bims-nenemi Biomed News
on Neuroinflammation, neurodegeneration and mitochondria
Issue of 2022–07–24
eightteen papers selected by
Marco Tigano, Thomas Jefferson University
  1. The mitochondrial unfolded protein response (UPRmt): shielding against toxicity to mitochondria in cancer.
  2. ADAR1 averts fatal type I interferon induction by ZBP1.
  3. Activation of the integrated stress response is a vulnerability for multidrug-resistant FBXW7-deficient cells.
  4. AIFM1 is a component of the mitochondrial disulfide relay that drives complex I assembly through efficient import of NDUFS5.
  5. Identification of human mitochondrial RNA cleavage sites and candidate RNA processing factors.
  6. Apoptotic caspases suppress an MDA5-driven IFN response during productive replication of human papillomavirus type 31.
  7. ADAR1 mutation causes ZBP1-dependent immunopathology.
  8. AKAP1 contributes to impaired mtDNA replication and mitochondrial dysfunction in podocytes of diabetic kidney disease.
  9. Mutational Screening for Mitochondrial tRNA Genes in 100 Women with Pre-eclampsia.
  10. Pathological mitophagy disrupts mitochondrial homeostasis in Leber's hereditary optic neuropathy.
  11. Endothelial Cells as a Key Cell Type for Innate Immunity: A Focused Review on RIG-I Signaling Pathway.
  12. ADAR1 prevents autoinflammation by suppressing spontaneous ZBP1 activation.
  13. Polymerogenic neuroserpin causes mitochondrial alterations and activates NFκB but not the UPR in a neuronal model of neurodegeneration FENIB.
  14. Mitochondrial DNA mutations in aging and cancer.
  15. Mitochondria and mitochondrial disorders: an overview update.
  16. Exploring the Effects of Mitonuclear Interactions on Mitochondrial DNA Gene Expression in Humans.
  17. RNA binding by ADAR3 inhibits adenosine-to-inosine editing and promotes expression of immune response protein MAVS.
  18. TFEB induces mitochondrial itaconate synthesis to suppress bacterial growth in macrophages.
  1. J Hematol Oncol. 2022 Jul 21. 15(1): 98
    The mitochondrial unfolded protein response (UPRmt): shielding against toxicity to mitochondria in cancer.
    Joseph R Inigo, Dhyan Chandra.
      Mitochondria are essential for tumor growth and progression. However, the heavy demand for mitochondrial activity in cancer leads to increased production of mitochondrial reactive oxygen species (mtROS), accumulation of mutations in mitochondrial DNA, and development of mitochondrial dysfunction. If left unchecked, excessive mtROS can damage and unfold proteins in the mitochondria to an extent that becomes lethal to the tumor. Cellular systems have evolved to combat mtROS and alleviate mitochondrial stress through a quality control mechanism called the mitochondrial unfolded protein response (UPRmt). The UPRmt system is composed of chaperones and proteases, which promote protein folding or eliminate mitochondrial proteins damaged by mtROS, respectively. UPRmt is conserved and activated in cancer in response to mitochondrial stress to maintain mitochondrial integrity and support tumor growth. In this review, we discuss how mitochondria become dysfunctional in cancer and highlight the tumor-promoting functions of key components of the UPRmt.
    Keywords:  Cancer; Mitochondrial chaperonins; Mitochondrial proteases; Mitochondrial proteostasis; Mitochondrial unfolded protein response
    DOI:  https://doi.org/10.1186/s13045-022-01317-0
  2. Nature. 2022 Jul 20.
    ADAR1 averts fatal type I interferon induction by ZBP1.
    Huipeng Jiao, Laurens Wachsmuth, Simone Wolf, Juliane Lohmann, Masahiro Nagata, Göksu Gökberk Kaya, Nikos Oikonomou, Vangelis Kondylis, Manuel Rogg, Martin Diebold, Simon E Tröder, Branko Zevnik, Marco Prinz, Christoph Schell, George R Young, George Kassiotis, Manolis Pasparakis.
      Mutations of the ADAR1 gene encoding an RNA deaminase cause severe diseases associated with chronic activation of type I interferon (IFN) responses, including Aicardi-Goutières syndrome and bilateral striatal necrosis1-3. The IFN-inducible p150 isoform of ADAR1 contains a Zα domain that recognizes RNA with an alternative left-handed double-helix structure, termed Z-RNA4,5. Hemizygous ADAR1 mutations in the Zα domain cause type I IFN-mediated pathologies in humans2,3 and mice6-8; however, it remains unclear how the interaction of ADAR1 with Z-RNA prevents IFN activation. Here we show that Z-DNA-binding protein 1 (ZBP1), the only other protein in mammals known to harbour Zα domains9, promotes type I IFN activation and fatal pathology in mice with impaired ADAR1 function. ZBP1 deficiency or mutation of its Zα domains reduced the expression of IFN-stimulated genes and largely prevented early postnatal lethality in mice with hemizygous expression of ADAR1 with mutated Zα domain (Adar1mZα/- mice). Adar1mZα/- mice showed upregulation and impaired editing of endogenous retroelement-derived complementary RNA reads, which represent a likely source of Z-RNAs activating ZBP1. Notably, ZBP1 promoted IFN activation and severe pathology in Adar1mZα/- mice in a manner independent of RIPK1, RIPK3, MLKL-mediated necroptosis and caspase-8-dependent apoptosis, suggesting a novel mechanism of action. Thus, ADAR1 prevents endogenous Z-RNA-dependent activation of pathogenic type I IFN responses by ZBP1, suggesting that ZBP1 could contribute to type I interferonopathies caused by ADAR1 mutations.
    DOI:  https://doi.org/10.1038/s41586-022-04878-9
  3. EMBO Mol Med. 2022 Jul 21. e15855
    Activation of the integrated stress response is a vulnerability for multidrug-resistant FBXW7-deficient cells.
    Laura Sanchez-Burgos, Belén Navarro-González, Santiago García-Martín, Oleksandra Sirozh, Jorge Mota-Pino, Elena Fueyo-Marcos, Héctor Tejero, Marta Elena Antón, Matilde Murga, Fátima Al-Shahrour, Oscar Fernandez-Capetillo.
      FBXW7 is one of the most frequently mutated tumor suppressors, deficiency of which has been associated with resistance to some anticancer therapies. Through bioinformatics and genome-wide CRISPR screens, we here reveal that FBXW7 deficiency leads to multidrug resistance (MDR). Proteomic analyses found an upregulation of mitochondrial factors as a hallmark of FBXW7 deficiency, which has been previously linked to chemotherapy resistance. Despite this increased expression of mitochondrial factors, functional analyses revealed that mitochondria are under stress, and genetic or chemical targeting of mitochondria is preferentially toxic for FBXW7-deficient cells. Mechanistically, the toxicity of therapies targeting mitochondrial translation such as the antibiotic tigecycline relates to the activation of the integrated stress response (ISR) in a GCN2 kinase-dependent manner. Furthermore, the discovery of additional drugs that are toxic for FBXW7-deficient cells showed that all of them unexpectedly activate a GCN2-dependent ISR regardless of their accepted mechanism of action. Our study reveals that while one of the most frequent mutations in cancer reduces the sensitivity to the vast majority of available therapies, it renders cells vulnerable to ISR-activating drugs.
    Keywords:  FBXW7; GCN2; ISR; drug resistance; mitochondria
    DOI:  https://doi.org/10.15252/emmm.202215855
  4. EMBO J. 2022 Jul 20. e110784
    AIFM1 is a component of the mitochondrial disulfide relay that drives complex I assembly through efficient import of NDUFS5.
    Silja Lucia Salscheider, Sarah Gerlich, Alfredo Cabrera-Orefice, Esra Peker, Robin Alexander Rothemann, Lena Maria Murschall, Yannik Finger, Karolina Szczepanowska, Zeinab Alsadat Ahmadi, Sergio Guerrero-Castillo, Alican Erdogan, Mark Becker, Muna Ali, Markus Habich, Carmelina Petrungaro, Nele Burdina, Guenter Schwarz, Merlin Klußmann, Ines Neundorf, David A Stroud, Michael T Ryan, Aleksandra Trifunovic, Ulrich Brandt, Jan Riemer.
      The mitochondrial intermembrane space protein AIFM1 has been reported to mediate the import of MIA40/CHCHD4, which forms the import receptor in the mitochondrial disulfide relay. Here, we demonstrate that AIFM1 and MIA40/CHCHD4 cooperate beyond this MIA40/CHCHD4 import. We show that AIFM1 and MIA40/CHCHD4 form a stable long-lived complex in vitro, in different cell lines, and in tissues. In HEK293 cells lacking AIFM1, levels of MIA40 are unchanged, but the protein is present in the monomeric form. Monomeric MIA40 neither efficiently interacts with nor mediates the import of specific substrates. The import defect is especially severe for NDUFS5, a subunit of complex I of the respiratory chain. As a consequence, NDUFS5 accumulates in the cytosol and undergoes rapid proteasomal degradation. Lack of mitochondrial NDUFS5 in turn results in stalling of complex I assembly. Collectively, we demonstrate that AIFM1 serves two overlapping functions: importing MIA40/CHCHD4 and constituting an integral part of the disulfide relay that ensures efficient interaction of MIA40/CHCHD4 with specific substrates.
    Keywords:  AIFM1; MIA40-CHCHD4; NDUFS5; complex I; mitochondrial disulfide relay
    DOI:  https://doi.org/10.15252/embj.2022110784
  5. BMC Biol. 2022 Jul 22. 20(1): 168
    Identification of human mitochondrial RNA cleavage sites and candidate RNA processing factors.
    Guillermo Carbajosa, Aminah T Ali, Alan Hodgkinson.
       BACKGROUND: The human mitochondrial genome is transcribed as long strands of RNA containing multiple genes, which require post-transcriptional cleavage and processing to release functional gene products that play vital roles in cellular energy production. Despite knowledge implicating mitochondrial post-transcriptional processes in pathologies such as cancer, cardiovascular disease and diabetes, very little is known about the way their function varies on a human population level and what drives changes in these processes to ultimately influence disease risk. Here, we develop a method to detect and quantify mitochondrial RNA cleavage events from standard RNA sequencing data and apply this approach to human whole blood data from > 1000 samples across independent cohorts.
    RESULTS: We detect 54 putative mitochondrial RNA cleavage sites that not only map to known gene boundaries, short RNA ends and RNA modification sites, but also occur at internal gene positions, suggesting novel mitochondrial RNA cleavage junctions. Inferred RNA cleavage rates correlate with mitochondrial-encoded gene expression across individuals, suggesting an impact on downstream processes. Furthermore, by comparing inferred cleavage rates to nuclear genetic variation and gene expression, we implicate multiple genes in modulating mitochondrial RNA cleavage (e.g. MRPP3, TBRG4 and FASTKD5), including a potentially novel role for RPS19 in influencing cleavage rates at a site near to the MTATP6-COX3 junction that we validate using shRNA knock down data.
    CONCLUSIONS: We identify novel cleavage junctions associated with mitochondrial RNA processing, as well as genes newly implicated in these processes, and detect the potential impact of variation in cleavage rates on downstream phenotypes and disease processes. These results highlight the complexity of the mitochondrial transcriptome and point to novel mechanisms through which nuclear-encoded genes can potentially influence key mitochondrial processes.
    Keywords:  Mitochondria; QTL; RNA; Transcriptomics
    DOI:  https://doi.org/10.1186/s12915-022-01373-5
  6. Proc Natl Acad Sci U S A. 2022 Jul 19. 119(29): e2200206119
    Apoptotic caspases suppress an MDA5-driven IFN response during productive replication of human papillomavirus type 31.
    Ning Huang, Des'ree Groover, Blossom Damania, Cary Moody.
      Human papillomaviruses (HPVs) infect the basal proliferating cells of the stratified epithelium, but the productive phase of the life cycle (consisting of viral genome amplification, late gene expression, and virion assembly) is restricted to the highly differentiated suprabasal cells. While much is known regarding the mechanisms that HPVs use to block activation of an innate immune response in undifferentiated cells, little is known concerning how HPV prevents an interferon (IFN) response upon differentiation. Here, we demonstrate that high-risk HPVs hijack a natural function of apoptotic caspases to suppress an IFN response in differentiating epithelial cells. We show that caspase inhibition results in the secretion of type I and type III IFNs that can act in a paracrine manner to induce expression of interferon-stimulated genes (ISGs) and block productive replication of HPV31. Importantly, we demonstrate that the expression of IFNs is triggered by the melanoma differentiation-associated gene 5 (MDA5)-mitochondrial antiviral-signaling protein (MAVS)-TBK1 (TANK-binding kinase 1) pathway, signifying a response to double-stranded RNA (dsRNA). Additionally, we identify a role for MDA5 and MAVS in restricting productive viral replication during the normal HPV life cycle. This study identifies a mechanism by which HPV reprograms the cellular environment of differentiating cells through caspase activation, co-opting a nondeath function of proteins normally involved in apoptosis to block antiviral signaling and promote viral replication.
    Keywords:  HPV; IFN; cancer; caspase; life cycle
    DOI:  https://doi.org/10.1073/pnas.2200206119
  7. Nature. 2022 Jul 20.
    ADAR1 mutation causes ZBP1-dependent immunopathology.
    Nicholas W Hubbard, Joshua M Ames, Megan Maurano, Lan H Chu, Kim Y Somfleth, Nandan S Gokhale, Margo Werner, Jessica M Snyder, Katrina Lichauco, Ram Savan, Daniel B Stetson, Andrew Oberst.
      The RNA-editing enzyme ADAR1 is essential for the suppression of innate immune activation and pathology caused by aberrant recognition of self-RNA, a role it carries out by disrupting the duplex structure of endogenous double-stranded RNA species1,2. A point mutation in the sequence encoding the Z-DNA-binding domain (ZBD) of ADAR1 is associated with severe autoinflammatory disease3-5. ZBP1 is the only other ZBD-containing mammalian protein6, and its activation can trigger both cell death and transcriptional responses through the kinases RIPK1 and RIPK3, and the protease caspase 8 (refs. 7-9). Here we show that the pathology caused by alteration of the ZBD of ADAR1 is driven by activation of ZBP1. We found that ablation of ZBP1 fully rescued the overt pathology caused by ADAR1 alteration, without fully reversing the underlying inflammatory program caused by this alteration. Whereas loss of RIPK3 partially phenocopied the protective effects of ZBP1 ablation, combined deletion of caspase 8 and RIPK3, or of caspase 8 and MLKL, unexpectedly exacerbated the pathogenic effects of ADAR1 alteration. These findings indicate that ADAR1 is a negative regulator of sterile ZBP1 activation, and that ZBP1-dependent signalling underlies the autoinflammatory pathology caused by alteration of ADAR1.
    DOI:  https://doi.org/10.1038/s41586-022-04896-7
  8. Int J Biol Sci. 2022 ;18(10): 4026-4042
    AKAP1 contributes to impaired mtDNA replication and mitochondrial dysfunction in podocytes of diabetic kidney disease.
    Jun Feng, Zhaowei Chen, Yiqiong Ma, Xueyan Yang, Zijing Zhu, Zongwei Zhang, Jijia Hu, Wei Liang, Guohua Ding.
      Podocyte injury is involved in the onset and progression of diabetic kidney disease (DKD) and is associated with mitochondrial abnormalities. Defective mitochondrial DNA (mtDNA) replication results in mitochondrial dysfunction. However, whether podocyte mtDNA replication is impaired in DKD is still unclear. A-kinase anchoring protein 1 (AKAP1) is localized in the outer mitochondrial membrane (OMM) and acts as a regulator and conductor of mitochondrial signals. Herein, we investigated the role of AKAP1 in high glucose-induced mtDNA replication. Decreased mtDNA replication and mitochondrial dysfunction occurred in podocytes of DKD. AKAP1 expression was up-regulated, and protein kinase C (PKC) signaling was activated under hyperglycemic conditions. AKAP1 recruited PKC and mediated La-related protein 1 (Larp1) phosphorylation, which reduced the expression of mitochondrial transcription factor A (TFAM), a key factor in mtDNA replication. In addition, mtDNA replication, mitochondrial function and podocyte injury were rescued by knocking down AKAP1 expression and the PKC inhibitor enzastaurin. In contrast, AKAP1 overexpression worsened the impairment of mtDNA replication and podocyte injury. In conclusion, our study revealed that AKAP1 phosphorylates Larp1 via PKC signaling activation to decrease mtDNA replication, which accelerates mitochondrial dysfunction and podocyte injury in DKD.
    Keywords:  AKAP1; Larp1; PKC; diabetic kidney disease; mitochondria; mtDNA replication; podocyte
    DOI:  https://doi.org/10.7150/ijbs.73493
  9. Hum Hered. 2022 Jul 18.
    Mutational Screening for Mitochondrial tRNA Genes in 100 Women with Pre-eclampsia.
    Baohua Zhou, Xuelian Chu, Caijuan Zhang, Xiufeng Liang.
       OBJECTIVES: Impairment of mitochondrial function caused by pathogenic mitochondrial DNA (mtDNA) mutations has been found to be associated with pre-eclampsia (PE). However, the underlying mechanism of PE remains poorly undetermined. The aim of this study is to evaluate the relationship between mitochondrial tRNAs (mt-tRNAs) variants and PE.
    MATERIAL AND METHODS: The mt-tRNAs variants in a cohort of 100 pregnant women with PE and 100 healthy subjects were examined by PCR-Sager sequencing. Moreover, the phylogenetic conservation analysis, mitochondrial haplogroup analysis, as well as pathogenicity scoring system were used to assess the potential pathogenicity of these tRNA variants.
    RESULTS: We identified five possible pathogenic mt-tRNA variants: tRNAPhe A608G, tRNAIle A4263G, tRNAAla T5587C, tRNALeu(CUN) G12294C and tRNAPro G15995A. We noticed that these variants were not detected in control subjects and occurred at the positions which were extremely conserved. Alternations in tRNAs structure caused by these variants may lead to the failures in tRNAs metabolism, which may subsequently may lead to the impairment of mitochondrial translation, as well as the respiratory chain functions. Thus, mt-tRNA variants may be involved in the pathogenesis of PE.
    CONCLUSIONS: Taken together, our data indicated that variants in mt-tRNA genes were the important contributors to PE; screening for mt-tRNA variants was recommended for early detection and prevention of PE.
    DOI:  https://doi.org/10.1159/000525663
  10. Cell Rep. 2022 Jul 19. pii: S2211-1247(22)00930-5. [Epub ahead of print]40(3): 111124
    Pathological mitophagy disrupts mitochondrial homeostasis in Leber's hereditary optic neuropathy.
    Alberto Danese, Simone Patergnani, Alessandra Maresca, Camille Peron, Andrea Raimondi, Leonardo Caporali, Saverio Marchi, Chiara La Morgia, Valentina Del Dotto, Claudia Zanna, Angelo Iannielli, Alice Segnali, Ivano Di Meo, Andrea Cavaliere, Magdalena Lebiedzinska-Arciszewska, Mariusz R Wieckowski, Andrea Martinuzzi, Milton N Moraes-Filho, Solange R Salomao, Adriana Berezovsky, Rubens Belfort, Christopher Buser, Fred N Ross-Cisneros, Alfredo A Sadun, Carlo Tacchetti, Vania Broccoli, Carlotta Giorgi, Valeria Tiranti, Valerio Carelli, Paolo Pinton.
      Leber's hereditary optic neuropathy (LHON), a disease associated with a mitochondrial DNA mutation, is characterized by blindness due to degeneration of retinal ganglion cells (RGCs) and their axons, which form the optic nerve. We show that a sustained pathological autophagy and compartment-specific mitophagy activity affects LHON patient-derived cells and cybrids, as well as induced pluripotent-stem-cell-derived neurons. This is variably counterbalanced by compensatory mitobiogenesis. The aberrant quality control disrupts mitochondrial homeostasis as reflected by defective bioenergetics and excessive reactive oxygen species production, a stress phenotype that ultimately challenges cell viability by increasing the rate of apoptosis. We counteract this pathological mechanism by using autophagy regulators (clozapine and chloroquine) and redox modulators (idebenone), as well as genetically activating mitochondrial biogenesis (PGC1-α overexpression). This study substantially advances our understanding of LHON pathophysiology, providing an integrated paradigm for pathogenesis of mitochondrial diseases and druggable targets for therapy.
    Keywords:  CP: Neuroscience; LHON; autophagy; cybrids; iPSCs; mitochondria; mitophagy; mtDNA; optic nerve; retinal ganglion cells; therapy
    DOI:  https://doi.org/10.1016/j.celrep.2022.111124
  11. Front Immunol. 2022 ;13 951614
    Endothelial Cells as a Key Cell Type for Innate Immunity: A Focused Review on RIG-I Signaling Pathway.
    Suowen Xu, Tengchuan Jin, Jianping Weng.
      The vascular endothelium consists of a highly heterogeneous monolayer of endothelial cells (ECs) which are the primary target for bacterial and viral infections due to EC's constant and close contact with the bloodstream. Emerging evidence has shown that ECs are a key cell type for innate immunity. Like macrophages, ECs serve as sentinels when sensing invading pathogens or microbial infection caused by viruses and bacteria. It remains elusive how ECs senses danger signals, transduce the signal and fulfil immune functions. Retinoic acid-inducible gene-I (RIG-I, gene name also known as DDX58) is an important member of RIG-I-like receptor (RLR) family that functions as an important pathogen recognition receptor (PRR) to execute immune surveillance and confer host antiviral response. Recent studies have demonstrated that virus infection, dsRNA, dsDNA, interferons, LPS, and 25-hydroxycholesterol (25-HC) can increase RIG-1 expression in ECs and propagate anti-viral response. Of translational significance, RIG-I activation can be inhibited by Panax notoginseng saponins, endogenous PPARγ ligand 15-PGJ2, tryptanthrin and 2-animopurine. Considering the pivotal role of inflammation and innate immunity in regulating endothelial dysfunction and atherosclerosis, here we provided a concise review of the role of RIG-I in endothelial cell function and highlight future direction to elucidate the potential role of RIG-I in regulating cardiovascular diseases as well as virus infectious disease, including COVID-19. Furthered understanding of RIG-I-mediated signaling pathways is important to control disorders associated with altered immunity and inflammation in ECs.
    Keywords:  DDX58; RIG-I; endothelial cells; immunity; inflammation
    DOI:  https://doi.org/10.3389/fimmu.2022.951614
  12. Nature. 2022 Jul 20.
    ADAR1 prevents autoinflammation by suppressing spontaneous ZBP1 activation.
    Richard de Reuver, Simon Verdonck, Evelien Dierick, Josephine Nemegeer, Eline Hessmann, Sadeem Ahmad, Maude Jans, Gillian Blancke, Filip Van Nieuwerburgh, Alexander Botzki, Lars Vereecke, Geert van Loo, Wim Declercq, Sun Hur, Peter Vandenabeele, Jonathan Maelfait.
      The RNA-editing enzyme adenosine deaminase acting on RNA 1 (ADAR1) limits the accumulation of endogenous immunostimulatory double-stranded RNA (dsRNA)1. In humans, reduced ADAR1 activity causes the severe inflammatory disease Aicardi-Goutières syndrome (AGS)2. In mice, complete loss of ADAR1 activity is embryonically lethal3-6, and mutations similar to those found in patients with AGS cause autoinflammation7-12. Mechanistically, adenosine-to-inosine (A-to-I) base modification of endogenous dsRNA by ADAR1 prevents chronic overactivation of the dsRNA sensors MDA5 and PKR3,7-10,13,14. Here we show that ADAR1 also inhibits the spontaneous activation of the left-handed Z-nucleic acid sensor ZBP1. Activation of ZBP1 elicits caspase-8-dependent apoptosis and MLKL-mediated necroptosis of ADAR1-deficient cells. ZBP1 contributes to the embryonic lethality of Adar-knockout mice, and it drives early mortality and intestinal cell death in mice deficient in the expression of both ADAR and MAVS. The Z-nucleic-acid-binding Zα domain of ADAR1 is necessary to prevent ZBP1-mediated intestinal cell death and skin inflammation. The Zα domain of ADAR1 promotes A-to-I editing of endogenous Alu elements to prevent dsRNA formation through the pairing of inverted Alu repeats, which can otherwise induce ZBP1 activation. This shows that recognition of Alu duplex RNA by ZBP1 may contribute to the pathological features of AGS that result from the loss of ADAR1 function.
    DOI:  https://doi.org/10.1038/s41586-022-04974-w
  13. Cell Mol Life Sci. 2022 Jul 21. 79(8): 437
    Polymerogenic neuroserpin causes mitochondrial alterations and activates NFκB but not the UPR in a neuronal model of neurodegeneration FENIB.
    E D'Acunto, L Gianfrancesco, I Serangeli, M D'Orsi, V Sabato, N A Guadagno, G Bhosale, S Caristi, A V Failla, A De Jaco, E Cacci, M R Duchen, G Lupo, G Galliciotti, E Miranda.
      The neurodegenerative condition FENIB (familiar encephalopathy with neuroserpin inclusion bodies) is caused by heterozygous expression of polymerogenic mutant neuroserpin (NS), with polymer deposition within the endoplasmic reticulum (ER) of neurons. We generated transgenic neural progenitor cells (NPCs) from mouse fetal cerebral cortex stably expressing either the control protein GFP or human wild type, polymerogenic G392E or truncated (delta) NS. This cellular model makes it possible to study the toxicity of polymerogenic NS in the appropriated cell type by in vitro differentiation to neurons. Our previous work showed that expression of G392E NS in differentiated NPCs induced an adaptive response through the upregulation of several genes involved in the defence against oxidative stress, and that pharmacological reduction of the antioxidant defences by drug treatments rendered G392E NS neurons more susceptible to apoptosis than control neurons. In this study, we assessed mitochondrial distribution and found a higher percentage of perinuclear localisation in G392E NS neurons, particularly in those containing polymers, a phenotype that was enhanced by glutathione chelation and rescued by antioxidant molecules. Mitochondrial membrane potential and contact sites between mitochondria and the ER were reduced in neurons expressing the G392E mutation. These alterations were associated with a pattern of ER stress that involved the ER overload response but not the unfolded protein response. Our results suggest that intracellular accumulation of NS polymers affects the interaction between the ER and mitochondria, causing mitochondrial alterations that contribute to the neuronal degeneration seen in FENIB patients.
    Keywords:  ER overload; MERCs; Neural progenitor cells; Neurodegeneration; Neurons; Oxidative stress; Protein conformational disease; Serpin polymers
    DOI:  https://doi.org/10.1007/s00018-022-04463-3
  14. Mol Oncol. 2022 Jul 17.
    Mitochondrial DNA mutations in aging and cancer.
    Anna Lm Smith, Julia C Whitehall, Laura C Greaves.
      Advancing age is a major risk factor for malignant transformation and the development of cancer. As such, over 50% of neoplasms occur in individuals over the age of 70. The pathologies of both aging and cancer have been characterized by respective groups of molecular hallmarks, and while some features are divergent between the two pathologies, several are shared. Perturbed mitochondrial function is one such common hallmark and this observation therefore suggests that mitochondrial alterations may be of significance in age-related cancer development. There is now considerable evidence documenting the accumulation of somatic mitochondrial DNA (mtDNA) mutations in aging human post-mitotic and replicative tissues. Similarly, mutations of the mitochondrial genome have been reported in human cancers for decades. The plethora of functions in which mitochondria partake, such as oxidative phosphorylation, redox balance, apoptosis, and numerous biosynthetic pathways, manifests a variety of ways in which alterations in mtDNA may contribute to tumor growth. However, the specific mechanisms by which mtDNA mutations contribute to tumor progression remain elusive and often contradictory. This review aims to consolidate current knowledge and describe future direction within the field.
    Keywords:  Aging; Cancer; Metabolism; Mitochondria; Mitochondrial DNA; Oxidative Phosphorylation
    DOI:  https://doi.org/10.1002/1878-0261.13291
  15. Endocr Regul. 2022 Jul 13. 56(3): 232-248
    Mitochondria and mitochondrial disorders: an overview update.
    Vibhuti Rambani, Dominika Hromnikova, Daniela Gasperikova, Martina Skopkova.
      Mitochondria, the cell powerhouse, are membrane-bound organelles present in the cytoplasm of almost all the eukaryotic cells. Their main function is to generate energy in the form of adenosine triphosphate (ATP). In addition, mitochondria store calcium for the cell signaling activities, generate heat, harbor pathways of intermediate metabolism and mediate cell growth and death. Primary mitochondrial diseases (MDs) form a clinically as well as genetically heterogeneous group of inherited disorders that result from the mitochondrial energetic metabolism malfunctions. The lifetime risk of the MDs development is estimated at 1:1470 of newborns, which makes them one of the most recurrent groups of inherited disorders with an important burden for society. MDs are progressive with wide range of symptoms of variable severity that can emerge congenitally or anytime during the life. MD can be caused by mutations in the mitochondrial DNA (mtDNA) or nuclear DNA genes. Mutations inducing impairment of mitochondrial function have been found in more than 400 genes. Furthermore, more than 1200 nuclear genes, which could play a role in the MDs' genetic etiology, are involved in the mitochondrial activities. However, the knowledge regarding the mechanism of the mitochondrial pathogenicity appears to be most essential for the development of effective patient's treatment suffering from the mitochondrial disease. This is an overview update focused on the mitochondrial biology and the mitochondrial diseases associated genes.
    Keywords:  genes; inherited disorder; mitochondria
    DOI:  https://doi.org/10.2478/enr-2022-0025
  16. Front Genet. 2022 ;13 797129
    Exploring the Effects of Mitonuclear Interactions on Mitochondrial DNA Gene Expression in Humans.
    Edmundo Torres-Gonzalez, Kateryna D Makova.
      Most mitochondrial protein complexes include both nuclear and mitochondrial gene products, which coevolved to work together. This coevolution can be disrupted due to disparity in genetic ancestry between the nuclear and mitochondrial genomes in recently admixed populations. Such mitonuclear DNA discordance might result in phenotypic effects. Several nuclear-encoded proteins regulate expression of mitochondrial DNA (mtDNA) genes. We hypothesized that mitonuclear DNA discordance affects expression of genes encoded by mtDNA. To test this, we utilized the data from the GTEx project, which contains expression levels for ∼100 African Americans and >600 European Americans. The varying proportion of African and European ancestry in recently admixed African Americans provides a range of mitonuclear discordance values, which can be correlated with mtDNA gene expression levels (adjusted for age and ischemic time). In contrast, European Americans did not undergo recent admixture. We demonstrated that, for most mtDNA protein-coding genes, expression levels in energetically-demanding tissues were lower in African Americans than in European Americans. Furthermore, gene expression levels were lower in individuals with higher mitonuclear discordance, independent of population. Moreover, we found a negative correlation between mtDNA gene expression and mitonuclear discordance. In African Americans, the average value of African ancestry was higher for nuclear-encoded mitochondrial than non-mitochondrial genes, facilitating a match in ancestry with the mtDNA and more optimal interactions. These results represent an example of a phenotypic effect of mitonuclear discordance on human admixed populations, and have potential biomedical applications.
    Keywords:  gene expression; genetic ancestry; mitochondrial DNA; mitonuclear DNA discordance; mitonuclear coevolution; mitonuclear incompatibility
    DOI:  https://doi.org/10.3389/fgene.2022.797129
  17. J Biol Chem. 2022 Jul 15. pii: S0021-9258(22)00709-8. [Epub ahead of print] 102267
    RNA binding by ADAR3 inhibits adenosine-to-inosine editing and promotes expression of immune response protein MAVS.
    Reshma Raghava Kurup, Eimile K Oakes, Aidan C Manning, Priyanka Mukherjee, Pranathi Vadlamani, Heather A Hundley.
      Members of the ADAR family of double-stranded RNA binding proteins regulate one of the most abundant RNA modifications in humans, the deamination of adenosine to inosine. Several transcriptome-wide studies have been carried out to identify RNA targets of the active deaminases ADAR1 and ADAR2. However, our understanding of ADAR3, the brain-specific deaminase-deficient ADAR family member, is limited to a few transcripts. In this study, we identified over 3,300 transcripts bound by ADAR3, and observed that binding of ADAR3 correlated with reduced editing of over 400 sites in the glioblastoma transcriptome. We further investigated the impact of ADAR3 on gene regulation of the transcript that encodes MAVS, an essential protein in the innate immune response pathway. We observed reduced editing in the MAVS 3' UTR in cells expressing increased ADAR3 or reduced ADAR1 suggesting ADAR3 acts as a negative regulator of ADAR1-mediated editing. While neither ADAR1 knock-down or ADAR3 overexpression affected MAVS mRNA expression, we demonstrate increased ADAR3 expression resulted in upregulation of MAVS protein expression. In addition, we created a novel genetic mutant of ADAR3 that exhibited enhanced RNA binding and MAVS upregulation compared to wildtype ADAR3. Interestingly, this ADAR3 mutant no longer repressed RNA editing, suggesting ADAR3 has a unique regulatory role beyond altering editing levels. Altogether, this study provides the first global view of ADAR3-bound RNAs in glioblastoma cells and identifies both a role for ADAR3 in repressing ADAR1-mediated editing and an RNA-binding dependent function of ADAR3 in regulating MAVS expression.
    Keywords:  A-to-I RNA editing; ADAR; ADARB2; MAVS; RNA binding protein; RNA modification; deaminase; double-stranded RNA; glioblastoma; post-transcriptional regulation
    DOI:  https://doi.org/10.1016/j.jbc.2022.102267
  18. Nat Metab. 2022 Jul 21.
    TFEB induces mitochondrial itaconate synthesis to suppress bacterial growth in macrophages.
    Ev-Marie Schuster, Maximilian W Epple, Katharina M Glaser, Michael Mihlan, Kerstin Lucht, Julia A Zimmermann, Anna Bremser, Aikaterini Polyzou, Nadine Obier, Nina Cabezas-Wallscheid, Eirini Trompouki, Andrea Ballabio, Jörg Vogel, Joerg M Buescher, Alexander J Westermann, Angelika S Rambold.
      Successful elimination of bacteria in phagocytes occurs in the phago-lysosomal system, but also depends on mitochondrial pathways. Yet, how these two organelle systems communicate is largely unknown. Here we identify the lysosomal biogenesis factor transcription factor EB (TFEB) as regulator for phago-lysosome-mitochondria crosstalk in macrophages. By combining cellular imaging and metabolic profiling, we find that TFEB activation, in response to bacterial stimuli, promotes the transcription of aconitate decarboxylase (Acod1, Irg1) and synthesis of its product itaconate, a mitochondrial metabolite with antimicrobial activity. Activation of the TFEB-Irg1-itaconate signalling axis reduces the survival of the intravacuolar pathogen Salmonella enterica serovar Typhimurium. TFEB-driven itaconate is subsequently transferred via the Irg1-Rab32-BLOC3 system into the Salmonella-containing vacuole, thereby exposing the pathogen to elevated itaconate levels. By activating itaconate production, TFEB selectively restricts proliferating Salmonella, a bacterial subpopulation that normally escapes macrophage control, which contrasts TFEB's role in autophagy-mediated pathogen degradation. Together, our data define a TFEB-driven metabolic pathway between phago-lysosomes and mitochondria that restrains Salmonella Typhimurium burden in macrophages in vitro and in vivo.
    DOI:  https://doi.org/10.1038/s42255-022-00605-w
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