bims-mimbat Biomed News
on Mitochondrial metabolism in brown adipose tissue
Issue of 2022‒11‒06
fourteen papers selected by
José Carlos de Lima-Júnior
Washington University
  1. TMBIM5 is the Ca2+ /H+ antiporter of mammalian mitochondria.
  2. Parkin regulates adiposity by coordinating mitophagy with mitochondrial biogenesis in white adipocytes.
  3. Mitochondrial Fission Process 1 controls inner membrane integrity and protects against heart failure.
  4. Reversal of mitochondrial malate dehydrogenase 2 enables anaplerosis via redox rescue in respiration-deficient cells.
  5. Coupling-dependent metabolic ultradian rhythms in confluent cells.
  6. Two sensory neurons coordinate the systemic mitochondrial stress response via GPCR signaling in C. elegans.
  7. Blockage of PPARγ T166 phosphorylation enhances the inducibility of beige adipocytes and improves metabolic dysfunctions.
  8. Adipose tissue macrophages exert systemic metabolic control by manipulating local iron concentrations.
  9. The mitochondrial sodium/calcium exchanger NCLX (Slc8b1) in B lymphocytes.
  10. Calmodulin promotes a Ca2+ -dependent conformational change in the C-terminal regulatory domain of CaV1.2.
  11. New 'kids' on the voltage-gated proton channel block.
  12. Serum plays an important role in reprogramming the seasonal transcriptional profile of brown bear adipocytes.
  13. Inhibitory Kcnip2 neurons of the spinal dorsal horn control behavioral sensitivity to environmental cold.
  14. Spatiotemporally mapping temperature dynamics of lysosomes and mitochondria using cascade organelle-targeting upconversion nanoparticles.
  1. EMBO Rep. 2022 Nov 02. e54978
    TMBIM5 is the Ca2+ /H+ antiporter of mammalian mitochondria.
    Shane Austin, Ronald Mekis, Sami E M Mohammed, Mariafrancesca Scalise, Wen-An Wang, Michele Galluccio, Christina Pfeiffer, Tamara Borovec, Katja Parapatics, Dijana Vitko, Nora Dinhopl, Nicolas Demaurex, Keiryn L Bennett, Cesare Indiveri, Karin Nowikovsky.
      Mitochondrial Ca2+ ions are crucial regulators of bioenergetics and cell death pathways. Mitochondrial Ca2+ content and cytosolic Ca2+ homeostasis strictly depend on Ca2+ transporters. In recent decades, the major players responsible for mitochondrial Ca2+ uptake and release have been identified, except the mitochondrial Ca2+ /H+ exchanger (CHE). Originally identified as the mitochondrial K+ /H+ exchanger, LETM1 was also considered as a candidate for the mitochondrial CHE. Defining the mitochondrial interactome of LETM1, we identify TMBIM5/MICS1, the only mitochondrial member of the TMBIM family, and validate the physical interaction of TMBIM5 and LETM1. Cell-based and cell-free biochemical assays demonstrate the absence or greatly reduced Na+ -independent mitochondrial Ca2+ release in TMBIM5 knockout or pH-sensing site mutants, respectively, and pH-dependent Ca2+ transport by recombinant TMBIM5. Taken together, we demonstrate that TMBIM5, but not LETM1, is the long-sought mitochondrial CHE, involved in setting and regulating the mitochondrial proton gradient. This finding provides the final piece of the puzzle of mitochondrial Ca2+ transporters and opens the door to exploring its importance in health and disease, and to developing drugs modulating Ca2+ exchange.
    Keywords:  LETM1; TMBIM5 (MICS1); mitochondrial Ca2+-H+ exchanger; mitochondrial metabolism; permeability transition pore
    DOI:  https://doi.org/10.15252/embr.202254978
  2. Nat Commun. 2022 Nov 04. 13(1): 6661
    Parkin regulates adiposity by coordinating mitophagy with mitochondrial biogenesis in white adipocytes.
    Timothy M Moore, Lijing Cheng, Dane M Wolf, Jennifer Ngo, Mayuko Segawa, Xiaopeng Zhu, Alexander R Strumwasser, Yang Cao, Bethan L Clifford, Alice Ma, Philip Scumpia, Orian S Shirihai, Thomas Q de Aguiar Vallim, Markku Laakso, Aldons J Lusis, Andrea L Hevener, Zhenqi Zhou.
      Parkin, an E3 ubiquitin ligase, plays an essential role in mitochondrial quality control. However, the mechanisms by which Parkin connects mitochondrial homeostasis with cellular metabolism in adipose tissue remain unclear. Here, we demonstrate that Park2 gene (encodes Parkin) deletion specifically from adipose tissue protects mice against high-fat diet and aging-induced obesity. Despite a mild reduction in mitophagy, mitochondrial DNA content and mitochondrial function are increased in Park2 deficient white adipocytes. Moreover, Park2 gene deletion elevates mitochondrial biogenesis by increasing Pgc1α protein stability through mitochondrial superoxide-activated NAD(P)H quinone dehydrogenase 1 (Nqo1). Both in vitro and in vivo studies show that Nqo1 overexpression elevates Pgc1α protein level and mitochondrial DNA content and enhances mitochondrial activity in mouse and human adipocytes. Taken together, our findings indicate that Parkin regulates mitochondrial homeostasis by balancing mitophagy and Pgc1α-mediated mitochondrial biogenesis in white adipocytes, suggesting a potential therapeutic target in adipocytes to combat obesity and obesity-associated disorders.
    DOI:  https://doi.org/10.1038/s41467-022-34468-2
  3. Nat Commun. 2022 Nov 04. 13(1): 6634
    Mitochondrial Fission Process 1 controls inner membrane integrity and protects against heart failure.
    Erminia Donnarumma, Michael Kohlhaas, Elodie Vimont, Etienne Kornobis, Thibault Chaze, Quentin Giai Gianetto, Mariette Matondo, Maryse Moya-Nilges, Christoph Maack, Timothy Wai.
      Mitochondria are paramount to the metabolism and survival of cardiomyocytes. Here we show that Mitochondrial Fission Process 1 (MTFP1) is an inner mitochondrial membrane (IMM) protein that is dispensable for mitochondrial division yet essential for cardiac structure and function. Constitutive knockout of cardiomyocyte MTFP1 in mice resulted in a fatal, adult-onset dilated cardiomyopathy accompanied by extensive mitochondrial and cardiac remodeling during the transition to heart failure. Prior to the onset of disease, knockout cardiac mitochondria displayed specific IMM defects: futile proton leak dependent upon the adenine nucleotide translocase and an increased sensitivity to the opening of the mitochondrial permeability transition pore, with which MTFP1 physically and genetically interacts. Collectively, our data reveal new functions of MTFP1 in the control of bioenergetic efficiency and cell death sensitivity and define its importance in preventing pathogenic cardiac remodeling.
    DOI:  https://doi.org/10.1038/s41467-022-34316-3
  4. Mol Cell. 2022 Oct 31. pii: S1097-2765(22)00962-5. [Epub ahead of print]
    Reversal of mitochondrial malate dehydrogenase 2 enables anaplerosis via redox rescue in respiration-deficient cells.
    Patricia Altea-Manzano, Anke Vandekeere, Joy Edwards-Hicks, Mar Roldan, Emily Abraham, Xhordi Lleshi, Ania Naila Guerrieri, Domenica Berardi, Jimi Wills, Jair Marques Junior, Asimina Pantazi, Juan Carlos Acosta, Rosario M Sanchez-Martin, Sarah-Maria Fendt, Miguel Martin-Hernandez, Andrew J Finch.
      Inhibition of the electron transport chain (ETC) prevents the regeneration of mitochondrial NAD+, resulting in cessation of the oxidative tricarboxylic acid (TCA) cycle and a consequent dependence upon reductive carboxylation for aspartate synthesis. NAD+ regeneration alone in the cytosol can rescue the viability of ETC-deficient cells. Yet, how this occurs and whether transfer of oxidative equivalents to the mitochondrion is required remain unknown. Here, we show that inhibition of the ETC drives reversal of the mitochondrial aspartate transaminase (GOT2) as well as malate and succinate dehydrogenases (MDH2 and SDH) to transfer oxidative NAD+ equivalents into the mitochondrion. This supports the NAD+-dependent activity of the mitochondrial glutamate dehydrogenase (GDH) and thereby enables anaplerosis-the entry of glutamine-derived carbon into the TCA cycle and connected biosynthetic pathways. Thus, under impaired ETC function, the cytosolic redox state is communicated into the mitochondrion and acts as a rheostat to support GDH activity and cell viability.
    Keywords:  anaplerosis; cancer; cancer metabolism; metabolism; mitochondrion; redox; redox transfer; respiration
    DOI:  https://doi.org/10.1016/j.molcel.2022.10.005
  5. Proc Natl Acad Sci U S A. 2022 Nov 08. 119(45): e2211142119
    Coupling-dependent metabolic ultradian rhythms in confluent cells.
    Shuzhang Yang, Shin Yamazaki, Kimberly H Cox, Yi-Lin Huang, Evan W Miller, Joseph S Takahashi.
      Ultradian rhythms in metabolism and physiology have been described previously in mammals. However, the underlying mechanisms for these rhythms are still elusive. Here, we report the discovery of temperature-sensitive ultradian rhythms in mammalian fibroblasts that are independent of both the cell cycle and the circadian clock. The period in each culture is stable over time but varies in different cultures (ranging from 3 to 24 h). We show that transient, single-cell metabolic pulses are synchronized into stable ultradian rhythms across contacting cells in culture by gap junction-mediated coupling. Coordinated rhythms are also apparent for other metabolic and physiological measures, including plasma membrane potential (Δψp), intracellular glutamine, α-ketoglutarate, intracellular adenosine triphosphate (ATP), cytosolic pH, and intracellular calcium. Moreover, these ultradian rhythms require extracellular glutamine, several different ion channels, and the suppression of mitochondrial ATP synthase by α-ketoglutarate, which provides a key feedback mechanism. We hypothesize that cellular coupling and metabolic feedback can be used by cells to balance energy demands for survival.
    Keywords:  cellular metabolism; gap junctions; ion channels; membrane potential; ultradian rhythms
    DOI:  https://doi.org/10.1073/pnas.2211142119
  6. Dev Cell. 2022 Oct 25. pii: S1534-5807(22)00720-1. [Epub ahead of print]
    Two sensory neurons coordinate the systemic mitochondrial stress response via GPCR signaling in C. elegans.
    Yangli Liu, Jun Zhou, Ning Zhang, Xueying Wu, Qian Zhang, Wenfeng Zhang, Xinyu Li, Ye Tian.
      Mitochondrial perturbations within neurons communicate stress signals to peripheral tissues, coordinating organismal-wide mitochondrial homeostasis for optimal fitness. However, the neuronal control of the systemic stress regulation remains poorly understood. Here, we identified a G-protein-coupled receptor (GPCR), SRZ-75, that couples with Gαq signaling in a pair of chemosensory ADL neurons to drive the mitochondrial unfolded protein response (UPRmt) activation in the intestine via the release of neuropeptides in Caenorhabditis elegans. Constitutive activation of Gαq signaling in the ADL neurons is sufficient to induce the intestinal UPRmt, leading to increased stress resistance and metabolic adaptations. Ablation of ADL neurons attenuates the intestinal UPRmt activation in response to various forms of neuronal mitochondrial dysfunction. Thus, GPCR and its Gαq downstream signaling in two sensory neurons coordinate the systemic UPRmt activation, representing a previously uncharacterized, but potentially conserved, neuronal signaling for organismal-wide mitochondrial stress regulation.
    Keywords:  ADL chemosensory neurons; G-protein-coupled receptor; GPCR; Gαq signaling; SRZ-75; UPR(mt); cell-non-autonomous regulation; the mitochondrial unfolded protein response
    DOI:  https://doi.org/10.1016/j.devcel.2022.10.001
  7. Cell Death Differ. 2022 Nov 03.
    Blockage of PPARγ T166 phosphorylation enhances the inducibility of beige adipocytes and improves metabolic dysfunctions.
    Nanfei Yang, Yuxin Wang, Qiang Tian, Qiuping Wang, Yan Lu, Luchen Sun, Sijie Wang, Yuncheng Bei, Jianguo Ji, Hu Zhou, Wei Yang, Pengju Yao, Wenyuan Zhu, Lingyun Sun, Zhifeng Huang, Xiaokun Li, Pingping Shen.
      Beige adipocytes in mammalian white adipose tissue (WAT) can reinforce fat catabolism and energy expenditure. Promoting beige adipocyte biogenesis is a tantalizing tactic for combating obesity and its associated metabolic disorders. Here, we report that a previously unidentified phosphorylation pattern (Thr166) in the DNA-binding domain of PPARγ regulates the inducibility of beige adipocytes. This unique posttranslational modification (PTM) pattern influences allosteric communication between PPARγ and DNA or coactivators, which impedes the PPARγ-mediated transactivation of beige cell-related gene expression in WAT. The genetic mutation mimicking T166 phosphorylation (p-T166) hinders the inducibility of beige adipocytes. In contrast, genetic or chemical intervention in this PTM pattern favors beige cell formation. Moreover, inhibition of p-T166 attenuates metabolic dysfunction in obese mice. Our results uncover a mechanism involved in beige cell fate determination. Moreover, our discoveries provide a promising strategy for guiding the development of novel PPARγ agonists for the treatment of obesity and related metabolic disorders.
    DOI:  https://doi.org/10.1038/s41418-022-01077-x
  8. Nat Metab. 2022 Nov 03.
    Adipose tissue macrophages exert systemic metabolic control by manipulating local iron concentrations.
    Nolwenn Joffin, Christy M Gliniak, Jan-Bernd Funcke, Vivian A Paschoal, Clair Crewe, Shiuhwei Chen, Ruth Gordillo, Christine M Kusminski, Da Young Oh, Werner J Geldenhuys, Philipp E Scherer.
      Iron is essential to many fundamental biological processes, but its cellular compartmentalization and concentration must be tightly controlled. Although iron overload can contribute to obesity-associated metabolic deterioration, the subcellular localization and accumulation of iron in adipose tissue macrophages is largely unknown. Here, we show that macrophage mitochondrial iron levels control systemic metabolism in male mice by altering adipocyte iron concentrations. Using various transgenic mouse models to manipulate the macrophage mitochondrial matrix iron content in an inducible fashion, we demonstrate that lowering macrophage mitochondrial matrix iron increases numbers of M2-like macrophages in adipose tissue, lowers iron levels in adipocytes, attenuates inflammation and protects from high-fat-diet-induced metabolic deterioration. Conversely, elevating macrophage mitochondrial matrix iron increases M1-like macrophages and iron levels in adipocytes, exacerbates inflammation and worsens high-fat-diet-induced metabolic dysfunction. These phenotypes are robustly reproduced by transplantation of a small amount of fat from transgenic to wild-type mice. Taken together, we identify macrophage mitochondrial iron levels as a crucial determinant of systemic metabolic homeostasis in mice.
    DOI:  https://doi.org/10.1038/s42255-022-00664-z
  9. Cell Calcium. 2022 Oct 20. pii: S0143-4160(22)00140-3. [Epub ahead of print]108 102667
    The mitochondrial sodium/calcium exchanger NCLX (Slc8b1) in B lymphocytes.
    Scott M Emrich, Ryan E Yoast, Adam J Fike, Kristen N Bricker, Ping Xin, Xuexin Zhang, Ziaur S M Rahman, Mohamed Trebak.
      Antigen receptor stimulation triggers cytosolic Ca2+ signals, which activate transcriptional and metabolic programs critical for immune function. B-cell receptor (BCR) engagement causes rapid cytosolic Ca2+ rise through the ubiquitous store-operated calcium entry (SOCE) pathway. Slc8b1, which encodes the mitochondrial Na+/Ca2+ exchanger (NCLX), extrudes Ca2+ out of the mitochondria and maintains optimal SOCE activity. Inhibition of NCLX in DT40 and A20 B lymphocyte lines was recently shown to impair cytosolic Ca2+ transients in response to antigen-receptor stimulation, however the downstream functional consequences of this impairment remain unclear. Here, we generated Slc8b1 knockout A20 B-cell lines using CRISPR/Cas9 technology and B-cell specific Slc8b1 knockout mice. Surprisingly, while loss of Slc8b1 in B lymphocytes led to reduction in SOCE, it had a marginal effect on mitochondrial Ca2+ extrusion, suggesting that NCLX is not the major mitochondrial Ca2+ extrusion mechanism in B cells. Furthermore, endoplasmic reticulum (ER) Ca2+ content and rates of ER depletion and refilling remained unaltered in Slc8b1 knockout B cells. Slc8b1 deficiency increased mitochondrial production of oxidants, reduced mitochondrial bioenergetics and altered mitochondrial ultrastructure. B-cell specific Slc8b1 knockout mice showed reduced germinal center B cell responses following foreign antigen and pathogen driven immune responses. Our studies provide novel insights into the function of Slc8b1 in germinal center B cells and its contribution to B-cell signaling and effector function.
    Keywords:  B lymphocytes; Ca(2+) signaling; Germinal Center; Mitochondrial Ca(2+); NCLX; SOCE; Slc8b1
    DOI:  https://doi.org/10.1016/j.ceca.2022.102667
  10. FEBS Lett. 2022 Oct 30.
    Calmodulin promotes a Ca2+ -dependent conformational change in the C-terminal regulatory domain of CaV1.2.
    Deepak Kumar Yadav, David E Anderson, Johannes W Hell, James B Ames.
      Calmodulin (CaM) binds to the membrane-proximal cytosolic C-terminal domain of CaV 1.2 (residues 1520-1669, CT(1520-1669)) and causes Ca2+ -induced conformational changes that promote Ca2+ -dependent channel inactivation (CDI). We report biophysical studies that probe the structural interaction between CT(1520-1669) and CaM. The recombinantly expressed CT(1520-1669) is insoluble, but can be solubilized in the presence of Ca2+ -saturated CaM (Ca4 /CaM), but not in the presence of Ca2+ -free CaM (apoCaM). We show that half-calcified CaM (Ca2 /CaM12 ) forms a complex with CT(1520-1669) that is less soluble than CT(1520-1669) bound to Ca4 /CaM. The NMR spectrum of CT(1520-1669) reveals spectral differences caused by the binding of Ca2 /CaM12 versus Ca4 /CaM, suggesting that the binding of Ca2+ to the CaM N-lobe may induce a conformational change in CT(1520-1669).
    Keywords:  CaV1.2; CaV1.4; IQ-switch; NMR| L-type Ca2+ Channel; calmodulin
    DOI:  https://doi.org/10.1002/1873-3468.14529
  11. FEBS J. 2022 Oct 31.
    New 'kids' on the voltage-gated proton channel block.
    Éva Korpos, Ferenc Papp.
      So far one gene for Hv1 has been detected in studied species. The work presented by Chaves et al. in The FEBS Journal reported an 'Unexpected expansion of the voltage-gated proton channel family'. They searched for proton channel candidates and found three sequences in the genome of Aplysia californica (Ac), which were named AcHv1, AcHv2 and AcHv3. Based on electrophysiological experiments, AcHv1 and AcHv2 are voltage-gated channels. While AcHv1 behaves like Hv1 in other species, that is, it is voltage and pH-dependent, it can be inhibited by zinc and conducts protons outwardly, AcHv2 conducts protons inwards at symmetrical pH. AcHv3 constantly leaks protons, and its C-terminal part contains several cytoplasmic retention motifs. Through carefully designed and carried out electrophysiological experiments, Chaves et al. determined the biophysical parameters of all three proton channels, such as the voltage and the pH dependence, the threshold-voltage, the gating charge and the time constants of activation and inactivation. Comment on: https://doi.org/10.1111/febs.16617.
    Keywords:  Aplysia californica; Hv1; patch-clamp; voltage-gated proton channel
    DOI:  https://doi.org/10.1111/febs.16670
  12. iScience. 2022 Oct 21. 25(10): 105084
    Serum plays an important role in reprogramming the seasonal transcriptional profile of brown bear adipocytes.
    Michael W Saxton, Blair W Perry, Brandon D Evans Hutzenbiler, Shawn Trojahn, Alexia Gee, Anthony P Brown, Gennifer E Merrihew, Jea Park, Omar E Cornejo, Michael J MacCoss, Charles T Robbins, Heiko T Jansen, Joanna L Kelley.
      Understanding how metabolic reprogramming happens in cells will aid the progress in the treatment of a variety of metabolic disorders. Brown bears undergo seasonal shifts in insulin sensitivity, including reversible insulin resistance in hibernation. We performed RNA-sequencing on brown bear adipocytes and proteomics on serum to identify changes possibly responsible for reversible insulin resistance. We observed dramatic transcriptional changes, which depended on both the cell and serum season of origin. Despite large changes in adipocyte gene expression, only changes in eight circulating proteins were identified as related to the seasonal shifts in insulin sensitivity, including some that have not previously been associated with glucose homeostasis. The identified serum proteins may be sufficient for shifting hibernation adipocytes to an active-like state.
    Keywords:  Fur-bearing animal physiology; Proteomics; Transcriptomics
    DOI:  https://doi.org/10.1016/j.isci.2022.105084
  13. Neuron. 2022 Oct 26. pii: S0896-6273(22)00912-6. [Epub ahead of print]
    Inhibitory Kcnip2 neurons of the spinal dorsal horn control behavioral sensitivity to environmental cold.
    Gioele W Albisetti, Robert P Ganley, Francesca Pietrafesa, Karolina Werynska, Marília Magalhaes de Sousa, Rebecca Sipione, Louis Scheurer, Michael R Bösl, Pawel Pelczar, Hendrik Wildner, Hanns Ulrich Zeilhofer.
      Proper sensing of ambient temperature is of utmost importance for the survival of euthermic animals, including humans. While considerable progress has been made in our understanding of temperature sensors and transduction mechanisms, the higher-order neural circuits processing such information are still only incompletely understood. Using intersectional genetics in combination with circuit tracing and functional neuron manipulation, we identified Kcnip2-expressing inhibitory (Kcnip2GlyT2) interneurons of the mouse spinal dorsal horn as critical elements of a neural circuit that tunes sensitivity to cold. Diphtheria toxin-mediated ablation of these neurons increased cold sensitivity without affecting responses to other somatosensory modalities, while their chemogenetic activation reduced cold and also heat sensitivity. We also show that Kcnip2GlyT2 neurons become activated preferentially upon exposure to cold temperatures and subsequently inhibit spinal nociceptive output neurons that project to the lateral parabrachial nucleus. Our results thus identify a hitherto unknown spinal circuit that tunes cold sensitivity.
    Keywords:  circuit; cold; cold allodynia; cold analgesia; cooling; dre recombinase; interneuron; intersectional gene targeting; kcnip2; pain
    DOI:  https://doi.org/10.1016/j.neuron.2022.10.008
  14. Proc Natl Acad Sci U S A. 2022 Nov 08. 119(45): e2207402119
    Spatiotemporally mapping temperature dynamics of lysosomes and mitochondria using cascade organelle-targeting upconversion nanoparticles.
    Xiangjun Di, Dejiang Wang, Qian Peter Su, Yongtao Liu, Jiayan Liao, Mahnaz Maddahfar, Jiajia Zhou, Dayong Jin.
      The intracellular metabolism of organelles, like lysosomes and mitochondria, is highly coordinated spatiotemporally and functionally. The activities of lysosomal enzymes significantly rely on the cytoplasmic temperature, and heat is constantly released by mitochondria as the byproduct of adenosine triphosphate (ATP) generation during active metabolism. Here, we developed temperature-sensitive LysoDots and MitoDots to monitor the in situ thermal dynamics of lysosomes and mitochondria. The design is based on upconversion nanoparticles (UCNPs) with high-density surface modifications to achieve the exceptionally high sensitivity of 2.7% K-1 and low uncertainty of 0.8 K for nanothermometry to be used in living cells. We show the measurement is independent of the ion concentrations and pH values. With Ca2+ ion shock, the temperatures of both lysosomes and mitochondria increased by ∼2 to 4 °C. Intriguingly, with chloroquine (CQ) treatment, the lysosomal temperature was observed to decrease by up to ∼3 °C, while mitochondria remained relatively stable. Lastly, with oxidative phosphorylation inhibitor treatment, we observed an ∼3 to 7 °C temperature increase and a thermal transition from mitochondria to lysosomes. These observations indicate different metabolic pathways and thermal transitions between lysosomes and mitochondria inside HeLa cells. The nanothermometry probes provide a powerful tool for multimodality functional imaging of subcellular organelles and interactions with high spatial, temporal, and thermal dynamics resolutions.
    Keywords:  lysosome; mitochondria; nanothermometry; upconversion nanoparticles (UCNPs)
    DOI:  https://doi.org/10.1073/pnas.2207402119
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