bims-nenemi Biomed News
on Neuroinflammation, neurodegeneration and mitochondria
Issue of 2024–08–18
fiveteen papers selected by
Marco Tigano, Thomas Jefferson University
  1. A spatial atlas of mitochondrial gene expression reveals dynamic translation hubs and remodeling in stress.
  2. Defective mitochondrial COX1 translation due to loss of COX14 function triggers ROS-induced inflammation in mouse liver.
  3. Heterogeneous brain region-specific responses to astrocytic mitochondrial DNA damage in mice.
  4. Structural basis of LRPPRC-SLIRP-dependent translation by the mitoribosome.
  5. OPA1 promotes ferroptosis by augmenting mitochondrial ROS and suppressing an integrated stress response.
  6. Mitochondrial-derived compartments remove surplus proteins from the outer mitochondrial membrane.
  7. Endocytosed dsRNAs induce lysosomal membrane permeabilization that allows cytosolic dsRNA translocation for Drosophila RNAi responses.
  8. Mitochondrial permeability transition dictates mitochondrial maturation upon switch in cellular identity of hematopoietic precursors.
  9. Mitochondrial-derived compartments are multilamellar domains that encase membrane cargo and cytosol.
  10. Mitochondrial complex I promotes kidney cancer metastasis.
  11. Mitochondrial network reorganization and transient expansion during oligodendrocyte generation.
  12. Mitoclone2: an R package for elucidating clonal structure in single-cell RNA-sequencing data using mitochondrial variants.
  13. Effects of isochlorogenic acid A on mitochondrial dynamics imbalance and RLR damage in PAM cells induced by combined mycotoxins.
  14. Type I interferon governs immunometabolic checkpoints that coordinate inflammation during Staphylococcal infection.
  15. Intracellular pH differentially regulates transcription of metabolic and signaling pathways in normal epithelial cells.
  1. bioRxiv. 2024 Aug 06. pii: 2024.08.05.604215. [Epub ahead of print]
    A spatial atlas of mitochondrial gene expression reveals dynamic translation hubs and remodeling in stress.
    Adam Begeman, John A Smolka, Ahmad Shami, Tejashree Pradip Waingankar, Samantha C Lewis.
      Mitochondrial genome expression is important for cellular bioenergetics. How mitochondrial RNA processing and translation are spatially organized across dynamic mitochondrial networks is not well understood. Here, we report that processed mitochondrial RNAs are consolidated with mitoribosome components into translation hubs distal to either nucleoids or processing granules in human cells. During stress, these hubs are remodeled into translationally repressed mesoscale bodies containing messenger, ribosomal, and double-stranded RNA. We show that the highly conserved helicase SUV3 contributes to the distribution of processed RNA within mitochondrial networks, and that stress bodies form downstream of proteostatic stress in cells lacking SUV3 unwinding activity. We propose that the spatial organization of nascent chain synthesis into discrete domains serves to throttle the flow of genetic information in stress to ensure mitochondrial quality control.
    DOI:  https://doi.org/10.1101/2024.08.05.604215
  2. Nat Commun. 2024 Aug 12. 15(1): 6914
    Defective mitochondrial COX1 translation due to loss of COX14 function triggers ROS-induced inflammation in mouse liver.
    Abhishek Aich, Angela Boshnakovska, Steffen Witte, Tanja Gall, Kerstin Unthan-Fechner, Roya Yousefi, Arpita Chowdhury, Drishan Dahal, Aditi Methi, Svenja Kaufmann, Ivan Silbern, Jan Prochazka, Zuzana Nichtova, Marcela Palkova, Miles Raishbrook, Gizela Koubkova, Radislav Sedlacek, Simon E Tröder, Branko Zevnik, Dietmar Riedel, Susann Michanski, Wiebke Möbius, Philipp Ströbel, Christian Lüchtenborg, Patrick Giavalisco, Henning Urlaub, Andre Fischer, Britta Brügger, Stefan Jakobs, Peter Rehling.
      Mitochondrial oxidative phosphorylation (OXPHOS) fuels cellular ATP demands. OXPHOS defects lead to severe human disorders with unexplained tissue specific pathologies. Mitochondrial gene expression is essential for OXPHOS biogenesis since core subunits of the complexes are mitochondrial-encoded. COX14 is required for translation of COX1, the central mitochondrial-encoded subunit of complex IV. Here we describe a COX14 mutant mouse corresponding to a patient with complex IV deficiency. COX14M19I mice display broad tissue-specific pathologies. A hallmark phenotype is severe liver inflammation linked to release of mitochondrial RNA into the cytosol sensed by RIG-1 pathway. We find that mitochondrial RNA release is triggered by increased reactive oxygen species production in the deficiency of complex IV. Additionally, we describe a COA3Y72C mouse, affected in an assembly factor that cooperates with COX14 in early COX1 biogenesis, which displays a similar yet milder inflammatory phenotype. Our study provides insight into a link between defective mitochondrial gene expression and tissue-specific inflammation.
    DOI:  https://doi.org/10.1038/s41467-024-51109-y
  3. Sci Rep. 2024 08 10. 14(1): 18586
    Heterogeneous brain region-specific responses to astrocytic mitochondrial DNA damage in mice.
    Daniela A Ayala, Anthony Matarazzo, Bonnie L Seaberg, Misha Patel, Eliana Tijerina, Camryn Matthews, Gabriel Bizi, Ashton Brown, Alan Ta, Mendell Rimer, Rahul Srinivasan.
      Astrocytes display context-specific diversity in their functions and respond to noxious stimuli between brain regions. Astrocytic mitochondria have emerged as key players in governing astrocytic functional heterogeneity, given their ability to dynamically adapt their morphology to regional demands on ATP generation and Ca2+ buffering functions. Although there is reciprocal regulation between mitochondrial dynamics and mitochondrial Ca2+ signaling in astrocytes, the extent of this regulation in astrocytes from different brain regions remains unexplored. Brain-wide, experimentally induced mitochondrial DNA (mtDNA) loss in astrocytes showed that mtDNA integrity is critical for astrocyte function, however, possible diverse responses to this noxious stimulus between brain areas were not reported in these experiments. To selectively damage mtDNA in astrocytes in a brain-region-specific manner, we developed a novel adeno-associated virus (AAV)-based tool, Mito-PstI expressing the restriction enzyme PstI, specifically in astrocytic mitochondria. Here, we applied Mito-PstI to two brain regions, the dorsolateral striatum and dentate gyrus, and we show that Mito-PstI induces astrocytic mtDNA loss in vivo, but with remarkable brain-region-dependent differences on mitochondrial dynamics, Ca2+ fluxes, and astrocytic and microglial reactivity. Thus, AAV-Mito-PstI is a novel tool to explore the relationship between astrocytic mitochondrial network dynamics and astrocytic mitochondrial Ca2+ signaling in a brain-region-selective manner.
    Keywords:  Astrocyte mitochondrial DNA; Calcium influx; Heterogenous; Hippocampus; Mitochondrial dynamics; Striatum
    DOI:  https://doi.org/10.1038/s41598-024-69499-w
  4. Nat Struct Mol Biol. 2024 Aug 12.
    Structural basis of LRPPRC-SLIRP-dependent translation by the mitoribosome.
    Vivek Singh, J Conor Moran, Yuzuru Itoh, Iliana C Soto, Flavia Fontanesi, Mary Couvillion, Martijn A Huynen, L Stirling Churchman, Antoni Barrientos, Alexey Amunts.
      In mammalian mitochondria, mRNAs are cotranscriptionally stabilized by the protein factor LRPPRC (leucine-rich pentatricopeptide repeat-containing protein). Here, we characterize LRPPRC as an mRNA delivery factor and report its cryo-electron microscopy structure in complex with SLIRP (SRA stem-loop-interacting RNA-binding protein), mRNA and the mitoribosome. The structure shows that LRPPRC associates with the mitoribosomal proteins mS39 and the N terminus of mS31 through recognition of the LRPPRC helical repeats. Together, the proteins form a corridor for handoff of the mRNA. The mRNA is directly bound to SLIRP, which also has a stabilizing function for LRPPRC. To delineate the effect of LRPPRC on individual mitochondrial transcripts, we used RNA sequencing, metabolic labeling and mitoribosome profiling, which showed a transcript-specific influence on mRNA translation efficiency, with cyclooxygenase 1 and 2 translation being the most affected. Our data suggest that LRPPRC-SLIRP acts in recruitment of mitochondrial mRNAs to modulate their translation. Collectively, the data define LRPPRC-SLIRP as a regulator of the mitochondrial gene expression system.
    DOI:  https://doi.org/10.1038/s41594-024-01365-9
  5. Mol Cell. 2024 Aug 09. pii: S1097-2765(24)00618-X. [Epub ahead of print]
    OPA1 promotes ferroptosis by augmenting mitochondrial ROS and suppressing an integrated stress response.
    Felix G Liang, Fereshteh Zandkarimi, Jaehoon Lee, Joshua L Axelrod, Ryan Pekson, Yisang Yoon, Brent R Stockwell, Richard N Kitsis.
      Ferroptosis, an iron-dependent form of nonapoptotic cell death mediated by lipid peroxidation, has been implicated in the pathogenesis of multiple diseases. Subcellular organelles play pivotal roles in the regulation of ferroptosis, but the mechanisms underlying the contributions of the mitochondria remain poorly defined. Optic atrophy 1 (OPA1) is a mitochondrial dynamin-like GTPase that controls mitochondrial morphogenesis, fusion, and energetics. Here, we report that human and mouse cells lacking OPA1 are markedly resistant to ferroptosis. Reconstitution with OPA1 mutants demonstrates that ferroptosis sensitization requires the GTPase activity but is independent of OPA1-mediated mitochondrial fusion. Mechanistically, OPA1 confers susceptibility to ferroptosis by maintaining mitochondrial homeostasis and function, which contributes both to the generation of mitochondrial lipid reactive oxygen species (ROS) and suppression of an ATF4-mediated integrated stress response. Together, these results identify an OPA1-controlled mitochondrial axis of ferroptosis regulation and provide mechanistic insights for therapeutically manipulating this form of cell death in diseases.
    Keywords:  ATF4; GPx4; OPA1; cell death; ferroptosis; integrated stress response; mitochondria; system X(c)(−); xCT
    DOI:  https://doi.org/10.1016/j.molcel.2024.07.020
  6. J Cell Biol. 2024 Nov 04. pii: e202307036. [Epub ahead of print]223(11):
    Mitochondrial-derived compartments remove surplus proteins from the outer mitochondrial membrane.
    Zachary N Wilson, Sai Sangeetha Balasubramaniam, Sara Wong, Max-Hinderk Schuler, Mitchell J Wopat, Adam L Hughes.
      The outer mitochondrial membrane (OMM) creates a boundary that imports most of the mitochondrial proteome while removing extraneous or damaged proteins. How the OMM senses aberrant proteins and remodels to maintain OMM integrity remains unresolved. Previously, we identified a mitochondrial remodeling mechanism called the mitochondrial-derived compartment (MDC) that removes a subset of the mitochondrial proteome. Here, we show that MDCs specifically sequester proteins localized only at the OMM, providing an explanation for how select mitochondrial proteins are incorporated into MDCs. Remarkably, selective sorting into MDCs also occurs within the OMM, as subunits of the translocase of the outer membrane (TOM) complex are excluded from MDCs unless assembly of the TOM complex is impaired. Considering that overloading the OMM with mitochondrial membrane proteins or mistargeted tail-anchored membrane proteins induces MDCs to form and sequester these proteins, we propose that one functional role of MDCs is to create an OMM-enriched trap that segregates and sequesters excess proteins from the mitochondrial surface.
    DOI:  https://doi.org/10.1083/jcb.202307036
  7. Nat Commun. 2024 Aug 14. 15(1): 6993
    Endocytosed dsRNAs induce lysosomal membrane permeabilization that allows cytosolic dsRNA translocation for Drosophila RNAi responses.
    Tsubasa Tanaka, Tamaki Yano, Shingo Usuki, Yoko Seo, Kento Mizuta, Maho Okaguchi, Maki Yamaguchi, Kazuko Hanyu-Nakamura, Noriko Toyama-Sorimachi, Katja Brückner, Akira Nakamura.
      RNA interference (RNAi) is a gene-silencing mechanism triggered by the cytosolic entry of double-stranded RNAs (dsRNAs). Many animal cells internalize extracellular dsRNAs via endocytosis for RNAi induction. However, it is not clear how the endocytosed dsRNAs are translocated into the cytosol across the endo/lysosomal membrane. Herein, we show that in Drosophila S2 cells, endocytosed dsRNAs induce lysosomal membrane permeabilization (LMP) that allows cytosolic dsRNA translocation. LMP mediated by dsRNAs requires the lysosomal Cl-/H+ antiporter ClC-b/DmOstm1. In clc-b or dmostm1 knockout S2 cells, extracellular dsRNAs are endocytosed and reach the lysosomes normally but fail to enter the cytosol. Pharmacological induction of LMP restores extracellular dsRNA-directed RNAi in clc-b or dmostm1-knockout cells. Furthermore, clc-b or dmostm1 mutant flies are defective in extracellular dsRNA-directed RNAi and its associated antiviral immunity. Therefore, endocytosed dsRNAs have an intrinsic ability to induce ClC-b/DmOstm1-dependent LMP that allows cytosolic dsRNA translocation for RNAi responses in Drosophila cells.
    DOI:  https://doi.org/10.1038/s41467-024-51343-4
  8. Commun Biol. 2024 Aug 09. 7(1): 967
    Mitochondrial permeability transition dictates mitochondrial maturation upon switch in cellular identity of hematopoietic precursors.
    Sandeep P Dumbali, Paulina D Horton, Travis I Moore, Pamela L Wenzel.
      The mitochondrial permeability transition pore (mPTP) is a supramolecular channel that regulates exchange of solutes across cristae membranes, with executive roles in mitochondrial function and cell death. The contribution of the mPTP to normal physiology remains debated, although evidence implicates the mPTP in mitochondrial inner membrane remodeling in differentiating progenitor cells. Here, we demonstrate that strict control over mPTP conductance shapes metabolic machinery as cells transit toward hematopoietic identity. Cells undergoing the endothelial-to-hematopoietic transition (EHT) tightly control chief regulatory elements of the mPTP. During EHT, maturing arterial endothelium restricts mPTP activity just prior to hematopoietic commitment. After transition in cellular identity, mPTP conductance is restored. In utero treatment with NIM811, a molecule that blocks sensitization of the mPTP to opening by Cyclophilin D (CypD), amplifies oxidative phosphorylation (OXPHOS) in hematopoietic precursors and increases hematopoiesis in the embryo. Additionally, differentiating pluripotent stem cells (PSCs) acquire greater organization of mitochondrial cristae and hematopoietic activity following knockdown of the CypD gene, Ppif. Conversely, knockdown of Opa1, a GTPase critical for proper cristae architecture, induces cristae irregularity and impairs hematopoiesis. These data elucidate a mechanism that regulates mitochondrial maturation in hematopoietic precursors and underscore a role for the mPTP in the acquisition of hematopoietic fate.
    DOI:  https://doi.org/10.1038/s42003-024-06671-y
  9. J Cell Biol. 2024 Nov 04. pii: e202307035. [Epub ahead of print]223(11):
    Mitochondrial-derived compartments are multilamellar domains that encase membrane cargo and cytosol.
    Zachary N Wilson, Matt West, Alyssa M English, Greg Odorizzi, Adam L Hughes.
      Preserving the health of the mitochondrial network is critical to cell viability and longevity. To do so, mitochondria employ several membrane remodeling mechanisms, including the formation of mitochondrial-derived vesicles (MDVs) and compartments (MDCs) to selectively remove portions of the organelle. In contrast to well-characterized MDVs, the distinguishing features of MDC formation and composition remain unclear. Here, we used electron tomography to observe that MDCs form as large, multilamellar domains that generate concentric spherical compartments emerging from mitochondrial tubules at ER-mitochondria contact sites. Time-lapse fluorescence microscopy of MDC biogenesis revealed that mitochondrial membrane extensions repeatedly elongate, coalesce, and invaginate to form these compartments that encase multiple layers of membrane. As such, MDCs strongly sequester portions of the outer mitochondrial membrane, securing membrane cargo into a protected domain, while also enclosing cytosolic material within the MDC lumen. Collectively, our results provide a model for MDC formation and describe key features that distinguish MDCs from other previously identified mitochondrial structures and cargo-sorting domains.
    DOI:  https://doi.org/10.1083/jcb.202307035
  10. Nature. 2024 Aug 14.
    Mitochondrial complex I promotes kidney cancer metastasis.
    Divya Bezwada, Luigi Perelli, Nicholas P Lesner, Ling Cai, Bailey Brooks, Zheng Wu, Hieu S Vu, Varun Sondhi, Daniel L Cassidy, Stacy Kasitinon, Sherwin Kelekar, Feng Cai, Arin B Aurora, McKenzie Patrick, Ashley Leach, Rashed Ghandour, Yuanyuan Zhang, Duyen Do, Phyllis McDaniel, Jessica Sudderth, Dennis Dumesnil, Sara House, Tracy Rosales, Alan M Poole, Yair Lotan, Solomon Woldu, Aditya Bagrodia, Xiaosong Meng, Jeffrey A Cadeddu, Prashant Mishra, Javier Garcia-Bermudez, Ivan Pedrosa, Payal Kapur, Kevin D Courtney, Craig R Malloy, Giannicola Genovese, Vitaly Margulis, Ralph J DeBerardinis.
      Most kidney cancers are metabolically dysfunctional1-4, but how this dysfunction affects cancer progression in humans is unknown. We infused 13C-labelled nutrients in over 80 patients with kidney cancer during surgical tumour resection. Labelling from [U-13C]glucose varies across subtypes, indicating that the kidney environment alone cannot account for all tumour metabolic reprogramming. Compared with the adjacent kidney, clear cell renal cell carcinomas (ccRCCs) display suppressed labelling of tricarboxylic acid (TCA) cycle intermediates in vivo and in ex vivo organotypic cultures, indicating that suppressed labelling is tissue intrinsic. [1,2-13C]acetate and [U-13C]glutamine infusions in patients, coupled with measurements of respiration in isolated human kidney and tumour mitochondria, reveal lower electron transport chain activity in ccRCCs that contributes to decreased oxidative and enhanced reductive TCA cycle labelling. However, ccRCC metastases unexpectedly have enhanced TCA cycle labelling compared with that of primary ccRCCs, indicating a divergent metabolic program during metastasis in patients. In mice, stimulating respiration or NADH recycling in kidney cancer cells is sufficient to promote metastasis, whereas inhibiting electron transport chain complex I decreases metastasis. These findings in humans and mice indicate that metabolic properties and liabilities evolve during kidney cancer progression, and that mitochondrial function is limiting for metastasis but not growth at the original site.
    DOI:  https://doi.org/10.1038/s41586-024-07812-3
  11. Nat Commun. 2024 Aug 14. 15(1): 6979
    Mitochondrial network reorganization and transient expansion during oligodendrocyte generation.
    Xhoela Bame, Robert A Hill.
      Oligodendrocyte precursor cells (OPCs) give rise to myelinating oligodendrocytes of the brain. This process persists throughout life and is essential for recovery from neurodegeneration. To better understand the cellular checkpoints that occur during oligodendrogenesis, we determined the mitochondrial distribution and morphometrics across the oligodendrocyte lineage in mouse and human cerebral cortex. During oligodendrocyte generation, mitochondrial content expands concurrently with a change in subcellular partitioning towards the distal processes. These changes are followed by an abrupt loss of mitochondria in the oligodendrocyte processes and myelin, coinciding with sheath compaction. This reorganization and extensive expansion and depletion take 3 days. Oligodendrocyte mitochondria are stationary over days while OPC mitochondrial motility is modulated by animal arousal state within minutes. Aged OPCs also display decreased mitochondrial size, volume fraction, and motility. Thus, mitochondrial dynamics are linked to oligodendrocyte generation, dynamically modified by their local microenvironment, and altered in the aging brain.
    DOI:  https://doi.org/10.1038/s41467-024-51016-2
  12. NAR Genom Bioinform. 2024 Sep;6(3): lqae095
    Mitoclone2: an R package for elucidating clonal structure in single-cell RNA-sequencing data using mitochondrial variants.
    Benjamin Story, Lars Velten, Gregor Mönke, Ahrmad Annan, Lars Steinmetz.
      Clonal cell population dynamics play a critical role in both disease and development. Due to high mitochondrial mutation rates under both healthy and diseased conditions, mitochondrial genomic variability is a particularly useful resource in facilitating the identification of clonal population structure. Here we present mitoClone2, an all-inclusive R package allowing for the identification of clonal populations through integration of mitochondrial heteroplasmic variants discovered from single-cell sequencing experiments. Our package streamlines the investigation of this phenomenon by providing: built-in compatibility with commonly used tools for the delineation of clonal structure, the ability to directly use multiplexed BAM files as input, annotations for both human and mouse mitochondrial genomes, and helper functions for calling, filtering, clustering, and visualizing variants.
    DOI:  https://doi.org/10.1093/nargab/lqae095
  13. Toxicology. 2024 Aug 11. pii: S0300-483X(24)00201-4. [Epub ahead of print]508 153920
    Effects of isochlorogenic acid A on mitochondrial dynamics imbalance and RLR damage in PAM cells induced by combined mycotoxins.
    Xinuo Lai, Peng Fan, Huidan Deng, Guilin Jia, Zhicai Zuo, Yanchun Hu, Ya Wang, Dongjie Cai, Liping Gou, Yiping Wen, Shumin Yu, Suizhong Cao, Liuhong Shen, Junliang Deng, Zhihua Ren.
      Mycotoxins have strong immunotoxicity and can induce oxidative stress and mitochondrial dynamics imbalance. Mitochondrial antiviral signaling protein (MAVS) in the RIG-I like receptor (RLR) pathway of innate immunity is located on mitochondria, and whether it is affected by mycotoxins has not been reported yet. This experiment used porcine alveolar macrophages (PAM) to evaluate the antagonism of three isomers of chlorogenic acid (chlorogenic acid, isochlorogenic acid A, and neochlorogenic acid) against combined mycotoxins (Aflatoxin B1, Deoxynivalenol, and Ochratoxin A) induced mitochondrial damage and their effects on the RLR pathway, providing assistance for further elucidating the mechanism of mycotoxin immunotoxicity. Western blotting, enzyme linked immunosorbent assay (ELISA), and flow cytometry were used to detect relevant indicators. All three types of chlorogenic acid treatment can antagonize the cytotoxicity induced by combined mycotoxins, especially isochlorogenic acid A, which can protect cells from mycotoxins damage by maintaining mitochondrial dynamic homeostasis and improving innate immune function related to the RLR pathway.
    Keywords:  Combined mycotoxins; Isochlorogenic acid A; Mitochondrial dynamics; RLR signaling pathway
    DOI:  https://doi.org/10.1016/j.tox.2024.153920
  14. Cell Rep. 2024 Aug 09. pii: S2211-1247(24)00957-4. [Epub ahead of print]43(8): 114607
    Type I interferon governs immunometabolic checkpoints that coordinate inflammation during Staphylococcal infection.
    Mack B Reynolds, Benjamin Klein, Michael J McFadden, Norah K Judge, Hannah E Navarrete, Britton C Michmerhuizen, Dominik Awad, Tracey L Schultz, Paul W Harms, Li Zhang, Teresa R O'Meara, Jonathan Z Sexton, Costas A Lyssiotis, J Michelle Kahlenberg, Mary X O'Riordan.
      Macrophage metabolic plasticity is central to inflammatory programming, yet mechanisms of coordinating metabolic and inflammatory programs during infection are poorly defined. Here, we show that type I interferon (IFN) temporally guides metabolic control of inflammation during methicillin-resistant Staphylococcus aureus (MRSA) infection. We find that staggered Toll-like receptor and type I IFN signaling in macrophages permit a transient energetic state of combined oxidative phosphorylation (OXPHOS) and aerobic glycolysis followed by inducible nitric oxide synthase (iNOS)-mediated OXPHOS disruption. This disruption promotes type I IFN, suppressing other pro-inflammatory cytokines, notably interleukin-1β. Upon infection, iNOS expression peaks at 24 h, followed by lactate-driven Nos2 repression via histone lactylation. Type I IFN pre-conditioning prolongs infection-induced iNOS expression, amplifying type I IFN. Cutaneous MRSA infection in mice constitutively expressing epidermal type I IFN results in elevated iNOS levels, impaired wound healing, vasculopathy, and lung infection. Thus, kinetically regulated type I IFN signaling coordinates immunometabolic checkpoints that control infection-induced inflammation.
    Keywords:  CP: Immunology; CP: Metabolism; Staphylococcus aureus; epigenetics; immunometabolism; inflammation; innate immunity; interferon; lactate; macrophage; nitric oxide; respiratory complex
    DOI:  https://doi.org/10.1016/j.celrep.2024.114607
  15. J Biol Chem. 2024 Aug 09. pii: S0021-9258(24)02159-8. [Epub ahead of print] 107658
    Intracellular pH differentially regulates transcription of metabolic and signaling pathways in normal epithelial cells.
    Ricardo Romero-Moreno, Brandon J Czowski, Lindsey Harris, Jessamine F Kuehn, Katharine A White.
      Intracellular pH (pHi) dynamics regulate normal cell function, and dysregulated pHi dynamics is an emerging hallmark of cancer (constitutively increased pHi) and neurodegeneration (constitutively decreased pHi). However, the molecular mechanisms by which pHi dynamics regulate cell biology are poorly understood. Here, we discovered that altering pHi in normal human breast epithelial cells triggers global transcriptional changes. We identified 176 genes differentially regulated by pHi, with pHi-dependent genes clustering in signaling and glycolytic pathways. Using various normal epithelial cell models, we showed pH-dependent Notch1 expression, with increased protein abundance at high pHi. This resulted in pH-dependent downstream signaling, with increased Notch1 signaling at high pHi. We also found that high pHi increased the expression of glycolytic enzymes and regulators of pyruvate fate, including lactate dehydrogenase and pyruvate dehydrogenase kinase. These transcriptional changes were sufficient to alter lactate production, with high pHi shifting these normal epithelial cells toward a glycolytic metabolism and increasing lactate production. Thus, pHi dynamics transcriptionally regulate signaling and metabolic pathways in normal epithelial cells. Our data reveal new molecular regulators of pHi-dependent biology and a role for increased pHi in driving the acquisition of cancer-associated signaling and metabolic changes in normal human epithelial cells.
    Keywords:  Intracellular pH; Notch1 signaling; glycolysis; lactate; metabolism; pyruvate
    DOI:  https://doi.org/10.1016/j.jbc.2024.107658
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