bims-nenemi Biomed News
on Neuroinflammation, neurodegeneration and mitochondria
Issue of 2022–12–11
fourteen papers selected by
Marco Tigano, Thomas Jefferson University
  1. Mitochondrial cristae architecture protects against mtDNA release and inflammation.
  2. FUNDC1 protects against doxorubicin-induced cardiomyocyte PANoptosis through stabilizing mtDNA via interaction with TUFM.
  3. The RNA-editing enzyme ADAR1: a regulatory hub that tunes multiple dsRNA-sensing pathways.
  4. A library of base editors for the precise ablation of all protein-coding genes in the mouse mitochondrial genome.
  5. Stress-induced reversible cell-cycle arrest requires PRC2/PRC1-mediated control of mitophagy in Drosophila germline stem cells and human iPSCs.
  6. Mitochondrial biology and dysfunction in secondary mitochondrial disease.
  7. Mitochondrial DNA heteroplasmy distinguishes disease manifestation in PINK1/PRKN-linked Parkinson's disease.
  8. Mitochondrial RNA stimulates heat production in young adipocytes to reduce obesity.
  9. Mitochondrial PARP1 regulates NAD+-dependent poly ADP-ribosylation of mitochondrial nucleoids.
  10. The role of cholesterol and mitochondrial bioenergetics in activation of the inflammasome in IBD.
  11. Xenotopic expression of alternative oxidase (AOX) to study mechanisms of mitochondrial disease.
  12. Mitochondrial dysfunction of induced pluripotent stem cells-based neurodegenerative disease modeling and therapeutic strategy.
  13. CRISPR screens for functional interrogation of immunity.
  14. Deoxyribonucleoside triphosphate pools in mammalian cells are expandable upon DNA damage.
  1. Cell Rep. 2022 Dec 06. pii: S2211-1247(22)01657-6. [Epub ahead of print]41(10): 111774
    Mitochondrial cristae architecture protects against mtDNA release and inflammation.
    Baiyu He, Huatong Yu, Shanshan Liu, Huayun Wan, Song Fu, Siqi Liu, Jun Yang, Zihan Zhang, Huanwei Huang, Qi Li, Fengchao Wang, Zhaodi Jiang, Qinghua Liu, Hui Jiang.
      Mitochondrial damage causes mitochondrial DNA (mtDNA) release to activate the type I interferon (IFN-I) response via the cGAS-STING pathway. mtDNA-induced inflammation promotes autoimmune- and aging-related degenerative disorders. However, the global picture of inflammation-inducing mitochondrial damages remains obscure. Here, we have performed a mitochondria-targeted CRISPR knockout screen for regulators of the IFN-I response. Strikingly, our screen reveals dozens of hits enriched with key regulators of cristae architecture, including phospholipid cardiolipin and protein complexes such as OPA1, mitochondrial contact site and cristae organization (MICOS), sorting and assembly machinery (SAM), mitochondrial intermembrane space bridging (MIB), prohibitin (PHB), and the F1Fo-ATP synthase. Disrupting these cristae organizers consistently induces mtDNA release and the STING-dependent IFN-I response. Furthermore, knocking out MTX2, a subunit of the SAM complex whose null mutations cause progeria in humans, induces a robust STING-dependent IFN-I response in mouse liver. Taken together, beyond revealing the central role of cristae architecture to prevent mtDNA release and inflammation, our results mechanistically link mitochondrial cristae disorganization and inflammation, two emerging hallmarks of aging and aging-related degenerative diseases.
    Keywords:  CP: Cell biology; CP: Molecular biology; MICOS; Metaxin2; OPA1; SAM; cGAS-STING; cristae architecture; inflammation; mtDNA release; type I interferon response
    DOI:  https://doi.org/10.1016/j.celrep.2022.111774
  2. Cell Death Dis. 2022 Dec 05. 13(12): 1020
    FUNDC1 protects against doxorubicin-induced cardiomyocyte PANoptosis through stabilizing mtDNA via interaction with TUFM.
    Yaguang Bi, Haixia Xu, Xiang Wang, Hong Zhu, Junbo Ge, Jun Ren, Yingmei Zhang.
      Doxorubicin (DOX) is an effective anthracycline chemotherapeutic anticancer drug with its life-threatening cardiotoxicity severely limiting its clinical application. Mitochondrial damage-induced cardiomyocyte death is considered an essential cue for DOX cardiotoxicity. FUN14 domain containing 1 (FUNDC1) is a mitochondrial membrane protein participating in the regulation of mitochondrial integrity in multiple diseases although its role in DOX cardiomyopathy remains elusive. Here, we examined whether PANoptosis, a novel type of programmed cell death closely associated with mitochondrial damage, was involved in DOX-induced heart injury, and FUNDC1-mediated regulation of cardiomyocyte PANoptosis, if any. FUNDC1 was downregulated in heart tissues in patients with dilated cardiomyopathy (DCM) and DOX-challenged mice. FUNDC1 deficiency aggravated DOX-induced cardiac dysfunction, mitochondrial injury, and cardiomyocyte PANoptosis. Further examination revealed that FUNDC1 countered cytoplasmic release of mitochondrial DNA (mtDNA) and activation of PANoptosome through interaction with mitochondrial Tu translation elongation factor (TUFM), a key factor in the translational expression and repair of mitochondrial DNA, via its 96-133 amino acid domain. TUFM intervention reversed FUNDC1-elicited protection against DOX-induced mtDNA cytosolic release and cardiomyocyte PANoptosis. Our findings shed light toward a beneficial role of FUNDC1 in DOX cardiotoxicity and cardiomyocyte PANoptosis, thus offering therapeutic promises in DOX-induced cardiotoxicity.
    DOI:  https://doi.org/10.1038/s41419-022-05460-x
  3. Int Immunol. 2022 Dec 05. pii: dxac056. [Epub ahead of print]
    The RNA-editing enzyme ADAR1: a regulatory hub that tunes multiple dsRNA-sensing pathways.
    Taisuke Nakahama, Yukio Kawahara.
      Adenosine deaminase acting on RNA 1 (ADAR1) is an RNA-editing enzyme that catalyzes adenosine-to-inosine conversions in double-stranded RNAs (dsRNAs). In mammals, ADAR1 is composed of two isoforms: a nuclear short p110 isoform and a cytoplasmic long p150 isoform. Whereas both isoforms contain right-handed dsRNA-binding and deaminase domains, ADAR1 p150 harbors a Zα domain that binds to left-handed dsRNAs, termed Z-RNAs. MDA5 sensing of endogenous dsRNAs as non-self leads to the induction of type I interferon (IFN)-stimulated genes, but recent studies revealed that ADAR1 p150-mediated RNA editing, but not ADAR1 p110, prevents this MDA5-mediated sensing. ADAR1 p150-specific RNA-editing sites are present and at least a Zα domain-Z-RNA interaction is required for this specificity. Mutations in the ADAR1 gene cause Aicardi-Goutières syndrome (AGS), an infant encephalopathy with type I IFN overproduction. Insertion of a point mutation in the Zα domain of the Adar1 gene induces AGS-like encephalopathy in mice, which is rescued by concurrent deletion of MDA5. This finding indicates that impaired ADAR1 p150-mediated RNA-editing is a mechanism underlying AGS caused by an ADAR1 mutation. ADAR1 p150 also prevents ZBP1 sensing of endogenous Z-RNA, which leads to programmed cell death, via the Zα domain and its RNA-editing activity. Furthermore, ADAR1 prevents PKR sensing of endogenous right-handed dsRNAs, which leads to translational shutdown and growth arrest. Thus, ADAR1 acts as a regulatory hub that blocks sensing of endogenous dsRNAs as non-self by multiple sensor proteins, both in RNA editing-dependent and -independent manners, and is a potential therapeutic target for diseases, especially cancer.
    Keywords:  Aicardi–Goutières syndrome; MDA5; PKR; Z-RNA; ZBP1
    DOI:  https://doi.org/10.1093/intimm/dxac056
  4. Nat Biomed Eng. 2022 Dec 05.
    A library of base editors for the precise ablation of all protein-coding genes in the mouse mitochondrial genome.
    Pedro Silva-Pinheiro, Christian D Mutti, Lindsey Van Haute, Christopher A Powell, Pavel A Nash, Keira Turner, Michal Minczuk.
      The development of curative treatments for mitochondrial diseases, which are often caused by mutations in mitochondrial DNA (mtDNA) that impair energy metabolism and other aspects of cellular homoeostasis, is hindered by an incomplete understanding of the underlying biology and a scarcity of cellular and animal models. Here we report the design and application of a library of double-stranded-DNA deaminase-derived cytosine base editors optimized for the precise ablation of every mtDNA protein-coding gene in the mouse mitochondrial genome. We used the library, which we named MitoKO, to produce near-homoplasmic knockout cells in vitro and to generate a mouse knockout with high heteroplasmy levels and no off-target edits. MitoKO should facilitate systematic and comprehensive investigations of mtDNA-related pathways and their impact on organismal homoeostasis, and aid the generation of clinically meaningful in vivo models of mtDNA dysfunction.
    DOI:  https://doi.org/10.1038/s41551-022-00968-1
  5. Stem Cell Reports. 2022 Nov 22. pii: S2213-6711(22)00537-9. [Epub ahead of print]
    Stress-induced reversible cell-cycle arrest requires PRC2/PRC1-mediated control of mitophagy in Drosophila germline stem cells and human iPSCs.
    Tommy H Taslim, Abdiasis M Hussein, Riya Keshri, Julien R Ishibashi, Tung C Chan, Bich N Nguyen, Shuozhi Liu, Daniel Brewer, Stuart Harper, Scott Lyons, Ben Garver, Jimmy Dang, Nanditaa Balachandar, Samriddhi Jhajharia, Debra Del Castillo, Julie Mathieu, Hannele Ruohola-Baker.
      Following acute genotoxic stress, both normal and tumorous stem cells can undergo cell-cycle arrest to avoid apoptosis and later re-enter the cell cycle to regenerate daughter cells. However, the mechanism of protective, reversible proliferative arrest, "quiescence," remains unresolved. Here, we show that mitophagy is a prerequisite for reversible quiescence in both irradiated Drosophila germline stem cells (GSCs) and human induced pluripotent stem cells (hiPSCs). In GSCs, mitofission (Drp1) or mitophagy (Pink1/Parkin) genes are essential to enter quiescence, whereas mitochondrial biogenesis (PGC1α) or fusion (Mfn2) genes are crucial for exiting quiescence. Furthermore, mitophagy-dependent quiescence lies downstream of mTOR- and PRC2-mediated repression and relies on the mitochondrial pool of cyclin E. Mitophagy-dependent reduction of cyclin E in GSCs and in hiPSCs during mTOR inhibition prevents the usual G1/S transition, pushing the cells toward reversible quiescence (G0). This alternative method of G1/S control may present new opportunities for therapeutic purposes.
    Keywords:  PRC2; cyclin E; epigenetic; mTOR; mitochondria; mitophagy; pluripotent stem cells
    DOI:  https://doi.org/10.1016/j.stemcr.2022.11.004
  6. Open Biol. 2022 Dec;12(12): 220274
    Mitochondrial biology and dysfunction in secondary mitochondrial disease.
    Megan J Baker, Jordan J Crameri, David R Thorburn, Ann E Frazier, Diana Stojanovski.
      Mitochondrial diseases are a broad, genetically heterogeneous class of metabolic disorders characterized by deficits in oxidative phosphorylation (OXPHOS). Primary mitochondrial disease (PMD) defines pathologies resulting from mutation of mitochondrial DNA (mtDNA) or nuclear genes affecting either mtDNA expression or the biogenesis and function of the respiratory chain. Secondary mitochondrial disease (SMD) arises due to mutation of nuclear-encoded genes independent of, or indirectly influencing OXPHOS assembly and operation. Despite instances of novel SMD increasing year-on-year, PMD is much more widely discussed in the literature. Indeed, since the implementation of next generation sequencing (NGS) techniques in 2010, many novel mitochondrial disease genes have been identified, approximately half of which are linked to SMD. This review will consolidate existing knowledge of SMDs and outline discrete categories within which to better understand the diversity of SMD phenotypes. By providing context to the biochemical and molecular pathways perturbed in SMD, we hope to further demonstrate the intricacies of SMD pathologies outside of their indirect contribution to mitochondrial energy generation.
    Keywords:  mitochondria; mitochondrial protein import; mitochondrial quality control; secondary mitochondrial disease
    DOI:  https://doi.org/10.1098/rsob.220274
  7. Brain. 2022 Dec 07. pii: awac464. [Epub ahead of print]
    Mitochondrial DNA heteroplasmy distinguishes disease manifestation in PINK1/PRKN-linked Parkinson's disease.
    Joanne Trinh, Andrew A Hicks, Inke R König, Sylvie Delcambre, Theresa Lüth, Susen Schaake, Kobi Wasner, Jenny Ghelfi, Max Borsche, Carles Vilariño-Güell, Faycel Hentati, Elisabeth L Germer, Peter Bauer, Masashi Takanashi, Vladimir Kostić, Anthony E Lang, Norbert Brüggemann, Peter P Pramstaller, Irene Pichler, Alex Rajput, Nobutaka Hattori, Matthew J Farrer, Katja Lohmann, Hansi Weissensteiner, Patrick May, Christine Klein, Anne Grünewald.
      Biallelic mutations in PINK1/PRKN cause recessive Parkinson's disease. Given the established role of PINK1/Parkin in regulating mitochondrial dynamics, we explored mitochondrial DNA (mtDNA) integrity and inflammation as disease modifiers in carriers of mutations in these genes. MtDNA integrity was investigated in a large collection of biallelic (n = 84) and monoallelic (n = 170) carriers of PINK1/PRKN mutations, idiopathic Parkinson's disease patients (n = 67) and controls (n = 90). In addition, we studied global gene expression and serum cytokine levels in a subset. Affected and unaffected PINK1/PRKN monoallelic mutation carriers can be distinguished by heteroplasmic mtDNA variant load (AUC = 0.83, CI:0.74-0.93). Biallelic PINK1/PRKN mutation carriers harbor more heteroplasmic mtDNA variants in blood (p = 0.0006, Z = 3.63) compared to monoallelic mutation carriers. This enrichment was confirmed in iPSC-derived (controls, n = 3; biallelic PRKN mutation carriers, n = 4) and postmortem (control, n = 1; biallelic PRKN mutation carrier, n = 1) midbrain neurons. Lastly, the heteroplasmic mtDNA variant load correlated with IL6 levels in PINK1/PRKN mutation carriers (r = 0.57, p = 0.0074). PINK1/PRKN mutations predispose individuals to mtDNA variant accumulation in a dose- and disease-dependent manner.
    Keywords:  PINK1; PRKN; modifiers; mtDNA heteroplasmy; penetrance
    DOI:  https://doi.org/10.1093/brain/awac464
  8. Nat Metab. 2022 Dec 06.
    Mitochondrial RNA stimulates heat production in young adipocytes to reduce obesity.
      
    DOI:  https://doi.org/10.1038/s42255-022-00686-7
  9. Exp Mol Med. 2022 Dec 06.
    Mitochondrial PARP1 regulates NAD+-dependent poly ADP-ribosylation of mitochondrial nucleoids.
    Jong-Hyuk Lee, Mansoor Hussain, Edward W Kim, Shang-Jung Cheng, Anthony K L Leung, Nima Borhan Fakouri, Deborah L Croteau, Vilhelm A Bohr.
      PARPs play fundamental roles in multiple DNA damage recognition and repair pathways. Persistent nuclear PARP activation causes cellular NAD+ depletion and exacerbates cellular aging. However, very little is known about mitochondrial PARP (mtPARP) and poly ADP-ribosylation (PARylation). The existence of mtPARP is controversial, and the biological roles of mtPARP-induced mitochondrial PARylation are unclear. Here, we demonstrate the presence of PARP1 and PARylation in purified mitochondria. The addition of the PARP1 substrate NAD+ to isolated mitochondria induced PARylation, which was suppressed by treatment with the inhibitor olaparib. Mitochondrial PARylation was also evaluated by enzymatic labeling of terminal ADP-ribose (ELTA). To further confirm the presence of mtPARP1, we evaluated mitochondrial nucleoid PARylation by ADP ribose-chromatin affinity purification (ADPr-ChAP) and PARP1 chromatin immunoprecipitation (ChIP). We observed that NAD+ stimulated PARylation and TFAM occupancy on the mtDNA regulatory region D-loop, inducing mtDNA transcription. These findings suggest that PARP1 is integrally involved in mitochondrial PARylation and that NAD+-dependent mtPARP1 activity contributes to mtDNA transcriptional regulation.
    DOI:  https://doi.org/10.1038/s12276-022-00894-x
  10. Front Immunol. 2022 ;13 1028953
    The role of cholesterol and mitochondrial bioenergetics in activation of the inflammasome in IBD.
    Jessica Astorga, Naschla Gasaly, Karen Dubois-Camacho, Marjorie De la Fuente, Glauben Landskron, Klaas Nico Faber, Félix A Urra, Marcela A Hermoso.
      Inflammatory Bowel Disease (IBD) is characterized by a loss of intestinal barrier function caused by an aberrant interaction between the immune response and the gut microbiota. In IBD, imbalance in cholesterol homeostasis and mitochondrial bioenergetics have been identified as essential events for activating the inflammasome-mediated response. Mitochondrial alterations, such as reduced respiratory complex activities and reduced production of tricarboxylic acid (TCA) cycle intermediates (e.g., citric acid, fumarate, isocitric acid, malate, pyruvate, and succinate) have been described in in vitro and clinical studies. Under inflammatory conditions, mitochondrial architecture in intestinal epithelial cells is dysmorphic, with cristae destruction and high dynamin-related protein 1 (DRP1)-dependent fission. Likewise, these alterations in mitochondrial morphology and bioenergetics promote metabolic shifts towards glycolysis and down-regulation of antioxidant Nuclear erythroid 2-related factor 2 (Nrf2)/Peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) signaling. Although the mechanisms underlying the mitochondrial dysfunction during mucosal inflammation are not fully understood at present, metabolic intermediates and cholesterol may act as signals activating the NLRP3 inflammasome in IBD. Notably, dietary phytochemicals exhibit protective effects against cholesterol imbalance and mitochondrial function alterations to maintain gastrointestinal mucosal renewal in vitro and in vivo conditions. Here, we discuss the role of cholesterol and mitochondrial metabolism in IBD, highlighting the therapeutic potential of dietary phytochemicals, restoring intestinal metabolism and function.
    Keywords:  IBD - inflammatory bowel disease; NLRP3 inflammasome; diet phytochemicals; inflammasome; intracellular cholesterol accumulation; mitochondrial dysfunction
    DOI:  https://doi.org/10.3389/fimmu.2022.1028953
  11. Biochim Biophys Acta Bioenerg. 2022 Dec 05. pii: S0005-2728(22)00417-0. [Epub ahead of print] 148947
    Xenotopic expression of alternative oxidase (AOX) to study mechanisms of mitochondrial disease.
    Carlo Viscomi, Anthony L Moore, Massimo Zeviani, Marten Szibor.
      The mitochondrial respiratory chain or electron transport chain (ETC) facilitates redox reactions which ultimately lead to the reduction of oxygen to water (respiration). Energy released by this process is used to establish a proton electrochemical gradient which drives ATP formation (oxidative phosphorylation, OXPHOS). It also plays an important role in vital processes beyond ATP formation and cellular metabolism, such as heat production, redox and ion homeostasis. Dysfunction of the ETC can thus impair cellular and organismal viability and is thought to be the underlying cause of a heterogeneous group of so-called mitochondrial diseases. Plants, yeasts, and many lower organisms, but not insects and vertebrates, possess an enzymatic mechanism that confers resistance to respiratory stress conditions, i.e. the alternative oxidase (AOX). Even in cells that naturally lack AOX, it is autonomously imported into the mitochondrial compartment upon xenotopic expression, where it refolds and becomes catalytically engaged when the cytochrome segment of the ETC is blocked. AOX was therefore proposed as a tool to study disease etiologies. To this end, AOX has been xenotopically expressed in mammalian cells and disease models of the fruit fly and mouse. Surprisingly, AOX showed remarkable rescue effects in some cases, whilst in others it had no effect or even exacerbated a condition. Here we summarize what has been learnt from the use of AOX in various disease models and discuss issues which still need to be addressed in order to understand the role of the ETC in health and disease.
    Keywords:  Alternative oxidase; Disease models; Mitochondria; Mitochondrial disease; Mouse; Xenogene
    DOI:  https://doi.org/10.1016/j.bbabio.2022.148947
  12. Front Cell Dev Biol. 2022 ;10 1030390
    Mitochondrial dysfunction of induced pluripotent stem cells-based neurodegenerative disease modeling and therapeutic strategy.
    Hong-Mei Luo, Jia Xu, Dan-Xia Huang, Yun-Qiang Chen, Yi-Zhou Liu, Ya-Jie Li, Hong Chen.
      Neurodegenerative diseases (NDDs) are disorders in which neurons are lost owing to various factors, resulting in a series of dysfunctions. Their rising prevalence and irreversibility have brought physical pain to patients and economic pressure to both individuals and society. However, the pathogenesis of NDDs has not yet been fully elucidated, hampering the use of precise medication. Induced pluripotent stem cell (IPSC) modeling provides a new method for drug discovery, and exploring the early pathological mechanisms including mitochondrial dysfunction, which is not only an early but a prominent pathological feature of NDDs. In this review, we summarize the iPSC modeling approach of Alzheimer's disease, Parkinson's disease, and Amyotrophic lateral sclerosis, as well as outline typical mitochondrial dysfunction and recapitulate corresponding therapeutic strategies.
    Keywords:  IPSCs (induced pluripotent stem cells); mitochondrial dynamic; mitochondrial dysfunction; mitochondrial energy metabolism; mitochondrial transport; neurodegenerative diseases; therapeutic strategy
    DOI:  https://doi.org/10.3389/fcell.2022.1030390
  13. Nat Rev Immunol. 2022 Dec 08.
    CRISPR screens for functional interrogation of immunity.
    Hao Shi, John G Doench, Hongbo Chi.
      CRISPR-based technologies represent a major breakthrough in biomedical science as they offer a powerful platform for unbiased screening and functional genomics in various fields, including immunology. Pooled and arrayed CRISPR screens have uncovered previously unknown intracellular drivers in innate and adaptive immune cells for immune regulation as well as intercellular regulators mediating cell-cell interactions. Recent single-cell CRISPR screening platforms expand the readouts to the transcriptome and enable the inference of gene regulatory networks for better mechanistic insights. CRISPR screens also allow for mapping of genetic interactions to identify genes that synergize or alleviate complex immune phenotypes. Here, we review the progress in and emerging adaptation of CRISPR technologies to advance our fundamental immunological knowledge and identify novel disease targets for immunotherapy of infection, inflammation and cancer.
    DOI:  https://doi.org/10.1038/s41577-022-00802-4
  14. Cell Metab. 2022 Dec 06. pii: S1550-4131(22)00497-1. [Epub ahead of print]34(12): 1897-1898
    Deoxyribonucleoside triphosphate pools in mammalian cells are expandable upon DNA damage.
    Rui Liu, Qianming Chen.
      The rapid increase of dNTP pools in mammalian cells upon DNA damage has been previously documented. Alterations in protein modifications or interactions can rapidly modulate the activity and protein stability of mammalian RNR, and activation of PRPS1/2-dependent generation of PRPP enhances the production of the indispensable ribose sugar for nucleotide biosynthesis.
    DOI:  https://doi.org/10.1016/j.cmet.2022.11.006
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