bims-nenemi Biomed News
on Neuroinflammation, neurodegeneration and mitochondria
Issue of 2023‒01‒08
thirteen papers selected by
Marco Tigano
Thomas Jefferson University
  1. Endoplasmic reticulum protein BIK binds to and inhibits mitochondria-localized anti-apoptotic proteins.
  2. Pnpt1 mediates NLRP3 inflammasome activation by MAVS and metabolic reprogramming in macrophages.
  3. An RNA stem-loop functions in conjunction with an upstream open reading frame to direct preferential translation in the integrated stress response.
  4. Human mitochondria require mtRF1 for translation termination at non-canonical stop codons.
  5. The mitochondrial Hsp70 controls the assembly of the F1FO-ATP synthase.
  6. Potent ClpP agonists with anticancer properties bind with improved structural complementarity and alter the mitochondrial N-terminome.
  7. Crosstalk between mitophagy and innate immunity in viral infection.
  8. The nucleoprotein of influenza A virus inhibits the innate immune response by inducing mitophagy.
  9. A Drosophila model of the neurological symptoms in Mpv17-related diseases.
  10. TPX2 prompts mitotic survival via the induction of BCL2L1 through YAP1 protein stabilization in human embryonic stem cells.
  11. Inner mitochondrial membrane protein Prohibitin 1 mediates Nix-induced, Parkin-independent mitophagy.
  12. The endoplasmic reticulum kinase PERK interacts with the oxidoreductase ERO1 to metabolically adapt mitochondria.
  13. Comparing RNA-sequencing datasets from astrocytes, oligodendrocytes, and microglia in multiple sclerosis identifies novel dysregulated genes relevant to inflammation and myelination.
  1. J Biol Chem. 2023 Jan 02. pii: S0021-9258(22)01306-0. [Epub ahead of print] 102863
    Endoplasmic reticulum protein BIK binds to and inhibits mitochondria-localized anti-apoptotic proteins.
    Elizabeth J Osterlund, Nehad Hirmiz, Dang Nguyen, James M Pemberton, Qiyin Fang, David W Andrews.
      The pro-apoptotic BH3-only endoplasmic reticulum (ER) resident protein BIK, positively regulates mitochondrial outer membrane permeabilization (MOMP), the point-of-no-return in apoptosis. It is generally accepted that BIK functions at a distance from mitochondria by binding and sequestering anti-apoptotic proteins at the ER thereby promoting ER calcium release. Although BIK is predominantly localized to the ER, we detect by FLIM-FRET microscopy, BH3 region-dependent direct binding between BIK and mitochondria-localized chimeric mutants of the anti-apoptotic proteins BCL-XL and BCL-2 in both BMK and MCF-7 cells. Direct binding was accompanied by cell-type specific differential relocalization in response to co-expression of either BIK or one of its target binding partners, BCL-XL, when co-expressed in cells. In BMK cells with genetic deletion of both BAX and BAK (BMK-DKO) our data suggest a fraction of BIK protein moves towards mitochondria in response to the expression of a mitochondria-localized BCL-XL mutant. In contrast, in MCF-7 cells our data suggest BIK is localized at both ER and mitochondria-associated endoplasmic reticulum membranes (MAMs) and binds to the mitochondria-localized BCL-XL mutant via relocalization of BCL-XL to ER and MAMs. Rather than functioning at a distance, our data suggest BIK initiates MOMP via direct interactions with ER and mitochondria-localized anti-apoptotic proteins, that occur via ER-mitochondria contact sites, and/or by relocalization of either BIK or anti-apoptotic proteins in cells.
    Keywords:  BCL-2 family; BCL-2 interacting killer; BIK; FLIM-FRET; apoptosis; subcellular localization fluorescence lifetime imaging microscopy
    DOI:  https://doi.org/10.1016/j.jbc.2022.102863
  2. Cell Mol Immunol. 2023 Jan 04.
    Pnpt1 mediates NLRP3 inflammasome activation by MAVS and metabolic reprogramming in macrophages.
    Chia George Hsu, Wenjia Li, Mark Sowden, Camila Lage Chávez, Bradford C Berk.
      Polyribonucleotide nucleotidyltransferase 1 (Pnpt1) plays critical roles in mitochondrial homeostasis by controlling mitochondrial RNA (mt-RNA) processing, trafficking and degradation. Pnpt1 deficiency results in mitochondrial dysfunction that triggers a type I interferon response, suggesting a role in inflammation. However, the role of Pnpt1 in inflammasome activation remains largely unknown. In this study, we generated myeloid-specific Pnpt1-knockout mice and demonstrated that Pnpt1 depletion enhanced interleukin-1 beta (IL-1β) and interleukin-18 (IL-18) secretion in a mouse sepsis model. Using cultured peritoneal and bone marrow-derived macrophages, we demonstrated that Pnpt1 regulated NLRP3 inflammasome-dependent IL-1β release in response to lipopolysaccharide (LPS), followed by nigericin, ATP or poly (I:C) treatment. Pnpt1 deficiency in macrophages increased glycolysis after LPS administration and mt-reactive oxygen species (mt-ROS) after NLRP3 inflammasome activation. Pnpt1 activation of the inflammasome was dependent on increased glycolysis and the expression of mitochondrial antiviral-signaling protein (MAVS) but not NF-κB signaling. Collectively, these data suggest that Pnpt1 is an important mediator of inflammation, as shown by activation of the NLRP3 inflammasome in murine sepsis and cultured macrophages.
    Keywords:  Inflammasome; Macrophage; Mitochondria; Pnpt1
    DOI:  https://doi.org/10.1038/s41423-022-00962-2
  3. J Biol Chem. 2022 Dec 31. pii: S0021-9258(22)01307-2. [Epub ahead of print] 102864
    An RNA stem-loop functions in conjunction with an upstream open reading frame to direct preferential translation in the integrated stress response.
    Parth H Amin, Kenneth R Carlson, Ronald C Wek.
      In response to environmental stresses, cells invoke translational control to conserve resources and rapidly reprogram gene expression for optimal adaptation. A central mechanism for translational control involves phosphorylation of the α subunit of eIF2 (p-eIF2α), which reduces delivery of initiator tRNA to ribosomes. Because p-eIF2α is invoked by multiple protein kinases, each responding to distinct stresses, this pathway is named the Integrated stress response (ISR). While p-eIF2α lowers bulk translation initiation, many stress-related mRNAs are preferentially translated. The process by which ribosomes delineate gene transcripts for preferential translation is known to involve upstream open reading frames (uORFs) embedded in the targeted mRNAs. In this study, we used polysome analyses and reporter assays to address the mechanisms directing preferential translation of human IBTKα in the ISR. The IBTKα mRNA encodes four uORFs, with only 5'-proximal uORF1 and uORF2 being translated. Of importance, the 5'-leader of IBTKα mRNA also contains a phylogenetically conserved stem-loop of moderate stability that is situated 11 nucleotides downstream of uORF2. The uORF2 is well translated and functions in combination with the stem-loop to effectively lower translation reinitiation at the IBTKα coding sequence. Upon stress induced p-eIF2α, the uORF2/stem loop element can be bypassed to enhance IBTKα translation by a mechanism that may involve the modestly translated uORF1. Our study demonstrates that uORFs in conjunction with RNA secondary structures can be critical elements that serve as the "bar code" by which scanning ribosomes can delineate which mRNAs are preferentially translated in the ISR.
    Keywords:  Integrated stress response; eIF2 phosphorylation; translational control
    DOI:  https://doi.org/10.1016/j.jbc.2022.102864
  4. Nat Commun. 2023 Jan 03. 14(1): 30
    Human mitochondria require mtRF1 for translation termination at non-canonical stop codons.
    Annika Krüger, Cristina Remes, Dmitrii Igorevich Shiriaev, Yong Liu, Henrik Spåhr, Rolf Wibom, Ilian Atanassov, Minh Duc Nguyen, Barry S Cooperman, Joanna Rorbach.
      The mitochondrial translation machinery highly diverged from its bacterial counterpart. This includes deviation from the universal genetic code, with AGA and AGG codons lacking cognate tRNAs in human mitochondria. The locations of these codons at the end of COX1 and ND6 open reading frames, respectively, suggest they might function as stop codons. However, while the canonical stop codons UAA and UAG are known to be recognized by mtRF1a, the release mechanism at AGA and AGG codons remains a debated issue. Here, we show that upon the loss of another member of the mitochondrial release factor family, mtRF1, mitoribosomes accumulate specifically at AGA and AGG codons. Stalling of mitoribosomes alters COX1 transcript and protein levels, but not ND6 synthesis. In addition, using an in vitro reconstituted mitochondrial translation system, we demonstrate the specific peptide release activity of mtRF1 at the AGA and AGG codons. Together, our results reveal the role of mtRF1 in translation termination at non-canonical stop codons in mitochondria.
    DOI:  https://doi.org/10.1038/s41467-022-35684-6
  5. Nat Commun. 2023 Jan 03. 14(1): 39
    The mitochondrial Hsp70 controls the assembly of the F1FO-ATP synthase.
    Jiyao Song, Liesa Steidle, Isabelle Steymans, Jasjot Singh, Anne Sanner, Lena Böttinger, Dominic Winter, Thomas Becker.
      The mitochondrial F1FO-ATP synthase produces the bulk of cellular ATP. The soluble F1 domain contains the catalytic head that is linked via the central stalk and the peripheral stalk to the membrane embedded rotor of the FO domain. The assembly of the F1 domain and its linkage to the peripheral stalk is poorly understood. Here we show a dual function of the mitochondrial Hsp70 (mtHsp70) in the formation of the ATP synthase. First, it cooperates with the assembly factors Atp11 and Atp12 to form the F1 domain of the ATP synthase. Second, the chaperone transfers Atp5 into the assembly line to link the catalytic head with the peripheral stalk. Inactivation of mtHsp70 leads to integration of assembly-defective Atp5 variants into the mature complex, reflecting a quality control function of the chaperone. Thus, mtHsp70 acts as an assembly and quality control factor in the biogenesis of the F1FO-ATP synthase.
    DOI:  https://doi.org/10.1038/s41467-022-35720-5
  6. Structure. 2022 Dec 15. pii: S0969-2126(22)00488-9. [Epub ahead of print]
    Potent ClpP agonists with anticancer properties bind with improved structural complementarity and alter the mitochondrial N-terminome.
    Mark F Mabanglo, Keith S Wong, Marim M Barghash, Elisa Leung, Stephanie H W Chuang, Afshan Ardalan, Emily M Majaesic, Cassandra J Wong, Shen Zhang, Henk Lang, Donald S Karanewsky, Andrew A Iwanowicz, Lee M Graves, Edwin J Iwanowicz, Anne-Claude Gingras, Walid A Houry.
      The mitochondrial ClpP protease is responsible for mitochondrial protein quality control through specific degradation of proteins involved in several metabolic processes. ClpP overexpression is also required in many cancer cells to eliminate reactive oxygen species (ROS)-damaged proteins and to sustain oncogenesis. Targeting ClpP to dysregulate its function using small-molecule agonists is a recent strategy in cancer therapy. Here, we synthesized imipridone-derived compounds and related chemicals, which we characterized using biochemical, biophysical, and cellular studies. Using X-ray crystallography, we found that these compounds have enhanced binding affinities due to their greater shape and charge complementarity with the surface hydrophobic pockets of ClpP. N-terminome profiling of cancer cells upon treatment with one of these compounds revealed the global proteomic changes that arise and identified the structural motifs preferred for protein cleavage by compound-activated ClpP. Together, our studies provide the structural and molecular basis by which dysregulated ClpP affects cancer cell viability and proliferation.
    Keywords:  ClpP agonist; ClpP protease; HYTANE mass spectrometry; N-terminome; TR compounds; X-ray crystallography; cancer; drug design; imipridones; mitochondria
    DOI:  https://doi.org/10.1016/j.str.2022.12.002
  7. Front Microbiol. 2022 ;13 1064045
    Crosstalk between mitophagy and innate immunity in viral infection.
    Cheng Fu, Nan Cao, Wenjun Liu, Zilin Zhang, Zihui Yang, Wenhui Zhu, Shuangqi Fan.
      Mitochondria are important organelles involved in cell metabolism and programmed cell death in eukaryotic cells and are closely related to the innate immunity of host cells against viruses. Mitophagy is a process in which phagosomes selectively phagocytize damaged or dysfunctional mitochondria to form autophagosomes and is degraded by lysosomes, which control mitochondrial mass and maintain mitochondrial dynamics and cellular homeostasis. Innate immunity is an important part of the immune system and plays a vital role in eliminating viruses. Viral infection causes many physiological and pathological alterations in host cells, including mitophagy and innate immune pathways. Accumulating evidence suggests that some virus promote self-replication through regulating mitophagy-mediated innate immunity. Clarifying the regulatory relationships among mitochondria, mitophagy, innate immunity, and viral infection will shed new insight for pathogenic mechanisms and antiviral strategies. This review systemically summarizes the activation pathways of mitophagy and the relationship between mitochondria and innate immune signaling pathways, and then discusses the mechanisms of viruses on mitophagy and innate immunity and how viruses promote self-replication by regulating mitophagy-mediated innate immunity.
    Keywords:  innate immunity; mechanisms; mitochondria; mitophagy; viral infection
    DOI:  https://doi.org/10.3389/fmicb.2022.1064045
  8. Autophagy. 2023 Jan 01. 1-18
    The nucleoprotein of influenza A virus inhibits the innate immune response by inducing mitophagy.
    Bo Zhang, Shuai Xu, Minxuan Liu, Yanli Wei, Qian Wang, Wentao Shen, Cao-Qi Lei, Qiyun Zhu.
      Mitophagy is a form of autophagy that plays a key role in maintaining the homeostasis of functional mitochondria in the cell. Viruses have evolved various strategies to manipulate mitophagy to escape host immune responses and promote virus replication. In this study, the nucleoprotein (NP) of H1N1 virus (PR8 strain) was identified as a regulator of mitophagy. We revealed that NP-mediated mitophagy leads to the degradation of the mitochondria-anchored protein MAVS, thereby blocking MAVS-mediated antiviral signaling and promoting virus replication. The NP-mediated mitophagy is dependent on the interaction of NP with MAVS and the cargo receptor TOLLIP. Moreover, Y313 of NP is a key residue for the MAVS-NP interaction and NP-mediated mitophagy. The NPY313F mutation significantly attenuates the virus-induced mitophagy and the virus replication in vitro and in vivo. Taken together, our findings uncover a novel mechanism by which the NP of influenza virus induces mitophagy to attenuate innate immunity.Abbreviations: ACTB: actin beta; ATG7: autophagy related 7; ATG12: autophagy related 12; CCCP: carbonyl cyanide 3-chlorophenyl hydrazone; co-IP: co-immunoprecipitation; COX4/COXIV: cytochrome c oxidase subunit 4; DAPI: 4',6-diamidino-2-phenylindole, dihydrochloride; EID50: 50% egg infective dose; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GFP: green fluorescent protein; HEK: human embryonic kidney; hpi: hours post-infection; IAV: influenza A virus; IFN: interferon; IP: immunoprecipitation; LAMP1: lysosomal associated membrane protein 1; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MAVS: mitochondrial antiviral signaling protein; Mdivi-1: mitochondrial division inhibitor 1; MLD50: 50% mouse lethal dose; MOI: multiplicity of infection; NBR1: NBR1 autophagy cargo receptor; NP: nucleoprotein; PB1: basic polymerase 1; RFP: red fluorescent protein; RIGI: RNA sensor RIG-I; RIGI-N: RIGI-CARD; SeV: Sendai virus; SQSTM1/p62: sequestosome 1; TIMM23: translocase of inner mitochondrial membrane 23; TOLLIP: toll interacting protein; TOMM20: translocase of outer mitochondrial membrane 20; TUBA: tubulin alpha; Vec: empty vector; vRNP: viral ribonucleoprotein.
    Keywords:  Influenza A virus; MAVS; TOLLIP; mitophagy; nucleoprotein
    DOI:  https://doi.org/10.1080/15548627.2022.2162798
  9. Sci Rep. 2022 Dec 31. 12(1): 22632
    A Drosophila model of the neurological symptoms in Mpv17-related diseases.
    Atsushi Kodani, Mizuki Yamaguchi, Ririka Itoh, Man Anh Huynh, Hideki Yoshida.
      Mutations in the Mpv17 gene are responsible for MPV17-related hepatocerebral mitochondrial DNA depletion syndrome and Charcot-Marie-Tooth (CMT) disease. Although several models including mouse, zebrafish, and cultured human cells, have been developed, the models do not show any neurological defects, which are often observed in patients. Therefore, we knocked down CG11077 (Drosophila Mpv17; dMpv17), an ortholog of human MPV17, in the nervous system in Drosophila melanogaster and investigated the behavioral and cellular phenotypes. The resulting dMpv17 knockdown larvae showed impaired locomotor activity and learning ability consistent with mitochondrial defects suggested by the reductions in mitochondrial DNA and ATP production and the increases in the levels of lactate and reactive oxygen species. Furthermore, an abnormal morphology of the neuromuscular junction, at the presynaptic terminal, was observed in dMpv17 knockdown larvae. These results reproduce well the symptoms of human diseases and partially reproduce the phenotypes of Mpv17-deficient model organisms. Therefore, we suggest that neuron-specific dMpv17 knockdown in Drosophila is a useful model for investigation of MPV17-related hepatocerebral mitochondrial DNA depletion syndrome and CMT caused by Mpv17 dysfunction.
    DOI:  https://doi.org/10.1038/s41598-022-27329-x
  10. Exp Mol Med. 2023 Jan 04.
    TPX2 prompts mitotic survival via the induction of BCL2L1 through YAP1 protein stabilization in human embryonic stem cells.
    Yun-Jeong Kim, Young-Hyun Go, Ho-Chang Jeong, Eun-Ji Kwon, Seong-Min Kim, Hyun Sub Cheong, Wantae Kim, Hyoung Doo Shin, Haeseung Lee, Hyuk-Jin Cha.
      Genetic alterations have been reported for decades in most human embryonic stem cells (hESCs). Survival advantage, a typical trait acquired during long-term in vitro culture, results from the induction of BCL2L1 upon frequent copy number variation (CNV) at locus 20q11.21 and is one of the strongest candidates associated with genetic alterations that occur via escape from mitotic stress. However, the underlying mechanisms for BCL2L1 induction remain unknown. Furthermore, abnormal mitosis and the survival advantage that frequently occur in late passage are associated with the expression of BCL2L1, which is in locus 20q11.21. In this study, we demonstrated that the expression of TPX2, a gene located in 20q11.21, led to BCL2L1 induction and consequent survival traits under mitotic stress in isogenic pairs of hESCs and human induced pluripotent stem cells (iPSCs) with normal and 20q11.21 CNVs. High Aurora A kinase activity by TPX2 stabilized the YAP1 protein to induce YAP1-dependent BCL2L1 expression. A chemical inhibitor of Aurora A kinase and knockdown of YAP/TAZ significantly abrogated the high tolerance to mitotic stress through BCL2L1 suppression. These results suggest that the collective expression of TPX2 and BCL2L1 from CNV at loci 20q11.21 and a consequent increase in YAP1 signaling promote genome instability during long-term in vitro hESC culture.
    DOI:  https://doi.org/10.1038/s12276-022-00907-9
  11. Sci Rep. 2023 Jan 02. 13(1): 18
    Inner mitochondrial membrane protein Prohibitin 1 mediates Nix-induced, Parkin-independent mitophagy.
    Kibrom M Alula, Yaritza Delgado-Deida, Rosemary Callahan, Andreas Till, Lucia Underwood, Winston E Thompson, Rhonda F Souza, Themistocles Dassopoulos, Joseph Onyiah, K Venuprasad, Arianne L Theiss.
      Autophagy of damaged mitochondria, called mitophagy, is an important organelle quality control process involved in the pathogenesis of inflammation, cancer, aging, and age-associated diseases. Many of these disorders are associated with altered expression of the inner mitochondrial membrane (IMM) protein Prohibitin 1. The mechanisms whereby dysfunction occurring internally at the IMM and matrix activate events at the outer mitochondrial membrane (OMM) to induce mitophagy are not fully elucidated. Using the gastrointestinal epithelium as a model system highly susceptible to autophagy inhibition, we reveal a specific role of Prohibitin-induced mitophagy in maintaining intestinal homeostasis. We demonstrate that Prohibitin 1 induces mitophagy in response to increased mitochondrial reactive oxygen species (ROS) through binding to mitophagy receptor Nix/Bnip3L and independently of Parkin. Prohibitin 1 is required for ROS-induced Nix localization to mitochondria and maintaining homeostasis of epithelial cells highly susceptible to mitochondrial dysfunction.
    DOI:  https://doi.org/10.1038/s41598-022-26775-x
  12. Cell Rep. 2022 Dec 23. pii: S2211-1247(22)01798-3. [Epub ahead of print] 111899
    The endoplasmic reticulum kinase PERK interacts with the oxidoreductase ERO1 to metabolically adapt mitochondria.
    Arthur Bassot, Junsheng Chen, Kei Takahashi-Yamashiro, Megan C Yap, Christine Silvia Gibhardt, Giang N T Le, Saaya Hario, Yusuke Nasu, Jack Moore, Tomas Gutiérrez, Lucas Mina, Heather Mast, Audric Moses, Rakesh Bhat, Klaus Ballanyi, Hélène Lemieux, Roberto Sitia, Ester Zito, Ivan Bogeski, Robert E Campbell, Thomas Simmen.
      Endoplasmic reticulum (ER) homeostasis requires molecular regulators that tailor mitochondrial bioenergetics to the needs of protein folding. For instance, calnexin maintains mitochondria metabolism and mitochondria-ER contacts (MERCs) through reactive oxygen species (ROS) from NADPH oxidase 4 (NOX4). However, induction of ER stress requires a quick molecular rewiring of mitochondria to adapt to new energy needs. This machinery is not characterized. We now show that the oxidoreductase ERO1⍺ covalently interacts with protein kinase RNA-like ER kinase (PERK) upon treatment with tunicamycin. The PERK-ERO1⍺ interaction requires the C-terminal active site of ERO1⍺ and cysteine 216 of PERK. Moreover, we show that the PERK-ERO1⍺ complex promotes oxidization of MERC proteins and controls mitochondrial dynamics. Using proteinaceous probes, we determined that these functions improve ER-mitochondria Ca2+ flux to maintain bioenergetics in both organelles, while limiting oxidative stress. Therefore, the PERK-ERO1⍺ complex is a key molecular machinery that allows quick metabolic adaptation to ER stress.
    Keywords:  CP: Metabolism; CP: Molecular biology; ER; ER stress; ERO1; MAMs; MERCs; PERK; bioenergetics; endoplasmic reticulum; mitochondria; mitochondria-associated membranes; mitochondria-endoplasmic reticulum contacts; oxidoreductase
    DOI:  https://doi.org/10.1016/j.celrep.2022.111899
  13. WIREs Mech Dis. 2023 Jan 04. e1594
    Comparing RNA-sequencing datasets from astrocytes, oligodendrocytes, and microglia in multiple sclerosis identifies novel dysregulated genes relevant to inflammation and myelination.
    Sienna S Drake, Aliyah Zaman, Tristan Simas, Alyson E Fournier.
      Central nervous system (CNS) inflammation is a key factor in multiple sclerosis (MS). Invasion of peripheral immune cells into the CNS resulting from an unknown signal or combination of signals results in activation of resident immune cells and the hallmark feature of the disease: demyelinating lesions. These lesion sites are an amalgam of reactive peripheral and central immune cells, astrocytes, damaged and dying oligodendrocytes, and injured neurons and axons. Sustained inflammation affects cells directly located within the lesion site and further abnormalities are apparent diffusely throughout normal-appearing white matter and grey matter. It is only relatively recently, using animal models, new tissue sampling techniques, and next-generation sequencing, that molecular changes occurring in CNS resident cells have been broadly captured. Advances in cell isolation through Fluorescence Activated Cell Sorting (FACS) and laser-capture microdissection together with the emergence of single-cell sequencing have enabled researchers to investigate changes in gene expression in astrocytes, microglia, and oligodendrocytes derived from animal models of MS as well as from primary patient tissue. The contribution of some dysregulated pathways has been followed up in individual studies; however, corroborating results often go unreported between sequencing studies. To this end, we have consolidated results from numerous RNA-sequencing studies to identify and review novel patterns of differentially regulated genes and pathways occurring within CNS glial cells in MS. This article is categorized under: Neurological Diseases > Molecular and Cellular Physiology.
    Keywords:  RNA-sequencing; astrocyte; microglia; multiple sclerosis; oligodendrocyte
    DOI:  https://doi.org/10.1002/wsbm.1594
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