bims-nenemi Biomed News
on Neuroinflammation, neurodegeneration and mitochondria
Issue of 2024–09–29
seven papers selected by
Marco Tigano, Thomas Jefferson University
  1. Macrophage NRF1 promotes mitochondrial protein turnover via the ubiquitin proteasome system to limit mitochondrial stress and inflammation.
  2. Junctophilin-2 is a double-stranded RNA-binding protein that regulates cardiomyocyte-autonomous innate immune response.
  3. Specific activation of the integrated stress response uncovers regulation of central carbon metabolism and lipid droplet biogenesis.
  4. Mitochondrial protein heterogeneity stems from the stochastic nature of co-translational protein targeting in cell senescence.
  5. The deubiquitinase Ubp3/Usp10 constrains glucose-mediated mitochondrial repression via phosphate budgeting.
  6. Subset-specific mitochondrial stress and DNA damage shape T cell responses to fever and inflammation.
  7. A transmitochondrial sodium gradient controls membrane potential in mammalian mitochondria.
  1. Cell Rep. 2024 Sep 25. pii: S2211-1247(24)01131-8. [Epub ahead of print]43(10): 114780
    Macrophage NRF1 promotes mitochondrial protein turnover via the ubiquitin proteasome system to limit mitochondrial stress and inflammation.
    Jiawei Yan, Xin Zhang, Huiying Wang, Xinglong Jia, Ruohong Wang, Shuangyang Wu, Zheng-Jiang Zhu, Minjia Tan, Tiffany Horng.
      Macrophage elaboration of inflammatory responses is dynamically regulated, shifting from acute induction to delayed suppression during the course of infection. Here, we show that such regulation of inflammation is modulated by dynamic shifts in metabolism. In macrophages exposed to the bacterial product lipopolysaccharide (LPS), an initial induction of protein biosynthesis is followed by compensatory induction of the transcription factor nuclear factor erythroid 2-like 1 (NRF1), leading to increased flux through the ubiquitin proteasome system (UPS). A major target of NRF1-mediated UPS flux is the mitochondrial proteome, and in the absence of NRF1, ubiquitinated mitochondrial proteins accumulate to trigger severe mitochondrial stress. Such mitochondrial stress engages the integrated stress response-ATF4 axis, which limits mitochondrial translation to attenuate mitochondrial stress but amplifies inflammatory responses to augment susceptibility to septic shock. Therefore, NRF1 mediates a dynamic regulation of mitochondrial proteostasis in inflammatory macrophages that contributes to curbing inflammatory responses.
    Keywords:  CP: Metabolism; CP: Molecular biology; NRF1; immunometabolism; inflammation; integrated stress response; macrophage; mitochondria; proteostasis
    DOI:  https://doi.org/10.1016/j.celrep.2024.114780
  2. Biochem Biophys Res Commun. 2024 Sep 20. pii: S0006-291X(24)01261-0. [Epub ahead of print]733 150725
    Junctophilin-2 is a double-stranded RNA-binding protein that regulates cardiomyocyte-autonomous innate immune response.
    Yun Shi, Seyedsaber Mirabdali, Stefan W Vetter, Ang Guo.
      Junctophilin-2 (JPH2) is traditionally recognized as a cardiomyocyte-enriched structural protein that anchors the junction between the plasma membrane and the endo/sarcoplasmic reticulum, facilitating excitation-induced cardiac contraction. In this study, we uncover a novel function of JPH2 as a double-stranded RNA (dsRNA)-binding protein, which forms complexes with dsRNA both in vitro and in cells. Stimulation by cytosolic dsRNA enhances the interaction of JPH2 with the dsRNA sensor MDA5. Notably, JPH2 inhibits MDA5's binding to its dsRNA ligand, likely by sequestering the dsRNA. Silencing JPH2 in cardiomyocytes increased the interaction between MDA5 and its dsRNA ligands, activated the MAVS/TBK1 signaling, and triggered spontaneous interferon-beta (IFNb1) production in the absence of foreign pathogen. Mouse hearts deficient in JPH2 exhibited upregulation of innate immune signaling cascade. Collectively, these findings identify JPH2 as a regulator of dsRNA sensing and highlight its role in suppressing the automatic activation of innate immune responses in cardiomyocytes, suggesting the cytosolic surface of the endo/sarcoplasmic reticulum as a hub for dsRNA sequestration.
    Keywords:  IFNb1; Innate immune; JPH2; MAVS; MDA5; RNA-Binding protein; dsRNA
    DOI:  https://doi.org/10.1016/j.bbrc.2024.150725
  3. Nat Commun. 2024 Sep 27. 15(1): 8301
    Specific activation of the integrated stress response uncovers regulation of central carbon metabolism and lipid droplet biogenesis.
    Katherine Labbé, Lauren LeBon, Bryan King, Ngoc Vu, Emily H Stoops, Nina Ly, Austin E Y T Lefebvre, Phillip Seitzer, Swathi Krishnan, Jin-Mi Heo, Bryson Bennett, Carmela Sidrauski.
      The integrated stress response (ISR) enables cells to cope with a variety of insults, but its specific contribution to downstream cellular outputs remains unclear. Using a synthetic tool, we selectively activate the ISR without co-activation of parallel pathways and define the resulting cellular state with multi-omics profiling. We identify time- and dose-dependent gene expression modules, with ATF4 driving only a small but sensitive subgroup that includes amino acid metabolic enzymes. This ATF4 response affects cellular bioenergetics, rerouting carbon utilization towards amino acid production and away from the tricarboxylic acid cycle and fatty acid synthesis. We also find an ATF4-independent reorganization of the lipidome that promotes DGAT-dependent triglyceride synthesis and accumulation of lipid droplets. While DGAT1 is the main driver of lipid droplet biogenesis, DGAT2 plays an essential role in buffering stress and maintaining cell survival. Together, we demonstrate the sufficiency of the ISR in promoting a previously unappreciated metabolic state.
    DOI:  https://doi.org/10.1038/s41467-024-52538-5
  4. Nat Commun. 2024 Sep 27. 15(1): 8274
    Mitochondrial protein heterogeneity stems from the stochastic nature of co-translational protein targeting in cell senescence.
    Abdul Haseeb Khan, Xuefang Gu, Rutvik J Patel, Prabha Chuphal, Matheus P Viana, Aidan I Brown, Brian M Zid, Tatsuhisa Tsuboi.
      A decline in mitochondrial function is a hallmark of aging and neurodegenerative diseases. It has been proposed that changes in mitochondrial morphology, including fragmentation of the tubular mitochondrial network, can lead to mitochondrial dysfunction, yet the mechanism of this loss of function is unclear. Most proteins contained within mitochondria are nuclear-encoded and must be properly targeted to the mitochondria. Here, we report that sustained mRNA localization and co-translational protein delivery leads to a heterogeneous protein distribution across fragmented mitochondria. We find that age-induced mitochondrial fragmentation drives a substantial increase in protein expression noise across fragments. Using a translational kinetic and molecular diffusion model, we find that protein expression noise is explained by the nature of stochastic compartmentalization and that co-translational protein delivery is the main contributor to increased heterogeneity. We observed that cells primarily reduce the variability in protein distribution by utilizing mitochondrial fission-fusion processes rather than relying on the mitophagy pathway. Furthermore, we are able to reduce the heterogeneity of the protein distribution by inhibiting co-translational protein targeting. This research lays the framework for a better understanding of the detrimental impact of mitochondrial fragmentation on the physiology of cells in aging and disease.
    DOI:  https://doi.org/10.1038/s41467-024-52183-y
  5. Elife. 2024 Sep 26. pii: RP90293. [Epub ahead of print]12
    The deubiquitinase Ubp3/Usp10 constrains glucose-mediated mitochondrial repression via phosphate budgeting.
    Vineeth Vengayil, Shreyas Niphadkar, Swagata Adhikary, Sriram Varahan, Sunil Laxman.
      Many cells in high glucose repress mitochondrial respiration, as observed in the Crabtree and Warburg effects. Our understanding of biochemical constraints for mitochondrial activation is limited. Using a Saccharomyces cerevisiae screen, we identified the conserved deubiquitinase Ubp3 (Usp10), as necessary for mitochondrial repression. Ubp3 mutants have increased mitochondrial activity despite abundant glucose, along with decreased glycolytic enzymes, and a rewired glucose metabolic network with increased trehalose production. Utilizing ∆ubp3 cells, along with orthogonal approaches, we establish that the high glycolytic flux in glucose continuously consumes free Pi. This restricts mitochondrial access to inorganic phosphate (Pi), and prevents mitochondrial activation. Contrastingly, rewired glucose metabolism with enhanced trehalose production and reduced GAPDH (as in ∆ubp3 cells) restores Pi. This collectively results in increased mitochondrial Pi and derepression, while restricting mitochondrial Pi transport prevents activation. We therefore suggest that glycolytic flux-dependent intracellular Pi budgeting is a key constraint for mitochondrial repression.
    Keywords:  GAPDH; S. cerevisiae; biochemistry; cancer biology; chemical biology; glycolysis; inorganic phosphate; metabolic flux; mitochondria; trehalose
    DOI:  https://doi.org/10.7554/eLife.90293
  6. Sci Immunol. 2024 Sep 20. 9(99): eadp3475
    Subset-specific mitochondrial stress and DNA damage shape T cell responses to fever and inflammation.
    Darren R Heintzman, Rachael C Sinard, Emilie L Fisher, Xiang Ye, Andrew R Patterson, Joel H Elasy, Kelsey Voss, Channing Chi, Ayaka Sugiura, Gabriel J Rodriguez-Garcia, Nowrin U Chowdhury, Emily N Arner, Evan S Krystoviak, Frank M Mason, Yasmine T Toudji, KayLee K Steiner, Wasay Khan, Lana M Olson, Angela L Jones, Hanna S Hong, Lindsay Bass, Katherine L Beier, Wentao Deng, Costas A Lyssiotis, Dawn C Newcomb, Alexander G Bick, W Kimryn Rathmell, John T Wilson, Jeffrey C Rathmell.
      Heat is a cardinal feature of inflammation, yet its impacts on immune cells remain uncertain. We show that moderate-grade fever temperatures (39°C) increased murine CD4 T cell metabolism, proliferation, and inflammatory effector activity while decreasing regulatory T cell suppressive capacity. However, heat-exposed T helper 1 (TH1) cells selectively developed mitochondrial stress and DNA damage that activated Trp53 and stimulator of interferon genes pathways. Although many TH1 cells subjected to such temperatures died, surviving TH1 cells exhibited increased mitochondrial mass and enhanced activity. Electron transport chain complex 1 (ETC1) was rapidly impaired under fever-range temperatures, a phenomenon that was specifically detrimental to TH1 cells. TH1 cells with elevated DNA damage and ETC1 signatures were also detected in human chronic inflammation. Thus, fever-relevant temperatures disrupt ETC1 to selectively drive apoptosis or adaptation of TH1 cells to maintain genomic integrity and enhance effector functions.
    DOI:  https://doi.org/10.1126/sciimmunol.adp3475
  7. Cell. 2024 Sep 17. pii: S0092-8674(24)00974-7. [Epub ahead of print]
    A transmitochondrial sodium gradient controls membrane potential in mammalian mitochondria.
    Pablo Hernansanz-Agustín, Carmen Morales-Vidal, Enrique Calvo, Paolo Natale, Yolanda Martí-Mateos, Sara Natalia Jaroszewicz, José Luis Cabrera-Alarcón, Rebeca Acín-Pérez, Iván López-Montero, Jesús Vázquez, José Antonio Enríquez.
      Eukaryotic cell function and survival rely on the use of a mitochondrial H+ electrochemical gradient (Δp), which is composed of an inner mitochondrial membrane (IMM) potential (ΔΨmt) and a pH gradient (ΔpH). So far, ΔΨmt has been assumed to be composed exclusively of H+. Here, using a rainbow of mitochondrial and nuclear genetic models, we have discovered that a Na+ gradient equates with the H+ gradient and controls half of ΔΨmt in coupled-respiring mammalian mitochondria. This parallelism is controlled by the activity of the long-sought Na+-specific Na+/H+ exchanger (mNHE), which we have identified as the P-module of complex I (CI). Deregulation of this mNHE function, without affecting the canonical enzymatic activity or the assembly of CI, occurs in Leber's hereditary optic neuropathy (LHON), which has profound consequences in ΔΨmt and mitochondrial Ca2+ homeostasis and explains the previously unknown molecular pathogenesis of this neurodegenerative disease.
    Keywords:  LHON; Na(+) gradient; complex I; mitochondrial Na(+)/H(+) antiporter; ΔΨmt
    DOI:  https://doi.org/10.1016/j.cell.2024.08.045
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