bims-nenemi Biomed News
on Neuroinflammation, neurodegeneration and mitochondria
Issue of 2024–04–21
seven papers selected by
Marco Tigano, Thomas Jefferson University
  1. Uncovering the impact of UV radiation on mitochondria in dermal cells: a STED nanoscopy study.
  2. Nano-flow cytometry unveils mitochondrial permeability transition process and multi-pathway cell death induction for cancer therapy.
  3. Mitochondrial reactive oxygen species impact human fibroblast responses to protracted γ-ray exposures.
  4. Enhanced ROS Production in Mitochondria from Prematurely Aging mtDNA Mutator Mice.
  5. Progression of herpesvirus infection remodels mitochondrial organization and metabolism.
  6. Cross-link assisted spatial proteomics to map sub-organelle proteomes and membrane protein topologies.
  7. Nanopore Detection of METTL3-Dependent m6A-Modified mRNA Reveals a New Mechanism Regulating Cardiomyocyte Mitochondrial Metabolism.
  1. Sci Rep. 2024 04 15. 14(1): 8675
    Uncovering the impact of UV radiation on mitochondria in dermal cells: a STED nanoscopy study.
    Hyung Jun Kim, Seon-Pil Jin, Jooyoun Kang, So Hyeon Bae, Jung Bae Son, Jang-Hee Oh, Hyewon Youn, Seong Keun Kim, Keon Wook Kang, Jin Ho Chung.
      Mitochondria are essential organelles in cellular energy metabolism and other cellular functions. Mitochondrial dysfunction is closely linked to cellular damage and can potentially contribute to the aging process. The purpose of this study was to investigate the subcellular structure of mitochondria and their activities in various cellular environments using super-resolution stimulated emission depletion (STED) nanoscopy. We examined the morphological dispersion of mitochondria below the diffraction limit in sub-cultured human primary skin fibroblasts and mouse skin tissues. Confocal microscopy provides only the overall morphology of the mitochondrial membrane and an indiscerptible location of nucleoids within the diffraction limit. Conversely, super-resolution STED nanoscopy allowed us to resolve the nanoscale distribution of translocase clusters on the mitochondrial outer membrane and accurately quantify the number of nucleoids per cell in each sample. Comparable results were obtained by analyzing the translocase distribution in the mouse tissues. Furthermore, we precisely and quantitatively analyzed biomolecular distribution in nucleoids, such as the mitochondrial transcription factor A (TFAM), using STED nanoscopy. Our findings highlight the efficacy of super-resolution fluorescence imaging in quantifying aging-related changes on the mitochondrial sub-structure in cells and tissues.
    DOI:  https://doi.org/10.1038/s41598-024-55778-z
  2. Cell Death Discov. 2024 Apr 15. 10(1): 176
    Nano-flow cytometry unveils mitochondrial permeability transition process and multi-pathway cell death induction for cancer therapy.
    Liyun Su, Jingyi Xu, Cheng Lu, Kaimin Gao, Yunyun Hu, Chengfeng Xue, Xiaomei Yan.
      Mitochondrial permeability transition (mPT)-mediated mitochondrial dysfunction plays a pivotal role in various human diseases. However, the intricate details of its mechanisms and the sequence of events remain elusive, primarily due to the interference caused by Bax/Bak-induced mitochondrial outer membrane permeabilization (MOMP). To address these, we have developed a methodology that utilizes nano-flow cytometry (nFCM) to quantitatively analyze the opening of mitochondrial permeability transition pore (mPTP), dissipation of mitochondrial membrane potential ( Δ Ψm), release of cytochrome c (Cyt c), and other molecular alternations of isolated mitochondria in response to mPT induction at the single-mitochondrion level. It was identified that betulinic acid (BetA) and antimycin A can directly induce mitochondrial dysfunction through mPT-mediated mechanisms, while cisplatin and staurosporine cannot. In addition, the nFCM analysis also revealed that BetA primarily induces mPTP opening through a reduction in Bcl-2 and Bcl-xL protein levels, along with an elevation in ROS content. Employing dose and time-dependent strategies of BetA, for the first time, we experimentally verified the sequential occurrence of mPTP opening and Δ Ψm depolarization prior to the release of Cyt c during mPT-mediated mitochondrial dysfunction. Notably, our study uncovers a simultaneous release of cell-death-associated factors, including Cyt c, AIF, PNPT1, and mtDNA during mPT, implying the initiation of multiple cell death pathways. Intriguingly, BetA induces caspase-independent cell death, even in the absence of Bax/Bak, thereby overcoming drug resistance. The presented findings offer new insights into mPT-mediated mitochondrial dysfunction using nFCM, emphasizing the potential for targeting such dysfunction in innovative cancer therapies and interventions.
    DOI:  https://doi.org/10.1038/s41420-024-01947-y
  3. Int J Radiat Biol. 2024 Apr 17. 1-13
    Mitochondrial reactive oxygen species impact human fibroblast responses to protracted γ-ray exposures.
    Luke A Whitcomb, Xu Cao, Dilip Thomas, Claudia Wiese, Alissa S Pessin, Robert Zhang, Joseph C Wu, Michael M Weil, Adam J Chicco.
      Purpose: Continuous exposure to ionizing radiation at a low dose rate poses significant health risks to humans on deep space missions, prompting the need for mechanistic studies to identify countermeasures against its deleterious effects. Mitochondria are a major subcellular locus of radiogenic injury, and may trigger secondary cellular responses through the production of reactive oxygen species (mtROS) with broader biological implications. Methods and Materials: To determine the contribution of mtROS to radiation-induced cellular responses, we investigated the impacts of protracted γ-ray exposures (IR; 1.1 Gy delivered at 0.16 mGy/min continuously over 5 days) on mitochondrial function, gene expression, and the protein secretome of human HCA2-hTERT fibroblasts in the presence and absence of a mitochondria-specific antioxidant mitoTEMPO (MT; 5 µM). Results: IR increased fibroblast mitochondrial oxygen consumption (JO2) and H2O2 release rates (JH2O2) under energized conditions, which corresponded to higher protein expression of NADPH Oxidase (NOX) 1, NOX4, and nuclear DNA-encoded subunits of respiratory chain Complexes I and III, but depleted mtDNA transcripts encoding subunits of the same complexes. This was associated with activation of gene programs related to DNA repair, oxidative stress, and protein ubiquination, all of which were attenuated by MT treatment along with radiation-induced increases in JO2 and JH2O2. IR also increased secreted levels of interleukin-8 and Type I collagens, while decreasing Type VI collagens and enzymes that coordinate assembly and remodeling of the extracellular matrix. MT treatment attenuated many of these effects while augmenting others, revealing complex effects of mtROS in fibroblast responses to IR. Conclusion: These results implicate mtROS production in fibroblast responses to protracted radiation exposure, and suggest potentially protective effects of mitochondrial-targeted antioxidants against radiogenic tissue injury in vivo.
    Keywords:  Mitochondria; fibroblasts; oxidative stress; space radiation
    DOI:  https://doi.org/10.1080/09553002.2024.2338518
  4. Biochemistry (Mosc). 2024 Feb;89(2): 279-298
    Enhanced ROS Production in Mitochondria from Prematurely Aging mtDNA Mutator Mice.
    Irina G Shabalina, Daniel Edgar, Natalia Gibanova, Anastasia V Kalinovich, Natasa Petrovic, Mikhail Yu Vyssokikh, Barbara Cannon, Jan Nedergaard.
      An increase in mitochondrial DNA (mtDNA) mutations and an ensuing increase in mitochondrial reactive oxygen species (ROS) production have been suggested to be a cause of the aging process ("the mitochondrial hypothesis of aging"). In agreement with this, mtDNA-mutator mice accumulate a large amount of mtDNA mutations, giving rise to defective mitochondria and an accelerated aging phenotype. However, incongruously, the rates of ROS production in mtDNA mutator mitochondria have generally earlier been reported to be lower - not higher - than in wildtype, thus apparently invalidating the "mitochondrial hypothesis of aging". We have here re-examined ROS production rates in mtDNA-mutator mice mitochondria. Using traditional conditions for measuring ROS (succinate in the absence of rotenone), we indeed found lower ROS in the mtDNA-mutator mitochondria compared to wildtype. This ROS mainly results from reverse electron flow driven by the membrane potential, but the membrane potential reached in the isolated mtDNA-mutator mitochondria was 33 mV lower than that in wildtype mitochondria, due to the feedback inhibition of succinate oxidation by oxaloacetate, and to a lower oxidative capacity in the mtDNA-mutator mice, explaining the lower ROS production. In contrast, in normal forward electron flow systems (pyruvate (or glutamate) + malate or palmitoyl-CoA + carnitine), mitochondrial ROS production was higher in the mtDNA-mutator mitochondria. Particularly, even during active oxidative phosphorylation (as would be ongoing physiologically), higher ROS rates were seen in the mtDNA-mutator mitochondria than in wildtype. Thus, when examined under physiological conditions, mitochondrial ROS production rates are indeed increased in mtDNA-mutator mitochondria. While this does not prove the validity of the mitochondrial hypothesis of aging, it may no longer be said to be negated in this respect. This paper is dedicated to the memory of Professor Vladimir P. Skulachev.
    Keywords:  ROS production; aging; membrane potential; mtDNA mutator mice; oxidative phosphorylation; succinate
    DOI:  https://doi.org/10.1134/S0006297924020081
  5. PLoS Pathog. 2024 Apr 15. 20(4): e1011829
    Progression of herpesvirus infection remodels mitochondrial organization and metabolism.
    Simon Leclerc, Alka Gupta, Visa Ruokolainen, Jian-Hua Chen, Kari Kunnas, Axel A Ekman, Henri Niskanen, Ilya Belevich, Helena Vihinen, Paula Turkki, Ana J Perez-Berna, Sergey Kapishnikov, Elina Mäntylä, Maria Harkiolaki, Eric Dufour, Vesa Hytönen, Eva Pereiro, Tony McEnroe, Kenneth Fahy, Minna U Kaikkonen, Eija Jokitalo, Carolyn A Larabell, Venera Weinhardt, Salla Mattola, Vesa Aho, Maija Vihinen-Ranta.
      Viruses target mitochondria to promote their replication, and infection-induced stress during the progression of infection leads to the regulation of antiviral defenses and mitochondrial metabolism which are opposed by counteracting viral factors. The precise structural and functional changes that underlie how mitochondria react to the infection remain largely unclear. Here we show extensive transcriptional remodeling of protein-encoding host genes involved in the respiratory chain, apoptosis, and structural organization of mitochondria as herpes simplex virus type 1 lytic infection proceeds from early to late stages of infection. High-resolution microscopy and interaction analyses unveiled infection-induced emergence of rough, thin, and elongated mitochondria relocalized to the perinuclear area, a significant increase in the number and clustering of endoplasmic reticulum-mitochondria contact sites, and thickening and shortening of mitochondrial cristae. Finally, metabolic analyses demonstrated that reactivation of ATP production is accompanied by increased mitochondrial Ca2+ content and proton leakage as the infection proceeds. Overall, the significant structural and functional changes in the mitochondria triggered by the viral invasion are tightly connected to the progression of the virus infection.
    DOI:  https://doi.org/10.1371/journal.ppat.1011829
  6. Nat Commun. 2024 Apr 17. 15(1): 3290
    Cross-link assisted spatial proteomics to map sub-organelle proteomes and membrane protein topologies.
    Ying Zhu, Kerem Can Akkaya, Julia Ruta, Nanako Yokoyama, Cong Wang, Max Ruwolt, Diogo Borges Lima, Martin Lehmann, Fan Liu.
      The functions of cellular organelles and sub-compartments depend on their protein content, which can be characterized by spatial proteomics approaches. However, many spatial proteomics methods are limited in their ability to resolve organellar sub-compartments, profile multiple sub-compartments in parallel, and/or characterize membrane-associated proteomes. Here, we develop a cross-link assisted spatial proteomics (CLASP) strategy that addresses these shortcomings. Using human mitochondria as a model system, we show that CLASP can elucidate spatial proteomes of all mitochondrial sub-compartments and provide topological insight into the mitochondrial membrane proteome. Biochemical and imaging-based follow-up studies confirm that CLASP allows discovering mitochondria-associated proteins and revising previous protein sub-compartment localization and membrane topology data. We also validate the CLASP concept in synaptic vesicles, demonstrating its applicability to different sub-cellular compartments. This study extends the scope of cross-linking mass spectrometry beyond protein structure and interaction analysis towards spatial proteomics, and establishes a method for concomitant profiling of sub-organelle and membrane proteomes.
    DOI:  https://doi.org/10.1038/s41467-024-47569-x
  7. Circulation. 2024 Apr 16. 149(16): 1319-1322
    Nanopore Detection of METTL3-Dependent m6A-Modified mRNA Reveals a New Mechanism Regulating Cardiomyocyte Mitochondrial Metabolism.
    Charles P Rabolli, Isabel S Naarmann-de Vries, Catherine A Makarewich, Kedryn K Baskin, Christoph Dieterich, Federica Accornero.
      
    Keywords:  RNA, messenger; mitochondria; myocytes, cardiac; nanopores
    DOI:  https://doi.org/10.1161/CIRCULATIONAHA.123.066473
This page is being maintained by Thomas Krichel. It was last updated on 2024‒11‒22 at 4:24.