bims-nenemi Biomed News
on Neuroinflammation, neurodegeneration and mitochondria
Issue of 2022‒05‒22
nine papers selected by
Marco Tigano
Thomas Jefferson University

  1. Orphanet J Rare Dis. 2022 May 17. 17(1): 204
      BACKGROUND: Mitochondrial diseases represent one of the most common groups of genetic diseases. With a prevalence greater than 1 in 5000 adults, such diseases still lack effective treatment. Current therapies are purely palliative and, in most cases, insufficient. Novel approaches to compensate and, if possible, revert mitochondrial dysfunction must be developed.RESULTS: In this study, we tackled the issue using as a model fibroblasts from a patient bearing a mutation in the GFM1 gene, which is involved in mitochondrial protein synthesis. Mutant GFM1 fibroblasts could not survive in galactose restrictive medium for more than 3 days, making them the perfect screening platform to test several compounds. Tetracycline enabled mutant GFM1 fibroblasts survival under nutritional stress. Here we demonstrate that tetracycline upregulates the mitochondrial Unfolded Protein Response (UPRmt), a compensatory pathway regulating mitochondrial proteostasis. We additionally report that activation of UPRmt improves mutant GFM1 cellular bioenergetics and partially restores mitochondrial protein expression.
    CONCLUSIONS: Overall, we provide compelling evidence to propose the activation of intrinsic cellular compensatory mechanisms as promising therapeutic strategy for mitochondrial diseases.
    Keywords:  GFM1; Mitochondria; Tetracycline; UPRmt
  2. Nat Chem Biol. 2022 May 16.
      Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype with the worst prognosis and few effective therapies. Here we identified MS023, an inhibitor of type I protein arginine methyltransferases (PRMTs), which has antitumor growth activity in TNBC. Pathway analysis of TNBC cell lines indicates that the activation of interferon responses before and after MS023 treatment is a functional biomarker and determinant of response, and these observations extend to a panel of human-derived organoids. Inhibition of type I PRMT triggers an interferon response through the antiviral defense pathway with the induction of double-stranded RNA, which is derived, at least in part, from inverted repeat Alu elements. Together, our results represent a shift in understanding the antitumor mechanism of type I PRMT inhibitors and provide a rationale and biomarker approach for the clinical development of type I PRMT inhibitors.
  3. Oncogenesis. 2022 May 19. 11(1): 26
      Tumor suppressor p53 plays a central role in preventing tumorigenesis. Here, we unravel how p53 modulates mitochondrial dynamics to restrain the metastatic properties of cancer cells. p53 inhibits the mammalian target of rapamycin complex 1 (mTORC1) signaling to attenuate the protein level of mitochondrial fission process 1 (MTFP1), which fosters the pro-fission dynamin-related protein 1 (Drp1) phosphorylation. This regulatory mechanism allows p53 to restrict cell migration and invasion governed by Drp1-mediated mitochondrial fission. Downregulating p53 expression or elevating the molecular signature of mitochondrial fission correlates with aggressive tumor phenotypes and poor prognosis in cancer patients. Upon p53 loss, exaggerated mitochondrial fragmentation stimulates the activation of the extracellular signal-regulated kinase 1/2 (ERK1/2) signaling resulting in epithelial-to-mesenchymal transition (EMT)-like changes in cell morphology, accompanied by accelerated matrix metalloproteinase 9 (MMP9) expression and invasive cell migration. Notably, blocking the activation of mTORC1/MTFP1/Drp1/ERK1/2 axis completely abolishes the p53 deficiency-driven cellular morphological switch, MMP9 expression, and cancer cell dissemination. Our findings unveil a hitherto unrecognized mitochondria-dependent molecular mechanism underlying the metastatic phenotypes of p53-compromised cancers.
  4. Aging (Albany NY). 2022 05 16. 14(undefined):
      Inflammation plays a crucial role in the etiology and pathogenesis of AMD (Age-related Macular Degeneration). Humanin G (HNG) is a Mitochondrial Derived Peptide (MDP) that is cytoprotective in AMD and can protect against mitochondrial and cellular stress induced by damaged AMD mitochondria. The goal of this study was to test our hypothesis that inflammation-associated marker protein levels are increased in AMD and treatment with HNG leads to reduction in their protein levels. Humanin protein levels were measured in the plasma of AMD patients and normal subjects using ELISA assay. Humanin G was added to AMD and normal (control) cybrids which had identical nuclei from mitochondria-deficient ARPE-19 cells but differed in mitochondrial DNA (mtDNA) content derived from clinically characterized AMD patients and normal (control) subjects. Cell lysates were extracted from untreated and HNG-treated AMD and normal cybrids, and the Luminex XMAP multiplex assay was used to measure the levels of inflammatory proteins. AMD plasma showed reduced Humanin protein levels, but higher protein levels of inflammation markers compared to control plasma samples. In AMD RPE cybrid cells, Humanin G reduced the CD62E/ E-Selectin, CD62P/ P-Selectin, ICAM-1, TNF-α, MIP-1α, IFN-γ, IL-1β, IL-13, and IL-17A protein levels, thereby suggesting that Humanin G may rescue from mtDNA-mediated inflammation in AMD cybrids. In conclusion, we present novel findings that: A) show reduced Humanin protein levels in AMD plasma vs. normal plasma; B) suggest the role of inflammatory markers in AMD pathogenesis, and C) highlight the positive effects of Humanin G in reducing inflammation in AMD.
    Keywords:  AMD; HNG; Humanin G; age-related macular degeneration; inflammation
  5. Nucleic Acids Res. 2022 May 17. pii: gkac361. [Epub ahead of print]
      DDX58 encodes RIG-I, a cytosolic RNA sensor that ensures immune surveillance of nonself RNAs. Individuals with RIG-IE510V and RIG-IQ517H mutations have increased susceptibility to Singleton-Merten syndrome (SMS) defects, resulting in tissue-specific (mild) and classic (severe) phenotypes. The coupling between RNA recognition and conformational changes is central to RIG-I RNA proofreading, but the molecular determinants leading to dissociated disease phenotypes remain unknown. Herein, we employed hydrogen/deuterium exchange mass spectrometry (HDX-MS) and single molecule magnetic tweezers (MT) to precisely examine how subtle conformational changes in the helicase insertion domain (HEL2i) promote impaired ATPase and erroneous RNA proofreading activities. We showed that the mutations cause a loosened latch-gate engagement in apo RIG-I, which in turn gradually dampens its self RNA (Cap2 moiety:m7G cap and N1-2-2'-O-methylation RNA) proofreading ability, leading to increased immunopathy. These results reveal HEL2i as a unique checkpoint directing two specialized functions, i.e. stabilizing the CARD2-HEL2i interface and gating the helicase from incoming self RNAs; thus, these findings add new insights into the role of HEL2i in the control of antiviral innate immunity and autoimmunity diseases.
  6. Oxid Med Cell Longev. 2022 ;2022 7702681
      The M2 isoform of pyruvate kinase (PKM2) is one isoform of pyruvate kinase (PK). PKM2 is expressed at high levels during embryonic development and tumor progression and is subject to complex allosteric regulation. PKM2 is a special glycolytic enzyme that regulates the final step of glycolysis; the role of PKM2 in the metabolism, survival, and apoptosis of cancer cells has received increasing attention. Mitochondria are directly or indirectly involved in the regulation of energy metabolism, susceptibility to oxidative stress, and cell death; however, the role of PKM2 in mitochondrial functions remains unclear. Herein, we review the related mechanisms of the role of PKM2 in the regulation of mitochondrial functions from the aspects of metabolism, reactive oxygen species (ROS), dynamic, and apoptosis, which can be highlighted as a target for the clinical management of cardiovascular and metabolic diseases.
  7. Anal Chem. 2022 May 19.
      Mitochondrial DNA (mtDNA) as a class of important genetic material is easily damaged, which can result in a series of metabolic diseases, hereditary disease, and so on. mtDNA is an ultrasensitive indicator for the health of living cells due to the extremely short physiological response time of mtDNA toward damage (ca. 5.0 min). Therefore, the development of specific ultrasensitive fluorescent probes that can in real-time monitor mtDNA in vivo are of great value. With this research, we developed a near-infrared twisted intramolecular charge transfer (TICT) fluorescent probe YON. YON is a thread-like molecule with an A-π-D-π-A structure, based on the dicyanoisophorone fluorophore. The molecular design of YON enabled the specific binding with dsDNA (binding constant (K) = 8.5 × 105 M-1) within 1.3 min. And the appropriate water-oil amphiphilicity makes YON significantly accumulate in the mitochondria, enabling the specific binding to mtDNA. The fluorescence intensity at 640 nm of YON enhanced linearly with increasing concentrations of mtDNA. Dicyanoisophorone as the strong electron-withdrawing group that was introduced into both ends of the molecule resulted in YON being a classic quadrupole, so it could ultrasensitively detect trace mtDNA. The minimum detection limit was 71 ng/mL. Moreover, the large Stokes shift (λex = 435 nm, λem = 640 nm) makes YON suitable for "interference-free" imaging of mtDNA. Therefore, YON was used to monitor trace changes of mtDNA in living cells; more importantly, it could be used to evaluate the health of cells by monitoring microchanges of mtDNA, enabling the ultrasensitive evaluation of apoptosis.
  8. Bioengineered. 2022 May;13(5): 12462-12474
      Esophageal squamous cell carcinoma (ESCC) is a common type of malignant cancer. There is growing evidence suggesting that exosomes may participate in the cellular communication of tumor-associated fibroblasts (TAFs). However, the cisplatin resistance of TAF-derived exosomes to ESCC cells remains to be further studied. Exosomes were isolated from TAFs and characterized with Western blot and TEM assays. ESCC cell lines (TE-1 and KYSE-150) were incubated with TAFs-derived exosomes. To explore the biological function of TAF-derived exosomes in ESCC cell proliferation, apoptosis, and chemosensitivity, we conducted MTT assays and Flow Cytometry. The effects in vivo were also verified via Xenograft mice models. We found that TAFs-derived exosomes led to enhanced cell proliferation and reduced apoptosis of cells, accompanied by increased expression of RIG-I/IFN-β, and TAFs derived exosomes may affect the chemosensitivity to cisplatin via RIG-I/IFN-β signaling in ESCC. Taken together, ESCC cells could communicate with TAFs cells via TAFs-derived exosomes. Our findings might represent a novel mechanism involved in ESCC and may provide a potential biomarker for ESCC.
    Keywords:  ESCC cells; TAFs; chemosensitivity; cisplatin; exosomes
  9. J Immunol. 2022 May 15. 208(10): 2259-2266
      Embryonic stem cells (ESCs) represent a unique cell population in the blastocyst stage embryo. They have been intensively studied as a promising cell source for regenerative medicine. Recent studies have revealed that both human and mouse ESCs are deficient in expressing IFNs and have attenuated inflammatory responses. Apparently, the ability to express IFNs and respond to certain inflammatory cytokines is not "innate" to ESCs but rather is developmentally acquired by somatic cells during differentiation. Accumulating evidence supports a hypothesis that the attenuated innate immune response may serve as a protective mechanism allowing ESCs to avoid immunological cytotoxicity. This review describes our current understanding of the molecular basis that shapes the immune properties of ESCs. We highlight the recent findings on Dicer and dsRNA-activated protein kinase R as novel regulators of ESC fate and antiviral immunity and discuss how ESCs use alternative mechanisms to accommodate their stem cell properties.