bims-nenemi Biomed News
on Neuroinflammation, neurodegeneration and mitochondria
Issue of 2023‒10‒29
thirteen papers selected by
Marco Tigano, Thomas Jefferson University
  1. Mitochondrial DNA Release Is Induced by Apoptotic Stress and Drives the SASP.
  2. The germline coordinates mitokine signaling.
  3. High-throughput single-cell analysis reveals progressive mitochondrial DNA mosaicism throughout life.
  4. CRISPR Screening in Tandem with Targeted mtDNA Damage Reveals WRNIP1 Essentiality.
  5. Excessive BNIP3- and BNIP3L-dependent mitophagy underlies the pathogenesis of FBXL4-mutated mitochondrial DNA depletion syndrome.
  6. Parkin Promotes Airway Inflammatory Response to Interferon Gamma.
  7. Mitochondrial gene expression is required for platelet function and blood clotting.
  8. Inflammatory signaling in NASH driven by hepatocyte mitochondrial dysfunctions.
  9. The biological function of cytoplasm-translocated ENDOG (endonuclease G).
  10. A genetically encoded tool to increase cellular NADH/NAD+ ratio in living cells.
  11. ZNF281 inhibits mitochondrial biogenesis to facilitate metastasis of hepatocellular carcinoma.
  12. A DRP-like pseudoenzyme coordinates with MICOS to promote cristae architecture.
  13. OptoProfilin: A Single Component Biosensor of Applied Cellular Stress.
  1. Cancer Discov. 2023 Oct 27. OF1
    Mitochondrial DNA Release Is Induced by Apoptotic Stress and Drives the SASP.
      Minority mitochondrial outer membrane permeabilization (miMOMP) during senescence drives the SASP.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2023-169
  2. bioRxiv. 2023 Oct 04. pii: 2023.08.21.554217. [Epub ahead of print]
    The germline coordinates mitokine signaling.
    Koning Shen, Jenni Durieux, Cesar G Mena, Brant M Webster, C Kimberly Tsui, Hanlin Zhang, Lawrence Joe, Kristen Berendzen, Andrew Dillin.
      The ability of mitochondria to coordinate stress responses across tissues is critical for health. In C. elegans , neurons experiencing mitochondrial stress elicit an inter-tissue signaling pathway through the release of mitokine signals, such as serotonin or the WNT ligand EGL-20, which activate the mitochondrial unfolded protein response (UPR MT ) in the periphery to promote organismal health and lifespan. We find that germline mitochondria play a surprising role in neuron-to-peripheral UPR MT signaling. Specifically, we find that germline mitochondria signal downstream of neuronal mitokines, like WNT and serotonin, and upstream of lipid metabolic pathways in the periphery to regulate UPR MT activation. We also find that the germline tissue itself is essential in UPR MT signaling. We propose that the germline has a central signaling role in coordinating mitochondrial stress responses across tissues, and germline mitochondria play a defining role in this coordination because of their inherent roles in germline integrity and inter-tissue signaling.
    DOI:  https://doi.org/10.1101/2023.08.21.554217
  3. Sci Adv. 2023 Oct 27. 9(43): eadi4038
    High-throughput single-cell analysis reveals progressive mitochondrial DNA mosaicism throughout life.
    Angelos Glynos, Lyuba V Bozhilova, Michele Frison, Stephen Burr, James B Stewart, Patrick F Chinnery.
      Heteroplasmic mitochondrial DNA (mtDNA) mutations are a major cause of inherited disease and contribute to common late-onset human disorders. The late onset and clinical progression of mtDNA-associated disease is thought to be due to changing heteroplasmy levels, but it is not known how and when this occurs. Performing high-throughput single-cell genotyping in two mouse models of human mtDNA disease, we saw unanticipated cell-to-cell differences in mtDNA heteroplasmy levels that emerged prenatally and progressively increased throughout life. Proliferating spleen cells and nondividing brain cells had a similar single-cell heteroplasmy variance, implicating mtDNA or organelle turnover as the major force determining cell heteroplasmy levels. The two different mtDNA mutations segregated at different rates with no evidence of selection, consistent with different rates of random genetic drift in vivo, leading to the accumulation of cells with a very high mutation burden at different rates. This provides an explanation for differences in severity seen in human diseases caused by similar mtDNA mutations.
    DOI:  https://doi.org/10.1126/sciadv.adi4038
  4. bioRxiv. 2023 Oct 03. pii: 2023.10.03.560559. [Epub ahead of print]
    CRISPR Screening in Tandem with Targeted mtDNA Damage Reveals WRNIP1 Essentiality.
    Tanja Sack, Piriththiv Dhavarasa, Daniel Szames, Siobhan O'Brien, Stephane Angers, Shana O Kelley.
      A major impediment to the characterization of mtDNA repair mechanisms, in comparison to nuclear DNA repair mechanisms, is the difficulty of specifically addressing mitochondrial damage. Using a mitochondria-penetrating peptide, we can deliver DNA-damaging agents directly to mitochondria, bypassing the nuclear compartment. Here, we describe the use of a mtDNA-damaging agent in tandem with CRISPR/Cas9 screening for the genome-wide discovery of factors essential for mtDNA damage response. Using mitochondria-targeted doxorubicin (mtDox) we generate mtDNA double-strand breaks (mtDSBs) specifically in this organelle. Combined with an untargeted Dox screen, we identify genes with significantly greater essentiality during mitochondrial versus nuclear DNA damage. We characterize the essentially of our top hit - WRNIP1 - observed here for the first time to respond to mtDNA damage. We further investigate the mitochondrial role of WRNIP1 in innate immune signaling and nuclear genome maintenance, outlining a model that experimentally supports mitochondrial turnover in response to mtDSBs.
    DOI:  https://doi.org/10.1101/2023.10.03.560559
  5. Autophagy. 2023 Oct 24.
    Excessive BNIP3- and BNIP3L-dependent mitophagy underlies the pathogenesis of FBXL4-mutated mitochondrial DNA depletion syndrome.
    Kun Gao, Yingji Chen, Ren Mo, Chenji Wang.
      Mitophagy, the process of removing damaged mitochondria to promote cell survival, plays a crucial role in cellular functionality. However, excessive, or uncontrolled mitophagy can lead to reduced mitochondrial content that burdens the remaining organelles, triggering mitophagy-mediated cell death. FBXL4 mutations, which affect the substrate-binding adaptor of the CUL1 (cullin 1)-RING ubiquitin ligase complex (CRL1), have been linked to mitochondrial DNA depletion syndrome type 13 (MTDPS13) characterized by reduced mtDNA content and impaired energy production in affected organs. However, the mechanism behind FBXL4 mutation-driven MTDPS13 remain poorly understood. In a recent study, we demonstrate that the CRL1-FBXL4 complex promotes the degradation of BNIP3 and BNIP3L, two key mitophagy cargo receptors. Deficiency of FBXL4 results in a strong accumulation of BNIP3 and BNIP3L proteins and triggers high levels of BNIP3- and BNIP3L-dependent mitophagy. Patient-derived FBXL4 mutations do not affect its interaction with BNIP3 and BNIP3L but impair the assembly of an active CRL1-FBXL4 complex. Furthermore, excessive mitophagy is observed in knockin mice carrying a patient-derived FBXL4 mutation, and in cortical neurons generated from human patient induced pluripotent stem cells (hiPSCs). These findings support the model that the CRL1-FBXL4 complex tightly restricts basal mitophagy, and its dysregulation leads to severe symptoms of MTDPS13.
    Keywords:  Lysosome; mitochondria; mitophagy; multi-system disorder; ubiquitination
    DOI:  https://doi.org/10.1080/15548627.2023.2274260
  6. Biomedicines. 2023 Oct 20. pii: 2850. [Epub ahead of print]11(10):
    Parkin Promotes Airway Inflammatory Response to Interferon Gamma.
    Kris Genelyn Dimasuay, Niccolette Schaunaman, Bruce Berg, Taylor Nichols, Hong Wei Chu.
      PURPOSE: Increased type 2 interferon (i.e., IFN-γ) signaling has been shown to be involved in airway inflammation in a subset of asthma patients who often show high levels of airway neutrophilic inflammation and poor response to corticosteroid treatment. How IFN-γ mediates airway inflammation in a mitochondrial dysfunction setting (e.g., Parkin up-regulation) remains poorly understood. The goal of this study was to determine the role of Parkin, an E3 ubiquitin ligase, in IFN-γ-mediated airway inflammation and the regulation of Parkin by IFN-γ.METHODS: A mouse model of IFN-γ treatment in wild-type and Parkin knockout mice, and cultured human primary airway epithelial cells with or without Parkin gene deficiency were used.
    RESULTS: Parkin was found to be necessary for the production of neutrophil chemokines (i.e., LIX and IL-8) and airway neutrophilic inflammation following IFN-γ treatment. Mechanistically, Parkin was induced by IFN-γ treatment both in vivo and in vitro, which was associated with less expression of a Parkin transcriptional repressor Thap11. Overexpression of Thap11 inhibited Parkin expression in IFN-γ-stimulated airway epithelial cells.
    CONCLUSIONS: Our data suggest a novel mechanism by which IFN-γ induces airway neutrophilic inflammation through the Thap11/Parkin axis. Inhibition of Parkin expression or activity may provide a new therapeutic target for the treatment of excessive neutrophilic inflammation in an IFN-γ-high environment.
    Keywords:  IFN-γ; Parkin; Thap11; inflammation; lung
    DOI:  https://doi.org/10.3390/biomedicines11102850
  7. Cell Rep. 2023 Oct 25. pii: S2211-1247(23)01324-4. [Epub ahead of print]42(11): 113312
    Mitochondrial gene expression is required for platelet function and blood clotting.
    Tara R Richman, Judith A Ermer, Jessica Baker, Stefan J Siira, Benjamin T Kile, Matthew D Linden, Oliver Rackham, Aleksandra Filipovska.
      Platelets are anucleate blood cells that contain mitochondria and regulate blood clotting in response to injury. Mitochondria contain their own gene expression machinery that relies on nuclear-encoded factors for the biogenesis of the oxidative phosphorylation system to produce energy required for thrombosis. The autonomy of the mitochondrial gene expression machinery from the nucleus is unclear, and platelets provide a valuable model to understand its importance in anucleate cells. Here, we conditionally delete Elac2, Ptcd1, or Mtif3 in platelets, which are essential for mitochondrial gene expression at the level of RNA processing, stability, or translation, respectively. Loss of ELAC2, PTCD1, or MTIF3 leads to increased megakaryocyte ploidy, elevated circulating levels of reticulated platelets, thrombocytopenia, and consequent extended bleeding time. Impaired mitochondrial gene expression reduces agonist-induced platelet activation. Transcriptomic and proteomic analyses show that mitochondrial gene expression is required for fibrinolysis, hemostasis, and blood coagulation in response to injury.
    Keywords:  CP: Immunology; megakaryocytes; mitochondria; mitochondrial gene expression; platelets; translation
    DOI:  https://doi.org/10.1016/j.celrep.2023.113312
  8. J Transl Med. 2023 Oct 26. 21(1): 757
    Inflammatory signaling in NASH driven by hepatocyte mitochondrial dysfunctions.
    Melissa Myint, Francesca Oppedisano, Valeria De Giorgi, Byeong-Moo Kim, Francesco M Marincola, Harvey J Alter, Salvatore Nesci.
      Liver steatosis, inflammation, and variable degrees of fibrosis are the pathological manifestations of nonalcoholic steatohepatitis (NASH), an aggressive presentation of the most prevalent chronic liver disease in the Western world known as nonalcoholic fatty liver (NAFL). Mitochondrial hepatocyte dysfunction is a primary event that triggers inflammation, affecting Kupffer and hepatic stellate cell behaviour. Here, we consider the role of impaired mitochondrial function caused by lipotoxicity during oxidative stress in hepatocytes. Dysfunction in oxidative phosphorylation and mitochondrial ROS production cause the release of damage-associated molecular patterns from dying hepatocytes, leading to activation of innate immunity and trans-differentiation of hepatic stellate cells, thereby driving fibrosis in NASH.
    Keywords:  Hepatic stellate cells; Inflammatory process; Mitochondrial dysfunction; NASH; Ox-mtDNA
    DOI:  https://doi.org/10.1186/s12967-023-04627-0
  9. Autophagy. 2023 Oct 27. 1-3
    The biological function of cytoplasm-translocated ENDOG (endonuclease G).
    Wenjun Wang, Jianshuang Li, Qinghua Zhou.
      ENDOG, a mitochondrial intermembrane space located endonuclease, participates in DNA fragmentation and apoptosis by translocating to the nucleus. ENDOG can also relocate to the mitochondrial matrix, where it regulates mitochondrial genome cleavage. However, the biological function of cytoplasm-translocated ENDOG remains unclear. Our previous study reported that starvation induces the release of ENDOG from mitochondria to the cytoplasm, promoting macroautophagy/autophagy in a process conserved across species. We demonstrate that ENDOG can be phosphorylated by GSK3B, which enhances ENDOG binding to YWHAG/14-3-3γ, and leads to the release of TSC2 and PIK3C3/VPS34 from YWHAG/14-3-3γ, followed by MTORC1 pathway suppression and autophagy initiation. Additionally, we recently reported that ENDOG can also activate the MTORC2-AKT-ACLY signaling axis by promoting the release of RICTOR and TSC2 from YWHAG/14-3-3γ, resulting in acetyl-CoA production. Furthermore, cytoplasmic ENDOG can translocate to the endoplasmic reticulum, where it binds with HSPA5/BIP to release ERN1/IRE1a-EIF2AK3/PERK to activate the endoplasmic reticulum stress response, eventually promoting lipid synthesis. Collectively, ENDOG will be released from the mitochondrial intermembrane space, and translocated to the mitochondrial matrix, cytoplasm, and nucleus during different stress stimulation, where it digests DNA or interacts with crucial proteins to regulate different biological functions, including apoptosis, autophagy, mitophagy, and lipid synthesis.
    Keywords:  Autophagy; ENDOG; MTORC1; MTORC2; endoplasmic reticulum
    DOI:  https://doi.org/10.1080/15548627.2023.2271750
  10. Nat Chem Biol. 2023 Oct 26.
    A genetically encoded tool to increase cellular NADH/NAD+ ratio in living cells.
    Xingxiu Pan, Mina L Heacock, Evana N Abdulaziz, Sara Violante, Austin L Zuckerman, Nirajan Shrestha, Canglin Yao, Russell P Goodman, Justin R Cross, Valentin Cracan.
      Impaired redox metabolism is a key contributor to the etiology of many diseases, including primary mitochondrial disorders, cancer, neurodegeneration and aging. However, mechanistic studies of redox imbalance remain challenging due to limited strategies that can perturb redox metabolism in various cellular or organismal backgrounds. Most studies involving impaired redox metabolism have focused on oxidative stress; consequently, less is known about the settings where there is an overabundance of NADH reducing equivalents, termed reductive stress. Here we introduce a soluble transhydrogenase from Escherichia coli (EcSTH) as a novel genetically encoded tool to promote reductive stress in living cells. When expressed in mammalian cells, EcSTH, and a mitochondrially targeted version (mitoEcSTH), robustly elevated the NADH/NAD+ ratio in a compartment-specific manner. Using this tool, we determined that metabolic and transcriptomic signatures of the NADH reductive stress are cellular background specific. Collectively, our novel genetically encoded tool represents an orthogonal strategy to promote reductive stress.
    DOI:  https://doi.org/10.1038/s41589-023-01460-w
  11. Cell Death Discov. 2023 Oct 25. 9(1): 396
    ZNF281 inhibits mitochondrial biogenesis to facilitate metastasis of hepatocellular carcinoma.
    Qingfang Zhao, Chenguang Zhang, Xialu Zhang, Shanshan Wang, Ting Guo, Yuzhe Yin, Hui Zhang, Zhuo Li, Yang Si, Yabin Lu, Shan Cheng, Wei Ding.
      Zinc finger protein 281 (ZNF281) has been shown to promote tumor progression. However, the underlying mechanism remains to be further elucidated. In this study, ZNF281 knockdown increased the expression of mitochondrial transcription factor A (TFAM) in hepatocellular carcinoma (HCC) cells, accompanied with increment of mitochondrial content, oxygen consumption rate (OCR) and levels of TCA cycle intermetabolites. Mechanistic investigation revealed that ZNF281 suppressed the transcription of TFAM, nuclear respiratory factor 1 (NRF1) and peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α). Furthermore, ZNF281 interacted with NRF1 and PGC-1α, and was recruited onto the promoter regions of TFAM, TFB1M and TFB2M repressing their expression. Knockdown of TFAM reversed ZNF281 depletion induced up-regulation of mitochondrial biogenesis and function, as well as impaired epithelial mesenchymal transition, invasion and metastasis of HCC cells. Our research uncovered a novel suppressive function of ZNF281 on mitochondrial biogenesis through inhibition of the NRF1/PGC-1α-TFAM axis, which may hold therapeutic potentials for HCC.
    DOI:  https://doi.org/10.1038/s41420-023-01691-9
  12. bioRxiv. 2023 Oct 04. pii: 2023.10.03.560745. [Epub ahead of print]
    A DRP-like pseudoenzyme coordinates with MICOS to promote cristae architecture.
    Abhishek Kumar, Mehmet Oguz Gok, Kailey N Nguyen, Michael L Reese, Jeremy G Wideman, Sergio A Muñoz-Gómez, Jonathan R Friedman.
      Mitochondrial cristae architecture is crucial for optimal respiratory function of the organelle. Cristae shape is maintained in part by the mitochondrial inner membrane-localized MICOS complex. While MICOS is required for normal cristae morphology, the precise mechanistic role of each of the seven human MICOS subunits, and how the complex coordinates with other cristae shaping factors, has not been fully determined. Here, we examine the MICOS complex in Schizosaccharomyces pombe , a minimal model whose genome only encodes for four core subunits. Using an unbiased proteomics approach, we identify a poorly characterized inner mitochondrial membrane protein that interacts with MICOS and is required to maintain cristae morphology, which we name Mmc1. We demonstrate that Mmc1 works in concert with MICOS complexes to promote normal mitochondrial morphology and respiratory function. Bioinformatic analyses reveal that Mmc1 is a distant relative of the Dynamin-Related Protein (DRP) family of GTPases, which are well established to shape and remodel membranes. We find that, like DRPs, Mmc1 self-associates and forms high molecular weight assemblies. Interestingly, however, Mmc1 is a pseudoenzyme that lacks key residues required for GTP binding and hydrolysis, suggesting it does not dynamically remodel membranes. These data are consistent with a model in which Mmc1 stabilizes cristae architecture by acting as a scaffold to support cristae ultrastructure on the matrix side of the inner membrane. Our study reveals a new class of proteins that evolved early in fungal phylogeny and is required for the maintenance of cristae architecture. This highlights the possibility that functionally analogous proteins work with MICOS to establish cristae morphology in metazoans.
    DOI:  https://doi.org/10.1101/2023.10.03.560745
  13. bioRxiv. 2023 Oct 04. pii: 2023.10.04.560945. [Epub ahead of print]
    OptoProfilin: A Single Component Biosensor of Applied Cellular Stress.
    Noah Mann, Jahiem Hill, Kenneth Wang, Robert M Hughes.
      The actin cytoskeleton is a biosensor of cellular stress and a potential prognosticator of human disease. In particular, aberrant cytoskeletal structures such as cofilin-actin rods and stress granules formed in response to energetic and oxidative stress are closely linked to neurodegenerative diseases such as Alzheimer's, Parkinson's, and ALS. Whether these cytoskeletal phenomena can be harnessed for the development of biosensors for cytoskeletal dysfunction and, by extension, neurodegenerative disease progression, remains an open question. In this work, we describe the design and development of an optogenetic iteration of profilin, an actin monomer binding protein with critical functions in cytoskeletal dynamics. We demonstrate that this optically activated profilin ('OptoProfilin') can act as an optically triggered biosensor of applied cellular stress in select immortalized cell lines. Notably, OptoProfilin is a single component biosensor, likely increasing its utility for experimentalists. While a large body of work closely links profilin activity with cellular stress and neurodegenerative disease, this, to our knowledge, is the first example of profilin as an optogenetic biosensor of stress-induced changes in the cytoskeleton.
    DOI:  https://doi.org/10.1101/2023.10.04.560945
This page is being maintained by Thomas Krichel. It was last updated on 2023‒10‒29 at 16:40.