bims-mimbat Biomed News
on Mitochondrial metabolism in brown adipose tissue
Issue of 2024–12–22
twelve papers selected by
José Carlos de Lima-Júnior, Washington University
  1. Role of cardiolipin in proton transmembrane flux and localization.
  2. Unveiling adipose populations linked to metabolic health in obesity.
  3. Mitochondrial respiration atlas reveals differential changes in mitochondrial function across sex and age.
  4. Subcellular NAD+ pools are interconnected and buffered by mitochondrial NAD.
  5. Mechanism of proton release during water oxidation in Photosystem II.
  6. How does mitochondrial Ca2+ change during ischemia and reperfusion? Implications for activation of the permeability transition pore.
  7. Regulation of SR and mitochondrial Ca2+ signaling by L-type Ca2+ channels and Na/Ca exchanger in hiPSC-CMs.
  8. Guardians of the cell: mitochondria as a rheostat for cellular NAD+ levels.
  9. Mapping mitochondrial aging.
  10. Metformin targets mitochondrial complex I to lower blood glucose levels.
  11. Why eating less slows ageing: this molecule is key.
  12. Heat acclimation induces hypothalamic temperature sensitivity that promotes heat tolerance.
  1. Biophys J. 2024 Dec 13. pii: S0006-3495(24)04076-1. [Epub ahead of print]
    Role of cardiolipin in proton transmembrane flux and localization.
    Sylvain Domitin, Nicolas Puff, Fanny Pilot-Storck, Laurent Tiret, Frederic Joubert.
      In eukaryotic cells, the phospholipid cardiolipin (CL) is a crucial component that influences the function and organization of the mitochondrial inner membrane. In this study, we examined its potential role in passive proton transmembrane flux using unilamellar vesicles composed of natural egg phosphatidylcholine (PC) alone or with the inclusion of 18 or 34 mol% CL. A membrane potential was induced by a potassium gradient, and oxonol VI dye was used to monitor membrane potential dissipation resulting from proton transmembrane efflux. Increasing the CL content led to a net increase in proton efflux, which was also dependent on the magnitude of the membrane potential. The same increase in proton efflux was measured in the presence of the equally negatively charged phosphatidylglycerol (PG), indicating that the charge of CL plays a more important role than its structure in this mechanism. When varying the proton membrane permeability (PH) using the protonophore CCCP, we observed that unlike PC liposomes, where a small amount of CCCP was sufficient to achieve maximum flux, a significantly larger amount of protonophore was required in the presence of CL. Conversely, increasing the buffer capacity increased proton flux, indicating that proton availability, rather than membrane permeability, may be the limiting factor for proton leak. Our findings demonstrated that a higher proton content associated with the membrane was correlated with an increasing leak in the presence of CL. Additionally, smaller liposome diameters appeared to favor proton leak. Taken together, our results suggest that the presence of negatively charged CL in a membrane traps protons and increases their leakage, potentially in a manner dependent on membrane curvature. We discuss possible mechanisms and implications of these findings for mitochondrial respiration function.
    DOI:  https://doi.org/10.1016/j.bpj.2024.12.015
  2. Cell Metab. 2024 Dec 11. pii: S1550-4131(24)00452-2. [Epub ahead of print]
    Unveiling adipose populations linked to metabolic health in obesity.
    Isabel Reinisch, Adhideb Ghosh, Falko Noé, Wenfei Sun, Hua Dong, Peter Leary, Arne Dietrich, Anne Hoffmann, Matthias Blüher, Christian Wolfrum.
      Precision medicine is still not considered as a standard of care in obesity treatment, despite a large heterogeneity in the metabolic phenotype of individuals with obesity. One of the strongest factors influencing the variability in metabolic disease risk is adipose tissue (AT) dysfunction; however, there is little understanding of the link between distinct cell populations, cell-type-specific transcriptional programs, and disease severity. Here, we generated a comprehensive cellular map of subcutaneous and visceral AT of individuals with metabolically healthy and unhealthy obesity. By combining single-nucleus RNA-sequencing data with bulk transcriptomics and clinical parameters, we identified that mesothelial cells, adipocytes, and adipocyte-progenitor cells exhibit the strongest correlation with metabolic disease. Furthermore, we uncovered cell-specific transcriptional programs, such as the transitioning of mesothelial cells to a mesenchymal phenotype, that are involved in uncoupling obesity from metabolic disease. Together, these findings provide valuable insights by revealing biological drivers of clinical endpoints.
    Keywords:  adipocytes; adipose tissue; insulin resistance; insulin sensitivity; mesothelial cells; metabolically healthy obesity; obesity; precision medicine; snRNA-seq; visceral adipose tissue
    DOI:  https://doi.org/10.1016/j.cmet.2024.11.006
  3. Elife. 2024 Dec 20. pii: RP96926. [Epub ahead of print]13
    Mitochondrial respiration atlas reveals differential changes in mitochondrial function across sex and age.
    Dylan C Sarver, Muzna Saqib, Fangluo Chen, G William Wong.
      Organ function declines with age, and large-scale transcriptomic analyses have highlighted differential aging trajectories across tissues. The mechanism underlying shared and organ-selective functional changes across the lifespan, however, still remains poorly understood. Given the central role of mitochondria in powering cellular processes needed to maintain tissue health, we therefore undertook a systematic assessment of respiratory activity across 33 different tissues in young (2.5 months) and old (20 months) mice of both sexes. Our high-resolution mitochondrial respiration atlas reveals: (1) within any group of mice, mitochondrial activity varies widely across tissues, with the highest values consistently seen in heart, brown fat, and kidney; (2) biological sex is a significant but minor contributor to mitochondrial respiration, and its contributions are tissue-specific, with major differences seen in the pancreas, stomach, and white adipose tissue; (3) age is a dominant factor affecting mitochondrial activity, especially across most brain regions, different fat depots, skeletal muscle groups, eyes, and different regions of the gastrointestinal tract; (4) age effects can be sex- and tissue-specific, with some of the largest effects seen in pancreas, heart, adipose tissue, and skeletal muscle; and (5) while aging alters the functional trajectories of mitochondria in a majority of tissues, some are remarkably resilient to age-induced changes. Altogether, our data provide the most comprehensive compendium of mitochondrial respiration and illuminate functional signatures of aging across diverse tissues and organ systems.
    Keywords:  aging; computational biology; mitochondria; mouse; respiration atlas; sex; systems biology
    DOI:  https://doi.org/10.7554/eLife.96926
  4. Nat Metab. 2024 Dec;6(12): 2319-2337
    Subcellular NAD+ pools are interconnected and buffered by mitochondrial NAD.
    Lena E Høyland, Magali R VanLinden, Marc Niere, Øyvind Strømland, Suraj Sharma, Jörn Dietze, Ingvill Tolås, Eva Lucena, Ersilia Bifulco, Lars J Sverkeli, Camila Cimadamore-Werthein, Hanan Ashrafi, Kjellfrid F Haukanes, Barbara van der Hoeven, Christian Dölle, Cédric Davidsen, Ina K N Pettersen, Karl J Tronstad, Svein A Mjøs, Faisal Hayat, Mikhail V Makarov, Marie E Migaud, Ines Heiland, Mathias Ziegler.
      The coenzyme NAD+ is consumed by signalling enzymes, including poly-ADP-ribosyltransferases (PARPs) and sirtuins. Ageing is associated with a decrease in cellular NAD+ levels, but how cells cope with persistently decreased NAD+ concentrations is unclear. Here, we show that subcellular NAD+ pools are interconnected, with mitochondria acting as a rheostat to maintain NAD+ levels upon excessive consumption. To evoke chronic, compartment-specific overconsumption of NAD+, we engineered cell lines stably expressing PARP activity in mitochondria, the cytosol, endoplasmic reticulum or peroxisomes, resulting in a decline of cellular NAD+ concentrations by up to 50%. Isotope-tracer flux measurements and mathematical modelling show that the lowered NAD+ concentration kinetically restricts NAD+ consumption to maintain a balance with the NAD+ biosynthesis rate, which remains unchanged. Chronic NAD+ deficiency is well tolerated unless mitochondria are directly targeted. Mitochondria maintain NAD+ by import through SLC25A51 and reversibly cleave NAD+ to nicotinamide mononucleotide and ATP when NMNAT3 is present. Thus, these organelles can maintain an additional, virtual NAD+ pool. Our results are consistent with a well-tolerated ageing-related NAD+ decline as long as the vulnerable mitochondrial pool is not directly affected.
    DOI:  https://doi.org/10.1038/s42255-024-01174-w
  5. Proc Natl Acad Sci U S A. 2024 Dec 24. 121(52): e2413396121
    Mechanism of proton release during water oxidation in Photosystem II.
    Friederike Allgöwer, Maximilian C Pöverlein, A William Rutherford, Ville R I Kaila.
      Photosystem II (PSII) catalyzes light-driven water oxidation that releases dioxygen into our atmosphere and provides the electrons needed for the synthesis of biomass. The catalysis occurs in the oxygen-evolving oxo-manganese-calcium (Mn4O5Ca) cluster that drives the oxidation and deprotonation of substrate water molecules leading to the O2 formation. However, despite recent advances, the mechanism of these reactions remains unclear and much debated. Here, we show that the light-driven Tyr161D1 (Yz) oxidation adjacent to the Mn4O5Ca cluster, decreases the barrier for proton transfer from the putative substrate water molecule (W3/Wx) to Glu310D2, accessible to the luminal bulk. By combining hybrid quantum/classical (QM/MM) free energy calculations with atomistic molecular dynamics simulations, we probe the energetics of the proton transfer along the Cl1 pathway. We demonstrate that the proton transfer occurs via water molecules and a cluster of conserved carboxylates, driven by redox-triggered electric fields directed along the pathway. Glu65D1 establishes a local molecular gate that controls the proton transfer to the luminal bulk, while Glu312D2 acts as a local proton storage site. The identified gating region could be important in preventing backflow of protons to the Mn4O5Ca cluster. The structural changes, derived here based on the dark-state PSII structure, strongly support recent time-resolved X-ray free electron laser data of the S3 → S4 transition (Bhowmick et al. Nature 617, 2023) and reveal the mechanistic basis underlying deprotonation of the substrate water molecules. Our findings provide insight into the water oxidation mechanism of PSII and show how the interplay between redox-triggered electric fields, ion-pairs, and hydration effects control proton transport reactions.
    Keywords:  bioenergetics; multiscale; photosynthesis; quantum/classical (QM/MM) simulations; water splitting
    DOI:  https://doi.org/10.1073/pnas.2413396121
  6. J Gen Physiol. 2025 Jan 06. pii: e202313520. [Epub ahead of print]157(1):
    How does mitochondrial Ca2+ change during ischemia and reperfusion? Implications for activation of the permeability transition pore.
    Elizabeth Murphy, David A Eisner.
      Cardiac ischemia followed by reperfusion results in cardiac cell death, which has been attributed to an increase of mitochondrial Ca2+ concentration, resulting in activation of the mitochondrial permeability transition pore (PTP). Evaluating this hypothesis requires understanding of the mechanisms responsible for control of mitochondrial Ca2+ in physiological conditions and how they are altered during both ischemia and reperfusion. Ca2+ influx is thought to occur through the mitochondrial Ca2+ uniporter (MCU). However, with deletion of the MCU, an increase in mitochondrial Ca2+ still occurs, suggesting an alternative Ca2+ influx mechanism during ischemia. There is less certainty about the mechanisms responsible for Ca2+ efflux, with contributions from both Ca2+/H+ exchange and a Na+-dependent Ca2+ efflux pathway. The molecular details of both mechanisms are not fully resolved. We discuss this and the contributions of both pathways to the accumulation of mitochondrial Ca2+ during ischemia and reperfusion. We further discuss the role of mitochondrial Ca2+ in activation of the PTP.
    DOI:  https://doi.org/10.1085/jgp.202313520
  7. Cell Calcium. 2024 Dec 12. pii: S0143-4160(24)00143-X. [Epub ahead of print]125 102985
    Regulation of SR and mitochondrial Ca2+ signaling by L-type Ca2+ channels and Na/Ca exchanger in hiPSC-CMs.
    Xiao-Hua Zhang, Martin Morad.
       RATIONALE & METHODS: While signaling of cardiac SR by surface membrane proteins (ICa & INCX) is well studied, the regulation of mitochondrial Ca2+ by plasmalemmal proteins remains less explored. Here we have examined the signaling of mitochondria and SR by surface-membrane calcium-transporting proteins, using genetically engineered targeted fluorescent probes, mito-GCamP6 and R-CEPIA1er.
    RESULTS: In voltage-clamped and TIRF-imaged cardiomyocytes, low Na+ induced SR Ca2+ release was suppressed by short pre-exposures to ∼100 nM FCCP, suggesting mitochondrial Ca2+ contribution to low Na+ triggered SR Ca2+release. Even though low Na+- or caffeine-triggered SR Ca2+ release activated global mitochondrial Ca2+ uptake, focal mitochondrial Ca2+ signals varied in kinetics and magnitude, showing uptake or release of calcium, depending on cellular location of mitochondria. In spontaneously pacing cells, sustained caffeine exposures depleted the SR Ca2+ content activating mitochondrial Ca2+ uptake followed by sustained mitochondrial pacing. Spontaneous hiPSCCMs pacing was strongly suppressed by L-type calcium channels blockers, but not by inhibiting SERCA2a by CPA.
    CONCLUSION: Spontaneous hiPSCCMs pacing is triggered by influx of calcium through L-type Ca2+ channel that gates the release of SR pools supplemented by NCX-mediated mitochondrial calcium contribution.
    Keywords:  Genetically targeted fluorescence probes; I(NCX) and I(Ca); Mitochondria Ca(2+) signaling; Sarcoplasmic reticulum; hiPSC—CMs
    DOI:  https://doi.org/10.1016/j.ceca.2024.102985
  8. Nat Metab. 2024 Dec;6(12): 2215-2217
    Guardians of the cell: mitochondria as a rheostat for cellular NAD+ levels.
    Fiona M Fitzpatrick, Nora Kory.
      
    DOI:  https://doi.org/10.1038/s42255-024-01160-2
  9. Elife. 2024 Dec 20. pii: e105191. [Epub ahead of print]13
    Mapping mitochondrial aging.
    Alessandro Bitto.
      Measuring mitochondrial respiration in frozen tissue samples provides the first comprehensive atlas of how aging affects mitochondrial function in mice.
    Keywords:  aging; cellular respiration; computational biology; mitochondria; mouse; respiration atlas; sex; systems biology
    DOI:  https://doi.org/10.7554/eLife.105191
  10. Sci Adv. 2024 Dec 20. 10(51): eads5466
    Metformin targets mitochondrial complex I to lower blood glucose levels.
    Colleen R Reczek, Ram P Chakrabarty, Karis B D'Alessandro, Zachary L Sebo, Rogan A Grant, Peng Gao, G R Budinger, Navdeep S Chandel.
      Metformin is among the most prescribed antidiabetic drugs, but the primary molecular mechanism by which metformin lowers blood glucose levels is unknown. Previous studies have proposed numerous mechanisms by which acute metformin lowers blood glucose, including the inhibition of mitochondrial complex I of the electron transport chain (ETC). Here, we used transgenic mice that globally express the Saccharomyces cerevisiae internal alternative NADH dehydrogenase (NDI1) protein to determine whether the glucose-lowering effect of acute oral administration of metformin requires inhibition of mitochondrial complex I of the ETC in vivo. NDI1 is a yeast NADH dehydrogenase enzyme that complements the loss of mammalian mitochondrial complex I electron transport function and is insensitive to pharmacologic mitochondrial complex I inhibitors including metformin. We demonstrate that NDI1 expression attenuates metformin's ability to lower blood glucose levels under standard chow and high-fat diet conditions. Our results indicate that acute oral administration of metformin targets mitochondrial complex I to lower blood glucose.
    DOI:  https://doi.org/10.1126/sciadv.ads5466
  11. Nature. 2024 Dec 18.
    Why eating less slows ageing: this molecule is key.
    Heidi Ledford.
      
    Keywords:  Ageing; Metabolism
    DOI:  https://doi.org/10.1038/d41586-024-04220-5
  12. Nat Neurosci. 2024 Dec 17.
    Heat acclimation induces hypothalamic temperature sensitivity that promotes heat tolerance.
      
    DOI:  https://doi.org/10.1038/s41593-024-01835-9
This page is being maintained by Thomas Krichel. It was last updated on 2024‒12‒22 at 20:51.