bims-mimbat Biomed News
on Mitochondrial metabolism in brown adipose tissue
Issue of 2023–01–15
thirteen papers selected by
José Carlos de Lima-Júnior, Washington University
  1. A critical assessment of the role of creatine in brown adipose tissue thermogenesis.
  2. Cryo-EM structures of mitochondrial respiratory complex I from Drosophila melanogaster.
  3. Multiscale molecular dynamics simulations predict arachidonic acid binding sites in human ASIC1a and ASIC3 transmembrane domains.
  4. Changes within the central stalk of E. coli F1Fo ATP synthase observed after addition of ATP.
  5. ER stress-associated transcription factor CREB3 is essential for normal Ca2+, ATP, and ROS homeostasis.
  6. Targeting succinate metabolism to decrease brain injury upon mechanical thrombectomy treatment of ischemic stroke.
  7. OxPhos defects cause hypermetabolism and reduce lifespan in cells and in patients with mitochondrial diseases.
  8. Inhibition of the proton-activated chloride channel PAC by PIP2.
  9. Individual response in body mass and basal metabolism to the risks of predation and starvation.
  10. Mitochondrial Ca2+ handling as a cell signaling hub: lessons from astrocyte function.
  11. Caveolin-2 in association with nuclear lamina controls adipocyte hypertrophy.
  12. Disruption of mitochondrial dynamics triggers muscle inflammation through interorganellar contacts and mitochondrial DNA mislocation.
  13. Bioenergetic State of Escherichia coli Controls Aminoglycoside Susceptibility.
  1. Nat Metab. 2023 Jan 09.
    A critical assessment of the role of creatine in brown adipose tissue thermogenesis.
    David G Nicholls, Martin D Brand.
      Brown adipose tissue is specialized for non-shivering thermogenesis, combining lipolysis with an extremely active mitochondrial electron transport chain and a unique regulated uncoupling protein, UCP1, allowing unrestricted respiration. Current excitement focuses on the presence of brown adipose tissue in humans and the possibility that it may contribute to diet-induced thermogenesis, countering obesity and obesity-related disease as well as protecting cardio-metabolic health. In common with other tissues displaying a high, variable respiration, the tissue possesses a creatine pool and mitochondrial and cytosolic creatine kinase isoforms. Genetic and pharmacological manipulation of these components have pleiotropic effects that appear to influence diet- and cold-induced metabolism in vivo and modeled in vitro. These findings have been used to advance the concept of a UCP1-independent diet-induced thermogenic mechanism based on a dissipative hydrolysis of phosphocreatine in beige and brown adipose tissue. Here we review the in vivo and in vitro experimental basis for this hypothesis, and explore alternative explanations. We conclude that there is currently no convincing evidence for a significant futile creatine cycle in these tissues.
    DOI:  https://doi.org/10.1038/s42255-022-00718-2
  2. Elife. 2023 Jan 09. pii: e84424. [Epub ahead of print]12
    Cryo-EM structures of mitochondrial respiratory complex I from Drosophila melanogaster.
    Ahmed-Noor A Agip, Injae Chung, Alvaro Sanchez-Martinez, Alexander J Whitworth, Judy Hirst.
      Respiratory complex I powers ATP synthesis by oxidative phosphorylation, exploiting the energy from NADH oxidation by ubiquinone to drive protons across an energy-transducing membrane. Drosophila melanogaster is a candidate model organism for complex I due to its high evolutionary conservation with the mammalian enzyme, well-developed genetic toolkit, and complex physiology for studies in specific cell types and tissues. Here, we isolate complex I from Drosophila and determine its structure, revealing a 43-subunit assembly with high structural homology to its 45-subunit mammalian counterpart, including a hitherto unknown homologue to subunit NDUFA3. The major conformational state of the Drosophila enzyme is the mammalian-type 'ready-to-go' active resting state, with a fully ordered and enclosed ubiquinone-binding site, but a subtly altered global conformation related to changes in subunit ND6. The mammalian-type 'deactive' pronounced resting state is not observed: in two minor states the ubiquinone-binding site is unchanged, but a deactive-type p-bulge is present in ND6-TMH3. Our detailed structural knowledge of Drosophila complex I provides a foundation for new approaches to disentangle mechanisms of complex I catalysis and regulation in bioenergetics and physiology.
    Keywords:  D. melanogaster; molecular biophysics; structural biology
    DOI:  https://doi.org/10.7554/eLife.84424
  3. J Gen Physiol. 2023 Mar 06. pii: e202213259. [Epub ahead of print]155(3):
    Multiscale molecular dynamics simulations predict arachidonic acid binding sites in human ASIC1a and ASIC3 transmembrane domains.
    Anna Ananchenko, Maria Musgaard.
      Acid-sensing ion channels (ASICs) play important roles in inflammatory pathways by conducting ions across the neuronal membrane in response to proton binding under acidic conditions. Recent studies have shown that ASICs can be modulated by arachidonic acid (AA), and, in the case of the ASIC3 subtype, even activated by AA at physiological pH. However, the mechanism by which these fatty acids act on the channel is still unknown. Here, we have used multiscale molecular dynamics simulations to predict a putative, general binding region of AA to models of the human ASIC protein. We have identified, in agreement with recent studies, residues in the outer leaflet transmembrane region which interact with AA. In addition, despite their similar modulation, we observe subtle differences in the AA interaction pattern between human ASIC1a and human ASIC3, which can be reversed by mutating three key residues at the outer leaflet portion of TM1. We further probed interactions with these residues in hASIC3 using atomistic simulations and identified possible AA coordinating interactions; salt bridge interactions of AA with R65hASIC3 and R68hASIC3 and AA tail interactions with the Y58hASIC3 aromatic ring. We have shown that longer fatty acid tails with more double bonds have increased relative occupancy in this region of the channel, a finding supported by recent functional studies. We further proposed that the modulatory effect of AA on ASIC does not result from changes in local membrane curvature. Rather, we speculate that it may occur through structural changes to the ion channel upon AA binding.
    DOI:  https://doi.org/10.1085/jgp.202213259
  4. Commun Biol. 2023 Jan 11. 6(1): 26
    Changes within the central stalk of E. coli F1Fo ATP synthase observed after addition of ATP.
    Meghna Sobti, Yi C Zeng, James L Walshe, Simon H J Brown, Robert Ishmukhametov, Alastair G Stewart.
      F1Fo ATP synthase functions as a biological generator and makes a major contribution to cellular energy production. Proton flow generates rotation in the Fo motor that is transferred to the F1 motor to catalyze ATP production, with flexible F1/Fo coupling required for efficient catalysis. F1Fo ATP synthase can also operate in reverse, hydrolyzing ATP and pumping protons, and in bacteria this function can be regulated by an inhibitory ε subunit. Here we present cryo-EM data showing E. coli F1Fo ATP synthase in different rotational and inhibited sub-states, observed following incubation with 10 mM MgATP. Our structures demonstrate how structural transitions within the inhibitory ε subunit induce torsional movement in the central stalk, thereby enabling its rotation within the Fο motor. This highlights the importance of the central rotor for flexible coupling of the F1 and Fo motors and provides further insight into the regulatory mechanism mediated by subunit ε.
    DOI:  https://doi.org/10.1038/s42003-023-04414-z
  5. Mitochondrion. 2023 Jan 07. pii: S1567-7249(23)00001-6. [Epub ahead of print]
    ER stress-associated transcription factor CREB3 is essential for normal Ca2+, ATP, and ROS homeostasis.
    Brandon S Smith, Tristen Hewitt, Marica Bakovic, Ray Lu.
      In mammalian cells, mitochondrial respiration produces reactive oxygen species (ROS) such as superoxide (O2-), which is then converted by the SOD1 enzyme into hydrogen peroxide (H2O2), the predominant form of cytosolic ROS. ROS at high levels can be toxic, but below this threshold are important for physiological processes acting as a second messenger similar to Ca2+. Mitochondrial Ca2+ influx from the ER increases ATP and ROS production, while ATP and ROS can regulate Ca2+ homeostasis, leading to an intricate interplay between Ca2+, ROS, and ATP synthesis. The Unfolded Protein Response (UPR) proteins ATF6α and XBP1 contribute to protection from oxidative stress through upregulation of Sod1 and Catalase genes. Here, UPR-associated protein CREB3 is shown to play a role in balancing Ca2+, ROS, and ATP homeostasis. Creb3-deficient mouse embryonic fibroblast cells (MEF-/-) were susceptible to H2O2-induced oxidative stress while having a functioning antioxidant gene expression response compared to MEF+/+. MEF-/- cells also contained elevated basal cytosolic ROS levels, which was attributed to drastically increased basal mitochondrial respiration and spare respiratory capacity relative to MEF+/+. MEF-/- cells also showed an increase in endoplasmic reticulum Ca2+ release and mitochondrial Ca2+ levels hinting at a potential cause for MEF-/- cell mitochondrial dysfunction. These results suggest that CREB3 is essential for maintaining proper Ca2+, ATP, and ROS homeostasis in mammalian cells.
    Keywords:  CREB3; Calcium; Cellular Respiration; Homeostasis; Mitochondria; Oxidative Stress; Reactive Oxygen Species
    DOI:  https://doi.org/10.1016/j.mito.2023.01.001
  6. Redox Biol. 2023 Feb;pii: S2213-2317(23)00001-0. [Epub ahead of print]59 102600
    Targeting succinate metabolism to decrease brain injury upon mechanical thrombectomy treatment of ischemic stroke.
    Amin Mottahedin, Hiran A Prag, Andreas Dannhorn, Richard Mair, Christina Schmidt, Ming Yang, Annabel Sorby-Adams, Jordan J Lee, Nils Burger, Duvaraka Kulaveerasingam, Margaret M Huang, Stefano Pluchino, Luca Peruzzotti-Jametti, Richard Goodwin, Christian Frezza, Michael P Murphy, Thomas Krieg.
      Current treatments for acute ischemic stroke aim to reinstate a normal perfusion in the ischemic territory but can also cause significant ischemia-reperfusion (IR) injury. Previous data in experimental models of stroke show that ischemia leads to the accumulation of succinate, and, upon reperfusion, the accumulated succinate is rapidly oxidized by succinate dehydrogenase (SDH) to drive superoxide production at mitochondrial complex I. Despite this process initiating IR injury and causing further tissue damage, the potential of targeting succinate metabolism to minimize IR injury remains unexplored. Using both quantitative and untargeted high-resolution metabolomics, we show a time-dependent accumulation of succinate in both human and mouse brain exposed to ischemia ex vivo. In a mouse model of ischemic stroke/mechanical thrombectomy mass spectrometry imaging (MSI) shows that succinate accumulation is confined to the ischemic region, and that the accumulated succinate is rapidly oxidized upon reperfusion. Targeting succinate oxidation by systemic infusion of the SDH inhibitor malonate upon reperfusion leads to a dose-dependent decrease in acute brain injury. Together these findings support targeting succinate metabolism upon reperfusion to decrease IR injury as a valuable adjunct to mechanical thrombectomy in ischemic stroke.
    DOI:  https://doi.org/10.1016/j.redox.2023.102600
  7. Commun Biol. 2023 Jan 12. 6(1): 22
    OxPhos defects cause hypermetabolism and reduce lifespan in cells and in patients with mitochondrial diseases.
    Gabriel Sturm, Kalpita R Karan, Anna S Monzel, Balaji Santhanam, Tanja Taivassalo, Céline Bris, Sarah A Ware, Marissa Cross, Atif Towheed, Albert Higgins-Chen, Meagan J McManus, Andres Cardenas, Jue Lin, Elissa S Epel, Shamima Rahman, John Vissing, Bruno Grassi, Morgan Levine, Steve Horvath, Ronald G Haller, Guy Lenaers, Douglas C Wallace, Marie-Pierre St-Onge, Saeed Tavazoie, Vincent Procaccio, Brett A Kaufman, Erin L Seifert, Michio Hirano, Martin Picard.
      Patients with primary mitochondrial oxidative phosphorylation (OxPhos) defects present with fatigue and multi-system disorders, are often lean, and die prematurely, but the mechanistic basis for this clinical picture remains unclear. By integrating data from 17 cohorts of patients with mitochondrial diseases (n = 690) we find evidence that these disorders increase resting energy expenditure, a state termed hypermetabolism. We examine this phenomenon longitudinally in patient-derived fibroblasts from multiple donors. Genetically or pharmacologically disrupting OxPhos approximately doubles cellular energy expenditure. This cell-autonomous state of hypermetabolism occurs despite near-normal OxPhos coupling efficiency, excluding uncoupling as a general mechanism. Instead, hypermetabolism is associated with mitochondrial DNA instability, activation of the integrated stress response (ISR), and increased extracellular secretion of age-related cytokines and metabokines including GDF15. In parallel, OxPhos defects accelerate telomere erosion and epigenetic aging per cell division, consistent with evidence that excess energy expenditure accelerates biological aging. To explore potential mechanisms for these effects, we generate a longitudinal RNASeq and DNA methylation resource dataset, which reveals conserved, energetically demanding, genome-wide recalibrations. Taken together, these findings highlight the need to understand how OxPhos defects influence the energetic cost of living, and the link between hypermetabolism and aging in cells and patients with mitochondrial diseases.
    DOI:  https://doi.org/10.1038/s42003-022-04303-x
  8. Elife. 2023 Jan 12. pii: e83935. [Epub ahead of print]12
    Inhibition of the proton-activated chloride channel PAC by PIP2.
    Ljubica Mihaljevic, Zheng Ruan, James Osei-Owusu, Wei Lü, Zhaozhu Qiu.
      Proton-Activated Chloride (PAC) channel is a ubiquitously expressed pH-sensing ion channel, encoded by PACC1 (TMEM206). PAC regulates endosomal acidification and macropinosome shrinkage by releasing chloride from the organelle lumens. It is also found at the cell surface, where it is activated under pathological conditions related to acidosis and contributes to acid-induced cell death. However, the pharmacology of the PAC channel is poorly understood. Here, we report that phosphatidylinositol (4,5)-bisphosphate (PIP2) potently inhibits PAC channel activity. We solved the cryo-electron microscopy structure of PAC with PIP2 at pH 4.0 and identified its putative binding site, which, surprisingly, locates on the extracellular side of the transmembrane domain (TMD). While the overall conformation resembles the previously resolved PAC structure in the desensitized state, the TMD undergoes remodeling upon PIP2-binding. Structural and electrophysiological analyses suggest that PIP2 inhibits the PAC channel by stabilizing the channel in a desensitized-like conformation. Our findings identify PIP2 as a new pharmacological tool for the PAC channel and lay the foundation for future drug discovery targeting this channel.
    Keywords:  human; molecular biophysics; structural biology
    DOI:  https://doi.org/10.7554/eLife.83935
  9. J Exp Biol. 2023 Jan 11. pii: jeb.244744. [Epub ahead of print]
    Individual response in body mass and basal metabolism to the risks of predation and starvation.
    Juli Broggi, Jan-Åke Nilsson.
      Wintering energy management in small passerines has focused on the adaptive regulation of daily acquisition of energy reserves within a starvation-predation trade-off framework. However, the possibility that the energetic cost of living i.e. basal metabolic rate (BMR) is being modulated as part of the management energy strategy has been largely neglected. Here we addressed this possibility by experimentally exposing captive great tits (Parus major) during winter, to two consecutive treatments of increased starvation and predation risk for each individual bird. Body mass and BMR were measured prior to and after each week-long treatment. We predicted that birds should be lighter but with a higher metabolic capacity (higher BMR) as a response to increased predation risk, and that birds should increase internal reserves while reducing their cost of living (lower BMR) when exposed to increased starvation risk. Wintering great tits kept a constant body mass independently of a week-long predation or starvation treatment. However, great tits reduced the cost of living (lower BMR) when exposed to the starvation treatment, while BMR remained unaffected by the predation treatment. Energy management in wintering small birds partly relies on BMR regulation, which challenges the current theoretical framework based on body mass regulation.
    Keywords:   Parus major ; Energy management; Food restriction; Optimal body mass theory; Predation risk; Winter ecology
    DOI:  https://doi.org/10.1242/jeb.244744
  10. Essays Biochem. 2023 Jan 13. pii: EBC20220094. [Epub ahead of print]
    Mitochondrial Ca2+ handling as a cell signaling hub: lessons from astrocyte function.
    João Victor Cabral-Costa, Alicia J Kowaltowski.
      Astrocytes are a heterogenous population of macroglial cells spread throughout the central nervous system with diverse functions, expression signatures, and intricate morphologies. Their subcellular compartments contain a distinct range of mitochondria, with functional microdomains exhibiting widespread activities, such as controlling local metabolism and Ca2+ signaling. Ca2+ is an ion of utmost importance, both physiologically and pathologically, and participates in critical central nervous system processes, including synaptic plasticity, neuron-astrocyte integration, excitotoxicity, and mitochondrial physiology and metabolism. The mitochondrial Ca2+ handling system is formed by the mitochondrial Ca2+ uniporter complex (MCUc), which mediates Ca2+ influx, and the mitochondrial Na+/Ca2+ exchanger (NCLX), responsible for most mitochondrial Ca2+ efflux, as well as additional components, including the mitochondrial permeability transition pore (mtPTP). Over the last decades, mitochondrial Ca2+ handling has been shown to be key for brain homeostasis, acting centrally in physiopathological processes such as astrogliosis, astrocyte-neuron activity integration, energy metabolism control, and neurodegeneration. In this review, we discuss the current state of knowledge regarding the mitochondrial Ca2+ handling system molecular composition, highlighting its impact on astrocytic homeostasis.
    Keywords:  MCU; NCLX; astrocytes; calcium signalling; metabolism; mitochondria
    DOI:  https://doi.org/10.1042/EBC20220094
  11. FASEB J. 2023 Feb;37(2): e22745
    Caveolin-2 in association with nuclear lamina controls adipocyte hypertrophy.
    Moonjeong Choi, Hayeong Kwon, Yunbae Pak.
      Here, we identify that Caveolin-2 (Cav-2), an integral membrane protein, controls adipocyte hypertrophy in association with nuclear lamina. In the hypertrophy stage of adipogenesis, pY19-Cav-2 association with lamin A/C facilitated the disengagement of CCAAT/enhancer-binding protein α (C/EBPα) and peroxisome proliferator-activated receptor γ (PPARγ) from lamin A/C and repressed Cav-2 promoter at the nuclear periphery for epigenetic activation of Cav-2, and thereby promoted C/EBPα and PPARγ-induced adipocyte hypertrophy. Stable expression of Cav-2 was required and retained by phosphorylation, deubiquitination, and association with lamin A/C for the adipocyte hypertrophy. However, obese adipocytes exhibited augmented Cav-2 stability resulting from the up-regulation of lamin A/C over lamin B1, protein tyrosine phosphatase 1B (PTP1B), and nuclear deubiquitinating enzyme (DUB), Uchl5. Our findings show a novel epigenetic regulatory mechanism of adipocyte hypertrophy by Cav-2 at the nuclear periphery.
    Keywords:  C/EBPα; Caveolin-2; PPARγ; PTP1B; Uchl5; adipocyte hypertrophy; lamin A/C; obesity
    DOI:  https://doi.org/10.1096/fj.202201028RR
  12. Nat Commun. 2023 Jan 06. 14(1): 108
    Disruption of mitochondrial dynamics triggers muscle inflammation through interorganellar contacts and mitochondrial DNA mislocation.
    Andrea Irazoki, Isabel Gordaliza-Alaguero, Emma Frank, Nikolaos Nikiforos Giakoumakis, Jordi Seco, Manuel Palacín, Anna Gumà, Lykke Sylow, David Sebastián, Antonio Zorzano.
      Some forms of mitochondrial dysfunction induce sterile inflammation through mitochondrial DNA recognition by intracellular DNA sensors. However, the involvement of mitochondrial dynamics in mitigating such processes and their impact on muscle fitness remain unaddressed. Here we report that opposite mitochondrial morphologies induce distinct inflammatory signatures, caused by differential activation of DNA sensors TLR9 or cGAS. In the context of mitochondrial fragmentation, we demonstrate that mitochondria-endosome contacts mediated by the endosomal protein Rab5C are required in TLR9 activation in cells. Skeletal muscle mitochondrial fragmentation promotes TLR9-dependent inflammation, muscle atrophy, reduced physical performance and enhanced IL6 response to exercise, which improved upon chronic anti-inflammatory treatment. Taken together, our data demonstrate that mitochondrial dynamics is key in preventing sterile inflammatory responses, which precede the development of muscle atrophy and impaired physical performance. Thus, we propose the targeting of mitochondrial dynamics as an approach to treating disorders characterized by chronic inflammation and mitochondrial dysfunction.
    DOI:  https://doi.org/10.1038/s41467-022-35732-1
  13. mBio. 2023 Jan 10. e0330222
    Bioenergetic State of Escherichia coli Controls Aminoglycoside Susceptibility.
    Jessica Y El Khoury, Jordi Zamarreño Beas, Allison Huguenot, Béatrice Py, Frédéric Barras.
      Aminoglycosides (AG) have been used against Gram-negative bacteria for decades. Yet, how bacterial metabolism and environmental conditions modify AG toxicity is poorly understood. Here, we show that the level of AG susceptibility varies depending on the nature of the respiratory chain that Escherichia coli uses for growth, i.e., oxygen, nitrate, or fumarate. We show that all components of the fumarate respiratory chain, namely, hydrogenases 2 and 3, the formate hydrogenlyase complex, menaquinone, and fumarate reductase are required for AG-mediated killing under fumarate respiratory conditions. In addition, we show that the AAA+ ATPase RavA and its Von Wildebrand domain-containing partner, ViaA, are essential for AG to act under fumarate respiratory conditions. This effect was true for all AG that were tested but not for antibiotics from other classes. In addition, we show that the sensitizing effect of RavA-ViaA is due to increased gentamicin uptake in a proton motive force-dependent manner. Interestingly, the sensitizing effect of RavA-ViaA was prominent in poor energy conservation conditions, i.e., with fumarate, but dispensable under high energy conservation conditions, i.e., in the presence of nitrate or oxygen. We propose that RavA-ViaA can facilitate uptake of AG across the membrane in low-energy cellular states. IMPORTANCE Antibiotic resistance is a major public health, social, and economic problem. Aminoglycosides (AG) are known to be highly effective against Gram-negative bacteria, but their use is limited to life-threatening infections because of their nephrotoxicity and ototoxicity at therapeutic dose. Elucidation of AG-sensitization mechanisms in bacteria would allow reduced effective doses of AG. Here, we have identified the molecular components involved in anaerobic fumarate respiration that are required for AG to kill. In addition to oxidoreductases and menaquinone, this includes new molecular players, RavA, an AAA+ ATPase, and ViaA, its partner that has the VWA motif. Remarkably, the influence of RavA-ViaA on AG susceptibility varies according to the type of bioenergetic metabolism used by E. coli. This is a significant advance because anaerobiosis is well known to reduce the antibacterial activity of AG. This study highlights the critical importance of the relationship between culture conditions, metabolism, and antibiotic susceptibility.
    Keywords:  Escherichia coli; RavA-ViaA; aminoglycosides; bioenergetics; fumarate respiration; proton motive force
    DOI:  https://doi.org/10.1128/mbio.03302-22
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