bims-nenemi Biomed News
on Neuroinflammation, neurodegeneration and mitochondria
Issue of 2023‒01‒01
nine papers selected by
Marco Tigano
Thomas Jefferson University
  1. Mitochondrial genome recovery by ATFS-1 is essential for development after starvation.
  2. DNA-protein cross-links between abasic DNA damage and mitochondrial transcription factor A (TFAM).
  3. A ubiquitination cascade regulating the integrated stress response and survival in carcinomas.
  4. Embryonic stem cell extracellular vesicles reverse the senescence of retinal pigment epithelial cells by the p38MAPK pathway.
  5. Cell-free circulating mitochondrial DNA: An emerging biomarker for airborne particulate matter associated with cardiovascular diseases.
  6. A High Throughput Screen with a Clonogenic Endpoint to Identify Radiation Modulators of Cancer.
  7. The ARTS of p53-dependent mitochondrial apoptosis.
  8. Ultrasensitive Small-Molecule Fluorescent Thermometer Reveals Hot Mitochondria in Surgically Resected Human Tumors.
  9. Editorial: The relationship of neuroinflammation with aging and neurodegenerative diseases.
  1. Cell Rep. 2022 Dec 27. pii: S2211-1247(22)01771-5. [Epub ahead of print]41(13): 111875
    Mitochondrial genome recovery by ATFS-1 is essential for development after starvation.
    Nandhitha Uma Naresh, Sookyung Kim, Tomer Shpilka, Qiyuan Yang, Yunguang Du, Cole M Haynes.
      Nutrient availability regulates the C. elegans life cycle as well as mitochondrial physiology. Food deprivation significantly reduces mitochondrial genome (mtDNA) numbers and leads to aging-related phenotypes. Here we show that the bZIP (basic leucine zipper) protein ATFS-1, a mediator of the mitochondrial unfolded protein response (UPRmt), is required to promote growth and establish a functional germline after prolonged starvation. We find that recovery of mtDNA copy numbers and development after starvation requires mitochondrion-localized ATFS-1 but not its nuclear transcription activity. We also find that the insulin-like receptor DAF-2 functions upstream of ATFS-1 to modulate mtDNA content. We show that reducing DAF-2 activity represses ATFS-1 nuclear function while causing an increase in mtDNA content, partly mediated by mitochondrion-localized ATFS-1. Our data indicate the importance of the UPRmt in recovering mitochondrial mass and suggest that atfs-1-dependent mtDNA replication precedes mitochondrial network expansion after starvation.
    Keywords:  ATFS-1; C. elegans; CP: Metabolism; CP: Molecular biology; DAF-2; UPR; UPRmt; insulin receptor; mitochondria; mtDNA; starvation; stress response
    DOI:  https://doi.org/10.1016/j.celrep.2022.111875
  2. Nucleic Acids Res. 2022 Dec 30. pii: gkac1214. [Epub ahead of print]
    DNA-protein cross-links between abasic DNA damage and mitochondrial transcription factor A (TFAM).
    Wenyan Xu, Jin Tang, Linlin Zhao.
      In higher eukaryotic cells, mitochondria are essential organelles for energy production, metabolism, and signaling. Mitochondrial DNA (mtDNA) encodes 13 protein subunits for oxidative phosphorylation and a set of tRNAs and rRNAs. mtDNA damage, sourced from endogenous chemicals and environmental factors, contributes to mitochondrial genomic instability, which has been associated with various mitochondrial diseases. DNA-protein cross-links (DPCs) are deleterious DNA lesions that threaten genomic integrity. Although much has been learned about the formation and repair of DPCs in the nucleus, little is known about DPCs in mitochondria. Here, we present in vitro and in cellulo data to demonstrate the formation of DPCs between a prevalent abasic (AP) DNA lesion and a DNA-packaging protein, mitochondrial transcription factor A (TFAM). TFAM cleaves AP-DNA and forms DPCs and single-strand breaks (SSB). Lys residues of TFAM are critical for the formation of TFAM-DPC and a reactive 3'-phospho-α,β-unsaturated aldehyde (3'pUA) residue on SSB. The 3'pUA residue reacts with two Cys of TFAM and contributes to the stable TFAM-DPC formation. Glutathione reacts with 3'pUA and competes with TFAM-DPC formation, corroborating our cellular experiments showing the accumulation of TFAM-DPCs under limiting glutathione. Our data point to the involvement of TFAM in AP-DNA turnover and fill a knowledge gap regarding the protein factors in processing damaged mtDNA.
    DOI:  https://doi.org/10.1093/nar/gkac1214
  3. Cancer Discov. 2022 Dec 28. pii: CD-22-1230. [Epub ahead of print]
    A ubiquitination cascade regulating the integrated stress response and survival in carcinomas.
    Lisa D Cervia, Tsukasa Shibue, Ashir A Borah, Benjamin Gaeta, Linh He, Lisa Leung, Naomi Li, Sydney M Moyer, Brian H Shim, Nancy Dumont, Alfredo Gonzalez, Nolan R Bick, Mariya Kazachkova, Joshua M Dempster, John Michael Krill-Burger, Federica Piccioni, Namrata D Udeshi, Meagan E Olive, Steven A Carr, David E Root, James M McFarland, Francisca Vazquez, William C Hahn.
      Systematic identification of signaling pathways required for the fitness of cancer cells will facilitate the development of new cancer therapies. We used gene essentiality measurements in 1,086 cancer cell lines to identify selective co-essentiality modules and found that a ubiquitin ligase complex composed of UBA6, BIRC6, KCMF1 and UBR4, which is required for the survival of a subset of epithelial tumors that exhibit a high degree of aneuploidy. Suppressing BIRC6 in cell lines that are dependent on this complex led to a substantial reduction in cell fitness in vitro and potent tumor regression in vivo. Mechanistically, BIRC6 suppression resulted in selective activation of the integrated stress response (ISR) by stabilization of the heme-regulated inhibitor (HRI), a direct ubiquitination target of the UBA6/BIRC6/KCMF1/UBR4 complex. These observations uncover a novel ubiquitination cascade that regulates ISR and highlight the potential of ISR activation as a new therapeutic strategy.
    DOI:  https://doi.org/10.1158/2159-8290.CD-22-1230
  4. Exp Eye Res. 2022 Dec 25. pii: S0014-4835(22)00446-8. [Epub ahead of print] 109365
    Embryonic stem cell extracellular vesicles reverse the senescence of retinal pigment epithelial cells by the p38MAPK pathway.
    Yurun Liu, Simin Gu, Yaru Su, Shoubi Wang, Yaqi Cheng, Xuan Sang, Lin Jin, Ying Liu, Chaoyang Li, Weiqin Liu, Minghao Chen, Xiaoran Wang, Zhichong Wang.
      Retinal pigment epithelial (RPE) cellular senescence is regarded as an initiator for age-related macular degeneration (AMD). We previously demonstrated that by the coculture way, embryonic stem cells (ESCs) can reverse the senescence of RPE cells, but xenograft cells can cause a plethora of adverse effects. Extracellular vesicles (EVs) derived from ESCs can act as messengers to mediate nearby cell activities and have the same potential as ESCs to reverse RPE senescence. Furthermore, ESC-EVs have achieved preliminary efficacy while treating many age-related diseases. The present study aimed to test the effect of ESC-EVs on the replicative senescence model of RPE cells as well as its mechanism. The results showed that ESC-EVs enhanced the proliferative ability and cell cycle transition of senescent RPE cells, whereas reduced the senescence-associated galactosidase (SA-β-gal) staining rate, as well as the levels of mitochondrial membrane potential (MMP) and reactive oxygen species (ROS). Moreover, classical markers of cellular senescence p21WAF1/CIP1 (p21) and p16INK4a (p16) were downregulated. The bioinformatic analysis and further study showed that the inhibition of the p38MAPK pathway by ESC-EVs played a pivotal role in RPE cellular senescence-reversing effect, which was ameliorated or even abolished when dehydrocorydaline were administrated simultaneously, demonstrating that ESC-EVs can effectively reverse RPE cellular senesence by inhibiting the p38MAPK pathway, thus highlights the potential of ESC-derived EVs as biomaterials for preventative and protective therapy in AMD.
    Keywords:  ESC; Extracellular vesicles; RPE; Senescence; p38MAPK
    DOI:  https://doi.org/10.1016/j.exer.2022.109365
  5. Free Radic Biol Med. 2022 Dec 28. pii: S0891-5849(22)01109-1. [Epub ahead of print]195 103-120
    Cell-free circulating mitochondrial DNA: An emerging biomarker for airborne particulate matter associated with cardiovascular diseases.
    Afreen Rehman, Roshani Kumari, Arunika Kamthan, Rajnarayan Tiwari, Rupesh Kumar Srivastava, Francois H van der Westhuizen, Pradyumna Kumar Mishra.
      The association of airborne particulate matter exposure with the deteriorating function of the cardiovascular system is fundamentally driven by the impairment of mitochondrial-nuclear crosstalk orchestrated by aberrant redox signaling. The loss of delicate balance in retrograde communication from mitochondria to the nucleus often culminates in the methylation of the newly synthesized strand of mitochondrial DNA (mtDNA) through DNA methyl transferases. In highly metabolic active tissues such as the heart, mtDNA's methylation state alteration impacts mitochondrial bioenergetics. It affects transcriptional regulatory processes involved in biogenesis, fission, and fusion, often accompanied by the integrated stress response. Previous studies have demonstrated a paradoxical role of mtDNA methylation in cardiovascular pathologies linked to air pollution. A pronounced alteration in mtDNA methylation contributes to systemic inflammation, an etiological determinant for several co-morbidities, including vascular endothelial dysfunction and myocardial injury. In the current article, we evaluate the state of evidence and examine the considerable promise of using cell-free circulating methylated mtDNA as a predictive biomarker to reduce the more significant burden of ambient air pollution on cardiovascular diseases.
    Keywords:  Environmental health; Mitochondria; Mitochondrial epigenetics; Oxidative stress; Translational research
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2022.12.083
  6. Radiat Res. 2022 Dec 29.
    A High Throughput Screen with a Clonogenic Endpoint to Identify Radiation Modulators of Cancer.
    Nathan P Gomes, Barbara Frederick, Jeremy R Jacobsen, Doug Chapnick, Tin Tin Su.
      Clonogenic assays evaluate the ability of single cells to proliferate and form colonies. This process approximates the regrowth and recurrence of tumors after treatment with radiation or chemotherapy, and thereby provides a drug discovery platform for compounds that block this process. However, because of their labor-intensive and cumbersome nature, adapting canonical clonogenic assays for high throughput screening (HTS) has been challenging. We overcame these barriers by developing an integrated system that automates cell- and liquid-handling, irradiation, dosimetry, drug administration, and incubation. Further, we developed a fluorescent live-cell based automated colony scoring methodology that identifies and counts colonies precisely based upon actual nuclei number rather than colony area, thereby eliminating errors in colony counts caused by radiation induced changes in colony morphology. We identified 13 cell lines from 7 cancer types, where radiation is a standard treatment module, that exhibit identical radiation and chemoradiation response regardless of well format and are amenable to miniaturization into small-well HTS formats. We performed pilot screens through a 1,584 compound NCI Diversity Set library using two cell lines representing different cancer indications. Radiation modulators identified in the pilot screens were validated in traditional clonogenic assays, providing proof-of-concept for the screen. The integrated methodology, hereafter "clonogenic HTS", exhibits excellent robustness (Z' values > 0.5) and shows high reproducibility (>95%). We propose that clonogenic HTS we developed can function as a drug discovery platform to identify compounds that inhibit tumor regrowth following radiation therapy, to identify new efficacious pair-wise combinations of known oncologic therapies, or to identify novel modulators of approved therapies.
    DOI:  https://doi.org/10.1667/RADE-22-00086.1
  7. J Mol Cell Biol. 2022 Dec 24. pii: mjac074. [Epub ahead of print]
    The ARTS of p53-dependent mitochondrial apoptosis.
    Qian Hao, Jiaxiang Chen, Hua Lu, Xiang Zhou.
      The tumor-suppressive activity of p53 is largely attributed to its ability to induce cell death, including apoptosis through transcription-dependent and -independent mechanisms. On the one hand, nuclear p53 transcriptionally activates the expression of a myriad of pro-apoptotic BCL-2 family genes, such as NOXA, PUMA, BID, BAD, BIK, BAX, etc., whereas inactivates the expression of anti-apoptotic BCL-2, BCL-XL, and MCL1, leading to mitochondrial apoptosis. On the other hand, cytoplasmic p53 also promotes mitochondrial apoptosis by directly associating with multiple BCL-2 family proteins in the mitochondria. Apoptosis-related protein in TGF-β signaling pathway (ARTS), a mitochondria-localized pro-apoptotic protein encoded by an alternative spliced variant of the SEPT4 gene, triggers apoptosis by facilitating proteasomal degradation of BCL-2 and XIAP upon pro-apoptotic stimuli. We recently identified SEPT4/ARTS as a new p53 target gene in response to genotoxic stress. ARTS in turn binds to p53, drives its mitochondrial localization, and enhances the interaction between p53 and BCL-XL, thereby promoting mitochondrial apoptosis. This review will illustrate the mechanisms of p53-induced mitochondrial apoptosis, offer some recently discovered new insights into the ARTS functions in regulating mitochondrial cell death, and discuss the clinical significance of ARTS in cancer and non-cancer diseases.
    Keywords:  ARTS; BCL-2 family; SEPT4; apoptosis; cancer therapy; p53
    DOI:  https://doi.org/10.1093/jmcb/mjac074
  8. ACS Sens. 2022 Dec 27.
    Ultrasensitive Small-Molecule Fluorescent Thermometer Reveals Hot Mitochondria in Surgically Resected Human Tumors.
    Qing Zhu, Yue Sun, Manlin Fu, Mianli Bian, Xiaomei Zhu, Kai Wang, Haoxing Geng, Wei Zeng, Wei Shen, Yi Hu.
      The Warburg effect suggests that upregulated glycolysis arising from high glucose uptake in cancer cells might be accompanied with suppressed mitochondrial respiration. However, recent studies have shown that the mitochondrial temperature in cancer cells could be relatively higher than that in normal cells, suggesting hyperactive mitochondrial respiration in cancer cells. However, hot mitochondria have not been reported in patients with cancer. Here, near-infrared small-molecule fluorescent probes TRNs are rationally designed with two ethyl amino groups as the temperature-sensitive moiety. Afterward, a mitochondrial targeting group is installed via ether bonds on TRN-8 to build MTN. To the best of our knowledge, MTN is the near-infrared probe with the highest sensitivity for mitochondrial temperature. Moreover, it also displays high photostability, wide linearity, and high specificity. Using MTN, we can monitor the ups and downs of mitochondrial temperature in cancer cells upon the perturbations of mitochondrial respiration. Furthermore, we demonstrate that the mitochondrial temperature in surgically resected human tumors is relatively higher than that in paracancerous tissues. Our results indicate that relatively hot mitochondria may exist in tumors from patients. We envisage that our study provides critical evidence for revisiting the Warburg effect and cancer metabolism.
    Keywords:  NIR; diethyl amino group; mitochondria; temperature-sensitive probe; tumor
    DOI:  https://doi.org/10.1021/acssensors.2c01563
  9. Front Aging Neurosci. 2022 ;14 1102613
    Editorial: The relationship of neuroinflammation with aging and neurodegenerative diseases.
    Guohao Wang, Peng Yin, Wei Zhang, Celia Giulietta Fernandez, Xingshun Xu.
      
    Keywords:  C-reactive protein; NLRP3 inflammasome; neurodegenerative diseases; neuroinflammation; phosphatidylserine (PS)
    DOI:  https://doi.org/10.3389/fnagi.2022.1102613
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