bims-mimbat Biomed News
on Mitochondrial metabolism in brown adipose tissue
Issue of 2023–07–30
seven papers selected by
José Carlos de Lima-Júnior, Washington University
  1. Quinone Catalysis Modulates Proton Transfer Reactions in the Membrane Domain of Respiratory Complex I.
  2. Highly recruited brown adipose tissue does not in itself protect against obesity.
  3. Mammary duct luminal epithelium controls adipocyte thermogenic programme.
  4. Hotly awaited structures obtained for the human protein UCP1.
  5. NFIA in adipocytes reciprocally regulates mitochondrial and inflammatory gene program to improve glucose homeostasis.
  6. Charge Regulation in a Rieske Proton Pump Pinpoints Zero, One, and Two Proton-Coupled Electron Transfer.
  7. Acidosis attenuates CPT-I supported bioenergetics as a potential mechanism limiting lipid oxidation.
  1. J Am Chem Soc. 2023 Jul 25.
    Quinone Catalysis Modulates Proton Transfer Reactions in the Membrane Domain of Respiratory Complex I.
    Hyunho Kim, Patricia Saura, Maximilian C Pöverlein, Ana P Gamiz-Hernandez, Ville R I Kaila.
      Complex I is a redox-driven proton pump that drives electron transport chains and powers oxidative phosphorylation across all domains of life. Yet, despite recently resolved structures from multiple organisms, it still remains unclear how the redox reactions in Complex I trigger proton pumping up to 200 Å away from the active site. Here, we show that the proton-coupled electron transfer reactions during quinone reduction drive long-range conformational changes of conserved loops and trans-membrane (TM) helices in the membrane domain of Complex I from Yarrowia lipolytica. We find that the conformational switching triggers a π → α transition in a TM helix (TM3ND6) and establishes a proton pathway between the quinone chamber and the antiporter-like subunits, responsible for proton pumping. Our large-scale (>20 μs) atomistic molecular dynamics (MD) simulations in combination with quantum/classical (QM/MM) free energy calculations show that the helix transition controls the barrier for proton transfer reactions by wetting transitions and electrostatic effects. The conformational switching is enabled by re-arrangements of ion pairs that propagate from the quinone binding site to the membrane domain via an extended network of conserved residues. We find that these redox-driven changes create a conserved coupling network within the Complex I superfamily, with point mutations leading to drastic activity changes and mitochondrial disorders. On a general level, our findings illustrate how catalysis controls large-scale protein conformational changes and enables ion transport across biological membranes.
    DOI:  https://doi.org/10.1021/jacs.3c03086
  2. Mol Metab. 2023 Jul 25. pii: S2212-8778(23)00116-3. [Epub ahead of print] 101782
    Highly recruited brown adipose tissue does not in itself protect against obesity.
    Gabriella von Essen, Erik Lindsund, Elaina M Maldonado, Petr Zouhar, Barbara Cannon, Jan Nedergaard.
       OBJECTIVE: The possibility to counteract the development of obesity in humans by recruiting brown or brite/beige adipose tissue (and thus UCP1) has attracted much attention. Here we examine if a diet that can activate diet-induced thermogenesis can exploit pre-enhanced amounts of UCP1 to counteract the development of diet-induced obesity.
    METHODS: To investigate the anti-obesity significance of highly augmented amounts of UCP1 for control of body energy reserves, we physiologically increased total UCP1 amounts in brown and brite/beige tissues in mice. We then examined the influence of the augmented UCP1 levels on metabolic parameters when the mice were exposed to a high-fat/high-sucrose diet under thermoneutral conditions.
    RESULTS: The total UCP1 levels achieved were about 50-fold higher in recruited than in non-recruited mice. Contrary to underlying expectations, in the mice with highly recruited UCP1 and exposed to a high-fat/high-sucrose diet the thermogenic capacity of this UCP1 was completely inactivate. The mice even transiently (in an adipostat-like manner) demonstrated a higher metabolic efficiency and fat gain than did non-recruited mice. This was accomplished without altering energy expenditure or food resorption efficiency. The metabolic efficiency was indistinguishable from that of mice totally devoid of UCP1.
    CONCLUSIONS: Although UCP1 protein may be available, it is not inevitably utilized for diet-induced thermogenesis. Thus, although attempts to recruit UCP1 in humans may become successful as such, it is only if constant activation of the UCP1 is also achieved that amelioration of obesity development could be attained.
    Keywords:  Diet-induced thermogenesis; UCP1; adipostat; beige adipose tissue; body weight regulation; glucose homeostasis
    DOI:  https://doi.org/10.1016/j.molmet.2023.101782
  3. Nature. 2023 Jul 26.
    Mammary duct luminal epithelium controls adipocyte thermogenic programme.
    Sanil Patel, Njeri Z R Sparman, Douglas Arneson, Alexandra Alvarsson, Luís C Santos, Samuel J Duesman, Alessia Centonze, Ephraim Hathaway, In Sook Ahn, Graciel Diamante, Ingrid Cely, Chung Hwan Cho, Noble Kumar Talari, Abha K Rajbhandari, Leigh Goedeke, Peng Wang, Atul J Butte, Cédric Blanpain, Karthickeyan Chella Krishnan, Aldons J Lusis, Sarah A Stanley, Xia Yang, Prashant Rajbhandari.
      Sympathetic activation during cold exposure increases adipocyte thermogenesis via the expression of mitochondrial protein uncoupling protein 1 (UCP1)1. The propensity of adipocytes to express UCP1 is under a critical influence of the adipose microenvironment and varies between sexes and among various fat depots2-7. Here we report that mammary gland ductal epithelial cells in the adipose niche regulate cold-induced adipocyte UCP1 expression in female mouse subcutaneous white adipose tissue (scWAT). Single-cell RNA sequencing shows that glandular luminal epithelium subtypes express transcripts that encode secretory factors controlling adipocyte UCP1 expression under cold conditions. We term these luminal epithelium secretory factors 'mammokines'. Using 3D visualization of whole-tissue immunofluorescence, we reveal sympathetic nerve-ductal contact points. We show that mammary ducts activated by sympathetic nerves limit adipocyte UCP1 expression via the mammokine lipocalin 2. In vivo and ex vivo ablation of mammary duct epithelium enhance the cold-induced adipocyte thermogenic gene programme in scWAT. Since the mammary duct network extends throughout most of the scWAT in female mice, females show markedly less scWAT UCP1 expression, fat oxidation, energy expenditure and subcutaneous fat mass loss compared with male mice, implicating sex-specific roles of mammokines in adipose thermogenesis. These results reveal a role of sympathetic nerve-activated glandular epithelium in adipocyte UCP1 expression and suggest that mammary duct luminal epithelium has an important role in controlling glandular adiposity.
    DOI:  https://doi.org/10.1038/s41586-023-06361-5
  4. Nature. 2023 Jul 24.
    Hotly awaited structures obtained for the human protein UCP1.
    Michael J Gaudry, Martin Jastroch.
      
    Keywords:  Cell biology; Structural biology
    DOI:  https://doi.org/10.1038/d41586-023-02334-w
  5. Proc Natl Acad Sci U S A. 2023 08;120(31): e2308750120
    NFIA in adipocytes reciprocally regulates mitochondrial and inflammatory gene program to improve glucose homeostasis.
    Yuta Hiraike, Kaede Saito, Misato Oguchi, Takahito Wada, Gotaro Toda, Shuichi Tsutsumi, Kana Bando, Junji Sagawa, Gaku Nagano, Haruya Ohno, Naoto Kubota, Tetsuya Kubota, Hiroyuki Aburatani, Takashi Kadowaki, Hironori Waki, Shintaro Yanagimoto, Toshimasa Yamauchi.
      Adipose tissue is central to regulation of energy homeostasis. Adaptive thermogenesis, which relies on mitochondrial oxidative phosphorylation (Ox-Phos), dissipates energy to counteract obesity. On the other hand, chronic inflammation in adipose tissue is linked to type 2 diabetes and obesity. Here, we show that nuclear factor I-A (NFIA), a transcriptional regulator of brown and beige adipocytes, improves glucose homeostasis by upregulation of Ox-Phos and reciprocal downregulation of inflammation. Mice with transgenic expression of NFIA in adipocytes exhibited improved glucose tolerance and limited weight gain. NFIA up-regulates Ox-Phos and brown-fat-specific genes by enhancer activation that involves facilitated genomic binding of PPARγ. In contrast, NFIA in adipocytes, but not in macrophages, down-regulates proinflammatory cytokine genes to ameliorate adipose tissue inflammation. NFIA binds to regulatory region of the Ccl2 gene, which encodes proinflammatory cytokine MCP-1 (monocyte chemoattractant protein-1), to down-regulate its transcription. CCL2 expression was negatively correlated with NFIA expression in human adipose tissue. These results reveal the beneficial effect of NFIA on glucose and body weight homeostasis and also highlight previously unappreciated role of NFIA in suppressing adipose tissue inflammation.
    Keywords:  adipocytes; diabetes; inflammation; transcription factor
    DOI:  https://doi.org/10.1073/pnas.2308750120
  6. J Am Chem Soc. 2023 Jul 24.
    Charge Regulation in a Rieske Proton Pump Pinpoints Zero, One, and Two Proton-Coupled Electron Transfer.
    Jordan C Koone, Mikaela Simmang, Devin L Saenger, Laura M Hunsicker-Wang, Bryan F Shaw.
      The degree to which redox-driven proton pumps regulate net charge during electron transfer (ΔZET) remains undetermined due to difficulties in measuring the net charge of solvated proteins. Values of ΔZET can reflect reorganization energies or redox potentials associated with ET and can be used to distinguish ET from proton(s)-coupled electron transfer (PCET). Here, we synthesized protein "charge ladders" of a Rieske [2Fe-2S] subunit from Thermus thermophilus (truncTtRp) and made 120 electrostatic measurements of ΔZET across pH. Across pH 5-10, truncTtRp is suspected of transitioning from ET to PCET, and then to two proton-coupled ET (2PCET). Upon reduction, we found that truncTtRp became more negative at pH 6.0 by one unit (ΔZET = -1.01 ± 0.14), consistent with single ET; was isoelectric at pH 8.8 (ΔZET = -0.01 ± 0.45), consistent with PCET; and became more positive at pH 10.6 (ΔZET = +1.37 ± 0.60), consistent with 2PCET. These ΔZET values are attributed to protonation of H154 and H134. Across pH, redox potentials of TtRp (measured previously) correlated with protonation energies of H154 and H134 and ΔZET for truncTtRp, supporting a discrete proton pumping mechanism for Rieske proteins at the Fe-coordinating histidines.
    DOI:  https://doi.org/10.1021/jacs.3c03006
  7. J Biol Chem. 2023 Jul 21. pii: S0021-9258(23)02107-5. [Epub ahead of print] 105079
    Acidosis attenuates CPT-I supported bioenergetics as a potential mechanism limiting lipid oxidation.
    Sara M Frangos, Geneviève J DesOrmeaux, Graham P Holloway.
      Fuel interactions in contracting muscle represent a complex interplay between enzymes regulating carbohydrate and fatty acid catabolism, converging in the mitochondrial matrix. While increasing exercise intensity promotes carbohydrate use at the expense of fatty acid oxidation, the mechanisms underlying this effect remain poorly elucidated. As a potential explanation, we investigated whether exercise-induced reductions in intramuscular pH (acidosis) attenuate carnitine palmitoyltransferase-I (CPT-I) supported bioenergetics, the rate-limiting step for fatty acid oxidation within mitochondria. Specifically, we assessed the effect of a physiologically relevant reduction in pH (pH 7.2 vs 6.8) on single and mixed substrate respiratory responses in murine skeletal muscle isolated mitochondria and permeabilized fibers. While pH did not influence OXPHOS stoichiometry (ADP/O ratios), coupling efficiency, oxygen affinity or ADP respiratory responses, acidosis impaired lipid bioenergetics by attenuating respiration with L-carnitine and palmitoyl-CoA, while enhancing the inhibitory effect of malonyl-CoA on CPT-I. These acidotic effects were largely retained following a single bout of intense exercise. At rest, pyruvate and succinate supported respiration were also impaired by acidosis. However, providing more pyruvate and ADP at pH 6.8 to model increases in glycolytic flux and ATP turnover with intense exercise, overcame the acidotic attenuation of carbohydrate-linked OXPHOS. Importantly, this situation is fundamentally different from lipids where CPT-I substrate sensitivity and availability is impaired at higher power outputs suggesting lipid metabolism may be more susceptible to the effects of acidosis, possibly contributing to fuel shifts with increasing exercise intensity.
    Keywords:  CPT-I; Mitochondrial bioenergetics; exercise; fuel metabolism; lipid metabolism; pH; skeletal muscle
    DOI:  https://doi.org/10.1016/j.jbc.2023.105079
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