh, Randy Schekman.

  Fusion of multivesicular bodies (MVBs) with the plasma membrane results in the secretion of intraluminal vesicles (ILVs), or exosomes. The sorting of one exosomal cargo RNA, miR223, is facilitated by the RNA-binding protein, YBX1 (Shurtleff et al., 2016). We found that miR223 specifically binds a 'cold shock' domain (CSD) of YBX1 through a 5' proximal sequence motif UCAGU that may represent a binding site or structural feature required for sorting. Prior to sorting into exosomes, most of the cytoplasmic miR223 resides in mitochondria. An RNA-binding protein localized to the mitochondrial matrix, YBAP1, appears to serve as a negative regulator of miR223 enrichment into exosomes. miR223 levels decreased in the mitochondria and increased in exosomes after loss of YBAP1. We observed YBX1 shuttle between mitochondria and endosomes in live cells. YBX1 also partitions into P body granules in the cytoplasm (Liu et al., 2021). We propose a model in which miR223 and likely other miRNAs are stored in mitochondria and are then mobilized by YBX1 to cytoplasmic phase condensate granules for capture into invaginations in the endosome that give rise to exosomes.

Keywords:  cell biology; human

DOI:  https://doi.org/10.7554/eLife.85878
Obesity (Silver Spring). 2023 Jul 26.

Mitochondrial sourcing of interferogenic ligands and an autoantigen in human obesity-associated metaflammation.

Amrit Raj Ghosh, Purbita Bandopadhyay, Jit Sarkar, Shashi Khanna, Tamonas Chaudhuri, Om Tantia, Partha Chakrabarti, Dipyaman Ganguly.

OBJECTIVE: Visceral adipose tissue (VAT) inflammation contributes to metabolic dysregulation in obesity. VAT recruitment and activation of plasmacytoid dendritic cells (pDCs) through toll-like receptor 9 (TLR9) recognition of self-DNA, leading to induction of type I interferons, are crucial innate triggers for this VAT inflammation. It was hypothesized that mitochondrial DNA (mtDNA) can contribute to TLR9 activation in VAT-recruited pDCs in obesity, and this study aimed to identify the carrier protein for ligand access to TLR9 and to explore whether this also provides for a source of autoantigens in this context.METHODS: VAT samples, used for gene expression studies as well as adipose explant cultures, were collected from patients with obesity (n = 54) and lean patients (n = 10). Supernatants from human pDC cultures, treated with adipose explant culture supernatants, were used for interferon α ELISA. Venous plasma, from patients with (n = 114) and without (n = 45) obesity, was used for an ELISA for autoantibodies.
RESULTS: MtDNA from VAT in obesity, in complex with mitochondrial transcription factor A protein (TFAM), acts as interferogenic ligands for pDCs. Humoral autoreactivity against TFAM is also induced in obesity.
CONCLUSIONS: Interferogenic ligands and an autoantigen can be sourced from dysfunctional mitochondria in VAT of humans with obesity. Further therapeutic and prognostic potential for this immune mechanism in obesity warrants exploration.

DOI: https://doi.org/10.1002/oby.23805
Cell Metab. 2023 Jul 20. pii: S1550-4131(23)00250-4. [Epub ahead of print]

The lncRNA HOXA11os regulates mitochondrial function in myeloid cells to maintain intestinal homeostasis.

Liraz Shmuel-Galia, Fiachra Humphries, Tim Vierbuchen, Zhaozhao Jiang, Nolan Santos, John Johnson, Boris Shklyar, Leonel Joannas, Nicholas Mustone, Shany Sherman, Doyle Ward, JeanMarie Houghton, Christina E Baer, Aisling O'Hara, Jorge Henao-Mejia, Kasper Hoebe, Katherine A Fitzgerald.

  This study reveals a previously uncharacterized mechanism to restrict intestinal inflammation via a regulatory RNA transcribed from a noncoding genomic locus. We identified a novel transcript of the lncRNA HOXA11os specifically expressed in the distal colon that is reduced to undetectable levels in colitis. HOXA11os is localized to mitochondria under basal conditions and interacts with a core subunit of complex 1 of the electron transport chain (ETC) to maintain its activity. Deficiency of HOXA11os in colonic myeloid cells results in complex I deficiency, dysfunctional oxidative phosphorylation (OXPHOS), and the production of mitochondrial reactive oxygen species (mtROS). As a result, HOXA11os-deficient mice develop spontaneous intestinal inflammation and are hypersusceptible to colitis. Collectively, these studies identify a new regulatory axis whereby a lncRNA maintains intestinal homeostasis and restricts inflammation in the colon through the regulation of complex I activity.

Keywords:  IBD; Krebs cycle; OXPHOS; colitis; complex I; intestinal inflammation; lncRNA; mitochondria; mtROS; mucosal inflammation; ncRNA

DOI:  https://doi.org/10.1016/j.cmet.2023.06.019
EMBO Rep. 2023 Jul 28. e55859

UBQLN2 and HSP70 participate in Parkin-mediated mitophagy by facilitating outer mitochondrial membrane rupture.

Qilian Ma, Jiaqi Xin, Qiang Peng, Ningning Li, Shan Sun, Hongyu Hou, Guoqiang Ma, Nana Wang, Li Zhang, Kin Yip Tam, Heiko Dussmann, Jochen Hm Prehn, Hongfeng Wang, Zheng Ying.

  Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two aging-related neurodegenerative diseases that share common key features, including aggregation of pathogenic proteins, dysfunction of mitochondria, and impairment of autophagy. Mutations in ubiquilin 2 (UBQLN2), a shuttle protein in the ubiquitin-proteasome system (UPS), can cause ALS/FTD, but the mechanism underlying UBQLN2-mediated pathogenesis is still uncertain. Recent studies indicate that mitophagy, a selective form of autophagy which is crucial for mitochondrial quality control, is tightly associated with neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, and ALS. In this study, we show that after Parkin-dependent ubiquitination of damaged mitochondria, UBQLN2 is recruited to poly-ubiquitinated mitochondria through the UBA domain. UBQLN2 cooperates with the chaperone HSP70 to promote UPS-driven degradation of outer mitochondrial membrane (OMM) proteins. The resulting rupture of the OMM triggers the autophagosomal recognition of the inner mitochondrial membrane receptor PHB2. UBQLN2 is required for Parkin-mediated mitophagy and neuronal survival upon mitochondrial damage, and the ALS/FTD pathogenic mutations in UBQLN2 impair mitophagy in primary cultured neurons. Taken together, our findings link dysfunctional mitophagy to UBQLN2-mediated neurodegeneration.

Keywords:  ALS; Parkin; UBQLN2; mitophagy; ubiquitin

DOI:  https://doi.org/10.15252/embr.202255859
Int J Biol Sci. 2023 ;19(11): 3428-3440

Lats2 deficiency protects the heart against myocardial infarction by reducing inflammation and inhibiting mitochondrial fission and STING/p65 signaling.

Libao Liu, Shuai Huang, Yingzhen Du, Hao Zhou, Kai Zhang, Jinyuan He.

  Large tumor suppressor kinase 2 (Lats2) is a member of the Hippo pathway, a critical regulator of organ size. Since Lats2 activity may trigger mitochondrial dysfunction, a key pathogenic factor in acute myocardial infarction (AMI), this study sought to investigate whether Lats2 deletion confers cardioprotection in AMI. AMI was induced in cardiomyocyte-specific Lats2 knockout (Lats2Cko) and control (Lats2flox) mice. Twenty-eight days after AMI surgery, myocardial performance and mitochondrial homeostasis were impaired in Lats2floxmice. In contrast, Lats2Cko mice exhibited markedly preserved cardiac structure and contraction/relaxation activity, decreased fibrosis, reduced circulating cardiac injury biomarker levels, and enhanced cardiomyocyte viability. Consistent with these findings, siRNA-mediated Lats2 silencing sustained mitochondrial respiration and inhibited apoptosis in hypoxia-treated HL-1 cardiomyocytes. Notably, Lats2 deficiency inhibited AMI/hypoxia-related mitochondrial fission and inactivated STING/p65 signaling by preventing hypoxia-induced release of mtDNA into the cytosol. Accordingly, pharmacological reactivation of STING signaling abolished the cardioprotective effects of Lats2 ablation. Those data suggest that AMI-induced Lats2 upregulation is associated with impaired cardiomyocyte viability and function resulting from enhanced mitochondrial fission, mtDNA release, and STING/p65 pathway activation.

Keywords:  Acute myocardial infarction; Lats2; STING; mitochondrial fission; mtDNA

DOI:  https://doi.org/10.7150/ijbs.84426
Front Immunol. 2023 ;14 1156774

Mitochondria-related genes and metabolic profiles of innate and adaptive immune cells in primary Sjögren's syndrome.

Danyang Luo, Lei Li, Yicheng Wu, Yi Yang, Yulin Ye, Jiawei Hu, Yiming Gao, Naiyan Zeng, Xiaochun Fei, Ning Li, Liting Jiang.

  Background: Primary Sjogren's syndrome (pSS) is a prototypical systemic autoimmune disease characterised by lymphocyte infiltration and immune-complex deposition in multiple organs. The specific distribution of immune cell populations and their relationship with mitochondria remain unknown.Methods: Histological analysis was performed to assess the specific distribution of innate and adaptive immune cell populations in labial salivary gland (LSG) samples from 30 patients with pSS and 13 patients with non-pSS. The ultrastructural morphometric features of mitochondria within immune cells were observed under the transmission electron microscope (TEM). RNA sequencing was performed on LSG samples from 40 patients with pSS and 7 non-pSS patients. The Single-sample Gene Set Enrichment Analysis (ssGSEA), ESTIMATE, and CIBERSORT algorithms and Pearson correlation coefficients were used to examine the relationship between mitochondria-related genes and immune infiltration. Weighted Gene Co-expression Network Analysis (WGCNA) was used to identify the mitochondria-specific genes and the related pathways based on the immune cell types.
Results: HE staining revealed a massive infiltration of plasma cells with abundant immunoglobulin protein distributed around phenotypically normal-appearing acinar and ductal tissues of patients with pSS. Immunohistochemical analyses revealed that innate immune cells (macrophages, eosinophils and NK cells) were distributed throughout the glandular tissue. Dominant adaptive immune cell infiltration composed of B cells, CD4+T cells and CD8+ T cells or ectopic lymphoid follicle-like structures were observed in the LSGs of patients with pSS. TEM validated the swelling of mitochondria with disorganised cristae in some lymphocytes that had invaded the glandular tissue. Subsequently, bioinformatic analysis revealed that innate and adaptive immune cells were associated with different mitochondrial metabolism pathways. Mitochondrial electron transport and respiratory chain complexes in the glandular microenvironment were positively correlated with innate immune cells, whereas amino acid and nucleic acid metabolism were negatively correlated with adaptive immune cells. In addition, mitochondrial biogenesis and mitochondrial apoptosis in the glandular microenvironment were closely associated with adaptive immune cells.
Conclusion: Innate and adaptive immune cells have distinct distribution profiles in the salivary gland tissues of patients with pSS and are associated with different mitochondrial metabolic pathways, which may contribute to disease progression.

Keywords:  RNA sequencing; Sjogren’s syndrome; immune cell; mitochondria; mitochondrial metabolism; transcriptomics

DOI:  https://doi.org/10.3389/fimmu.2023.1156774
Cell Death Discov. 2023 Jul 28. 9(1): 267

Ionizing radiation triggers mitophagy to enhance DNA damage in cancer cells.

Yanxian Ren, Pengfei Yang, Chenghao Li, Wen-An Wang, Tianyi Zhang, Jin Li, Haining Li, Chunlu Dong, Wenbo Meng, Heng Zhou.

Radiotherapy is an important cancer treatment strategy that causes DNA damage in tumor cells either directly or indirectly. Autophagy is a physiological process linked to DNA damage. Mitophagy is a form of autophagy, which specifically targets and eliminates impaired mitochondria, thereby upholding cellular homeostasis. However, the connection between DNA damage and mitophagy has yet to be fully elucidated. We found that mitophagy, as an upstream signal, increases ionizing radiation-induced DNA damage by downregulating or overexpressing key mitophagy proteins Parkin and BNIP3. Enhancing the basal level of mitophagy in conjunction with X-ray irradiation can potentially diminish cell cycle arrest at the G2/M phase, substantially elevate the accumulation of γ-H2AX, 53BP1, and PARP1 foci within the nucleus, augment DNA damage, and facilitate the demise of tumor cells. Consequently, this approach prolongs the survival of melanoma-bearing mice. The findings of this study are anticipated to offer a therapeutic approach for enhancing the therapeutic effectiveness of radiotherapy.

DOI: https://doi.org/10.1038/s41420-023-01573-0
Nucleic Acids Res. 2023 Jul 24. pii: gkad606. [Epub ahead of print]

Characterization of RNA driven structural changes in full length RIG-I leading to its agonism or antagonism.

Justyna Sikorska, Yan Hou, Paul Chiurazzi, Tony Siu, Gretchen A Baltus, Payal Sheth, David G McLaren, Quang Truong, Craig A Parish, Daniel F Wyss.

RIG-I (retinoic acid inducible gene-I) can sense subtle differences between endogenous and viral RNA in the cytoplasm, triggering an anti-viral immune response through induction of type I interferons (IFN) and other inflammatory mediators. Multiple crystal and cryo-EM structures of RIG-I suggested a mechanism in which the C-terminal domain (CTD) is responsible for the recognition of viral RNA with a 5'-triphoshate modification, while the CARD domains serve as a trigger for downstream signaling, leading to the induction of type I IFN. However, to date contradicting conclusions have been reached around the role of ATP in the mechanism of the CARD domains ejection from RIG-I's autoinhibited state. Here we present an application of NMR spectroscopy to investigate changes induced by the binding of 5'-triphosphate and 5'-OH dsRNA, both in the presence and absence of nucleotides, to full length RIG-I with all its methionine residues selectively labeled (Met-[ϵ-13CH3]). With this approach we were able to identify residues on the CTD, helicase domain, and CARDs that served as probes to sense RNA-induced conformational changes in those respective regions. Our results were analyzed in the context of either agonistic or antagonistic RNAs, by and large supporting a mechanism proposed by the Pyle Lab in which CARD release is primarily dependent on the RNA binding event.

DOI: https://doi.org/10.1093/nar/gkad606