bims-nenemi 2024-11-24 papers

bims-nenemi

Biomed News

on Neuroinflammation, neurodegeneration and mitochondria

Issue of 2024–11–24
ten papers selected by
Marco Tigano, Thomas Jefferson University

Pathogenic PDE12 variants impair mitochondrial RNA processing causing neonatal mitochondrial disease.
The Human Mitochondrial Genome Encodes for an Interferon-Responsive Host Defense Peptide.
Age-Dependent Pathogenesis of Influenza A Virus H7N9 Mediated Through PB1-F2-Induced Mitochondrial DNA Release and Activation of cGAS-STING-NF-κB Signaling.
PDE12 mediated pruning of the poly-A tail of mitochondrial DNA-encoded tRNAs is essential for survival.
GGNBP2 regulates MDA5 sensing triggered by self double-stranded RNA following loss of ADAR1 editing.
Acute suppression of mitochondrial ATP production prevents apoptosis and provides an essential signal for NLRP3 inflammasome activation.
NOTCH1 mitochondria localization during heart development promotes mitochondrial metabolism and the endothelial-to-mesenchymal transition in mice.
A STAT3-STING-IFN axis controls the metastatic spread of small cell lung cancer.
Coordinated translational control of multiple immune checkpoints by the integrated stress response pathway in lung cancer.
F2,6BP restores mitochondrial genome integrity in Huntington's Disease.

EMBO Mol Med. 2024 Nov 20.

Pathogenic PDE12 variants impair mitochondrial RNA processing causing neonatal mitochondrial disease.

Lindsey Van Haute, Petra Páleníková, Jia Xin Tang, Pavel A Nash, Mariella T Simon, Angela Pyle, Monika Oláhová, Christopher A Powell, Pedro Rebelo-Guiomar, Alexander Stover, Michael Champion, Charulata Deshpande, Emma L Baple, Karen L Stals, Sian Ellard, Olivia Anselem, Clémence Molac, Giulia Petrilli, Laurence Loeuillet, Sarah Grotto, Tania Attie-Bitach, Jose E Abdenur, Robert W Taylor, Michal Minczuk.

  Pathogenic variants in either the mitochondrial or nuclear genomes are associated with a diverse group of human disorders characterized by impaired mitochondrial function. Within this group, an increasing number of families have been identified, where Mendelian genetic disorders implicate defective mitochondrial RNA biology. The PDE12 gene encodes the poly(A)-specific exoribonuclease, involved in the quality control of mitochondrial non-coding RNAs. Here, we report that disease-causing PDE12 variants in three unrelated families are associated with mitochondrial respiratory chain deficiencies and wide-ranging clinical presentations in utero and within the neonatal period, with muscle and brain involvement leading to marked cytochrome c oxidase (COX) deficiency in muscle and severe lactic acidosis. Whole exome sequencing of affected probands revealed novel, segregating bi-allelic missense PDE12 variants affecting conserved residues. Patient-derived primary fibroblasts demonstrate diminished steady-state levels of PDE12 protein, whilst mitochondrial poly(A)-tail RNA sequencing (MPAT-Seq) revealed an accumulation of spuriously polyadenylated mitochondrial RNA, consistent with perturbed function of PDE12 protein. Our data suggest that PDE12 regulates mitochondrial RNA processing and its loss results in neurological and muscular phenotypes.

Keywords:  Exome Sequencing; Lactic Acidosis; Mitochondrial Disease; RNA Processing; tRNA

DOI:  https://doi.org/10.1038/s44321-024-00172-5
bioRxiv. 2024 Nov 01. pii: 2023.03.02.530691. [Epub ahead of print]

The Human Mitochondrial Genome Encodes for an Interferon-Responsive Host Defense Peptide.

M C Rice, M Imun, S W Jung, C Y Park, J S Kim, R W Lai, C R Barr, J M Son, K Tor, E Kim, R J Lu, I Cohen, B A Benayoun, C Lee.

The mitochondrial DNA (mtDNA) can trigger immune responses and directly entrap pathogens, but it is not known to encode for active immune factors. The immune system is traditionally thought to be exclusively nuclear-encoded. Here, we report the identification of a mitochondrial-encoded host defense peptide (HDP) that presumably derives from the primordial proto-mitochondrial bacteria. We demonstrate that MOTS-c (mitochondrial open reading frame from the twelve S rRNA type-c) is a mitochondrial-encoded amphipathic and cationic peptide with direct antibacterial and immunomodulatory functions, consistent with the peptide chemistry and functions of known HDPs. MOTS-c targeted E. coli and methicillin-resistant S. aureus (MRSA), in part, by targeting their membranes using its hydrophobic and cationic domains. In monocytes, IFNγ, LPS, and differentiation signals each induced the expression of endogenous MOTS-c. Notably, MOTS-c translocated to the nucleus to regulate gene expression during monocyte differentiation and programmed them into macrophages with unique transcriptomic signatures related to antigen presentation and IFN signaling. MOTS-c-programmed macrophages exhibited enhanced bacterial clearance and shifted metabolism. Our findings support MOTS-c as a first-in-class mitochondrial-encoded HDP and indicates that our immune system is not only encoded by the nuclear genome, but also by the co-evolved mitochondrial genome.

DOI: https://doi.org/10.1101/2023.03.02.530691
J Med Virol. 2024 Nov;96(11): e70062

Age-Dependent Pathogenesis of Influenza A Virus H7N9 Mediated Through PB1-F2-Induced Mitochondrial DNA Release and Activation of cGAS-STING-NF-κB Signaling.

Pak-Hin Hinson Cheung, Tin-Long Yuen, Tze-Tung Tang, Ho-Yin Leung, Terence Tak-Wang Lee, Pearl Chan, Yun Cheng, Sin-Yee Fung, Zi-Wei Ye, Chi-Ping Chan, Dong-Yan Jin.

  Exactly why human infection of avian influenza A virus H7N9 causes more severe disease in the elderly remains elusive. In this study, we found that H7N9 PB1-F2 is a pathogenic factor in 15-18-month-old BALB/C mice (aged mice) but not in 6-8-week-old young adult mice (young mice). Recombinant influenza A virus with H7N9 PB1-F2-knockout was less pathogenic in aged mice as indicated with delayed weight loss. In contrast, survival of young mice infected with this virus was diminished. Furthermore, tissue damage, inflammation, proinflammatory cytokine and 2'3'-cGAMP production in the lung were less pronounced in infected aged mice despite no change in viral titer. cGAS is known to produce 2'3'-cGAMP to boost proinflammatory cytokine expression through STING-NF-κB signaling. We found that H7N9 PB1-F2 promoted interferon β (IFNβ) and chemokine gene expression in cultured cells through the mitochondrial DNA-cGAS-STING-NF-κB pathway. H7N9 PB1-F2 formed protein aggregate and caused mitochondrial cristae collapse, complex V-dependent electron transport dysfunction, reverse electron transfer-dependent oxidized mitochondrial DNA release to the cytoplasm and activation of cGAS-STING-NF-κB signaling. PB1-F2 N57 truncation, which is frequently observed in human circulating strains, mitigated H7N9 PB1-F2-mediated mitochondrial dysfunction and cGAS activation. In addition, we found that PB1-F2 of pathogenic avian influenza viruses triggered more robust cGAS activation than their human-adapted descendants. Our findings provide one explanation to age-dependent pathogenesis of H7N9 infection.

Keywords:  H7N9; NF‐κB; PB1‐F2; STING; cGAS; influenza A virus; mitochondrial DNA release

DOI:  https://doi.org/10.1002/jmv.70062
EMBO Mol Med. 2024 Nov 20.

PDE12 mediated pruning of the poly-A tail of mitochondrial DNA-encoded tRNAs is essential for survival.

Chenxiao Yu, Marco Tigano, Erin L Seifert.

DOI: https://doi.org/10.1038/s44321-024-00171-6
Sci Immunol. 2024 Nov 22. 9(101): eadk0412

GGNBP2 regulates MDA5 sensing triggered by self double-stranded RNA following loss of ADAR1 editing.

Jacki E Heraud-Farlow, Scott R Taylor, Alistair M Chalk, Adriana Escudero, Shi-Bin Hu, Ankita Goradia, Tao Sun, Qin Li, Iva Nikolic, Jin Billy Li, Miguel Fidalgo, Diana Guallar, Kaylene J Simpson, Carl R Walkley.

Adenosine-to-inosine (A-to-I) editing of double-stranded RNA (dsRNA) by ADAR1 is an essential modifier of the immunogenicity of cellular dsRNA. The role of MDA5 in sensing unedited cellular dsRNA and the downstream activation of type I interferon (IFN) signaling are well established. However, we have an incomplete understanding of pathways that modify the response to unedited dsRNA. We performed a genome-wide CRISPR screen and showed that GGNBP2, CNOT10, and CNOT11 interact and regulate sensing of unedited cellular dsRNA. We found that GGNBP2 acts between dsRNA transcription and its cytoplasmic sensing by MDA5. GGNBP2 loss prevented induction of type I IFN and autoinflammation after the loss of ADAR1 editing activity by modifying the subcellular distribution of endogenous A-to-I editing substrates and reducing cytoplasmic dsRNA load. These findings reveal previously undescribed pathways to modify diseases associated with ADAR mutations and may be determinants of response or resistance to small-molecule ADAR1 inhibitors.

DOI: https://doi.org/10.1126/sciimmunol.adk0412
Immunity. 2024 Nov 15. pii: S1074-7613(24)00492-8. [Epub ahead of print]

Acute suppression of mitochondrial ATP production prevents apoptosis and provides an essential signal for NLRP3 inflammasome activation.

Benedikt S Saller, Svenja Wöhrle, Larissa Fischer, Clara Dufossez, Isabella L Ingerl, Susanne Kessler, Maria Mateo-Tortola, Oliver Gorka, Felix Lange, Yurong Cheng, Emilia Neuwirt, Adinarayana Marada, Christoph Koentges, Chiara Urban, Philipp Aktories, Peter Reuther, Sebastian Giese, Susanne Kirschnek, Carolin Mayer, Johannes Pilic, Hugo Falquez-Medina, Aline Oelgeklaus, Veerasikku Gopal Deepagan, Farzaneh Shojaee, Julia A Zimmermann, Damian Weber, Yi-Heng Tai, Anna Crois, Kevin Ciminski, Remi Peyronnet, Katharina S Brandenburg, Gang Wu, Ralf Baumeister, Thomas Heimbucher, Marta Rizzi, Dietmar Riedel, Martin Helmstädter, Joerg Buescher, Konstantin Neumann, Thomas Misgeld, Martin Kerschensteiner, Peter Walentek, Clemens Kreutz, Ulrich Maurer, Angelika S Rambold, James E Vince, Frank Edlich, Roland Malli, Georg Häcker, Katrin Kierdorf, Chris Meisinger, Anna Köttgen, Stefan Jakobs, Alexander N R Weber, Martin Schwemmle, Christina J Groß, Olaf Groß.

  How mitochondria reconcile roles in functionally divergent cell death pathways of apoptosis and NLRP3 inflammasome-mediated pyroptosis remains elusive, as is their precise role in NLRP3 activation and the evolutionarily conserved physiological function of NLRP3. Here, we have shown that when cells were challenged simultaneously, apoptosis was inhibited and NLRP3 activation prevailed. Apoptosis inhibition by structurally diverse NLRP3 activators, including nigericin, imiquimod, extracellular ATP, particles, and viruses, was not a consequence of inflammasome activation but rather of their effects on mitochondria. NLRP3 activators turned out as oxidative phosphorylation (OXPHOS) inhibitors, which we found to disrupt mitochondrial cristae architecture, leading to trapping of cytochrome c. Although this effect was alone not sufficient for NLRP3 activation, OXPHOS inhibitors became triggers of NLRP3 when combined with resiquimod or Yoda-1, suggesting that NLRP3 activation requires two simultaneous cellular signals, one of mitochondrial origin. Therefore, OXPHOS and apoptosis inhibition by NLRP3 activators provide stringency in cell death decisions.

Keywords:  ATP; NLRP3; OXPHOS; apoptosis; bioenergetics; cell death; chemical biology; cytochrome c; inflammasome; mitochondria; pyroptosis

DOI:  https://doi.org/10.1016/j.immuni.2024.10.012
Nat Commun. 2024 Nov 16. 15(1): 9945

NOTCH1 mitochondria localization during heart development promotes mitochondrial metabolism and the endothelial-to-mesenchymal transition in mice.

Jie Wang, Rui Zhao, Sha Xu, Xiang-Yu Zhou, Ke Cai, Yu-Ling Chen, Ze-Yu Zhou, Xin Sun, Yan Shi, Feng Wang, Yong-Hao Gui, Hui Tao, Jian-Yuan Zhao.

Notch signaling activation drives an endothelial-to-mesenchymal transition (EndMT) critical for heart development, although evidence suggests that the reprogramming of endothelial cell metabolism can regulate endothelial function independent of canonical cell signaling. Herein, we investigated the crosstalk between Notch signaling and metabolic reprogramming in the EndMT process. Biochemically, we find that the NOTCH1 intracellular domain (NICD1) localizes to endothelial cell mitochondria, where it interacts with and activates the complex to enhance mitochondrial metabolism. Targeting NICD1 to mitochondria induces more EndMT compared with wild-type NICD1, and small molecule activation of PDH during pregnancy improves the phenotype in a mouse model of congenital heart defect. A NOTCH1 mutation observed in non-syndromic tetralogy of Fallot patients decreases NICD1 mitochondrial localization and subsequent PDH activity in heart tissues. Altogether, our findings demonstrate NICD1 enrichment in mitochondria of the developing mouse heart, which induces EndMT by activating PDH and subsequently improving mitochondrial metabolism.

DOI: https://doi.org/10.1038/s41467-024-54407-7
Nat Immunol. 2024 Nov 21.

A STAT3-STING-IFN axis controls the metastatic spread of small cell lung cancer.

Aleks C Guanizo, Quinton Luong, W Samantha N Jayasekara, Eveline D de Geus, Chaitanya Inampudi, Vincent Senyang Xue, Jasmine Chen, Nicole A de Weerd, Antony Y Matthews, Michael P Gantier, Jesse J Balic, Surein Arulananda, Daniel J Garama, Paul J Hertzog, Vinod Ganju, D Neil Watkins, Jason E Cain, Daniel J Gough.

Small cell lung cancer (SCLC) is an aggressive neuroendocrine tumor characterized by a high metastatic potential with an overall survival rate of ~5%. The transcription factor signal transducer and activator of transcription 3 (STAT3) is overexpressed by >50% of tumors, including SCLC, but its role in SCLC development and metastasis is unclear. Here, we show that, while STAT3 deletion restricts primary tumor growth, it paradoxically enhances metastatic spread by promoting immune evasion. This occurs because STAT3 is crucial for maintaining the immune sensor stimulator of interferon (IFN) genes (STING). Without STAT3, the cyclic adenosine monophosphate-guanosine monophosphate synthase-STING pathway is inactive, resulting in decreased type I IFN secretion and an IFN gene signature. Importantly, restoration of IFN signaling through re-expression of endogenous STING, enforced expression of IFN response factor 7 or administration of recombinant type I IFN re-established antitumor immunity, inhibiting metastatic SCLC in vivo. These data show the potential of augmenting the innate immune response to block metastatic SCLC.

DOI: https://doi.org/10.1038/s41590-024-02014-5
bioRxiv. 2024 Oct 28. pii: 2024.10.23.619897. [Epub ahead of print]

Coordinated translational control of multiple immune checkpoints by the integrated stress response pathway in lung cancer.

Shayna Thomas-Jardin, Shruthy Suresh, Ariana Arce, Nicole Novaresi, Emily Stein, Lisa Thomas, Cheryl Lewis, Chul Ahn, Bret M Evers, Maria E Salvatierra, Wei Lui, Khaja Khan, Luisa Maris Solis Soto, Ignacio Wistuba, John D Minna, Kathryn A O'Donnell.

The integrated stress response (ISR) is an adaptive pathway hijacked by cancer cells to survive cellular stresses in the tumor microenvironment. ISR activation potently induces Programmed Death Ligand 1 (PD-L1), leading to suppression of anti-tumor immunity. Here we sought to uncover additional immune checkpoint proteins regulated by the ISR to elucidate mechanisms of tumor immune escape. We show that CD155 and PD-L1 are coordinately induced by the ISR, enhancing translation of both immune checkpoint proteins through bypass of inhibitory upstream open reading frames (uORFs) in their 5' UTRs. Analysis of primary human lung tumors identifies a significant correlation between PD-L1 and CD155 expression. ISR activation accelerates tumorigenesis and inhibits T cell function, effects that can be overcome by combining PD-1 blockade with the ISR inhibitor ISRIB. These studies uncover a novel mechanism by which two immune checkpoint proteins are coordinately regulated and suggest a new therapeutic strategy for lung cancer patients.
Statement of Significance: This study uncovers a novel mechanism for the coordinated translational regulation of the PD-L1/PD1 and CD155/TIGIT immune checkpoint pathways and highlights the ISR as a therapeutic vulnerability for lung cancer. Inhibition of the ISR pathway bolsters PD-1 blockade, potentially unveiling a new therapeutic strategy for lung cancer patients.

DOI: https://doi.org/10.1101/2024.10.23.619897
bioRxiv. 2024 Nov 04. pii: 2024.11.04.621834. [Epub ahead of print]

F2,6BP restores mitochondrial genome integrity in Huntington's Disease.

Anirban Chakraborty, Santi M Mandal, Mikita Mankevich, Sravan Gopalkrishnashetty Sreenivasmurthy, Muralidhar L Hegde, Balaji Krishnan, Gourisankar Ghosh, Tapas Hazra.

Several reports have indicated that impaired mitochondrial function contributes to the development and progression of Huntington's disease (HD). Mitochondrial genome damage, particularly DNA strand breaks (SBs), is a potential cause for its compromised functionality. We have recently demonstrated that the activity of polynucleotide kinase 3'-phosphatase (PNKP), a critical DNA end-processing enzyme, is significantly reduced in the nuclear extract of HD patients due to lower level of a metabolite fructose-2,6 bisphosphate (F2,6BP), a biosynthetic product of 6-phosphofructo-2-kinase fructose-2,6-bisphosphatase 3 (PFKFB3), leading to persistent DNA SBs with 3'-phosphate termini, refractory to subsequent steps for repair completion. PNKP also plays a pivotal role in maintaining mitochondrial genome integrity. In this report, we provide evidence that both PFKFB3 and F2,6BP, an allosteric modulator of glycolysis, are also present in the mitochondria. Notably, the level of F2,6BP, a cofactor of PNKP, is significantly decreased due to the degradation of PFKFB3 in the mitochondrial extract of HD patients' brain. PNKP activity is thus severely decreased in the mitochondrial extract; however, addition of F2,6BP restored PNKP activity. Moreover, supplementation of F2,6BP in HD mouse striatal neuronal cells restored mitochondrial genome integrity and partially restored mitochondrial membrane potential and prevented pathogenic aggregate formation. We observed similar restoration of mitochondrial genome integrity in HD drosophila supplemented with F2,6BP. Our findings, therefore, suggest that F2,6BP or its structural analog hold promise as a therapeutic for restoring both nuclear and mitochondrial genome integrity and thereby of organismal health.

DOI: https://doi.org/10.1101/2024.11.04.621834