bims-mimbat Biomed News
on Mitochondrial metabolism in brown adipose tissue
Issue of 2022‒12‒18
twelve papers selected by
José Carlos de Lima-Júnior
Washington University

  1. Cell Rep. 2022 Dec 13. pii: S2211-1247(22)01694-1. [Epub ahead of print]41(11): 111806
      In mammals, brown adipose tissue (BAT) is specialized to conduct non-shivering thermogenesis for survival under cold acclimation. Although emerging evidence suggests that lipid metabolites are essential for heat generation in cold-activated BAT, the underlying mechanisms of lipid uptake in BAT have not been thoroughly understood. Here, we show that very-low-density lipoprotein (VLDL) uptaken by VLDL receptor (VLDLR) plays important roles in thermogenic execution in BAT. Compared with wild-type mice, VLDLR knockout mice exhibit impaired thermogenic features. Mechanistically, VLDLR-mediated VLDL uptake provides energy sources for mitochondrial oxidation via lysosomal processing, subsequently enhancing thermogenic activity in brown adipocytes. Moreover, the VLDL-VLDLR axis potentiates peroxisome proliferator activated receptor (PPAR)β/δ activity with thermogenic gene expression in BAT. Accordingly, VLDL-induced thermogenic capacity is attenuated in brown-adipocyte-specific PPARβ/δ knockout mice. Collectively, these data suggest that the VLDL-VLDLR axis in brown adipocytes is a key factor for thermogenic execution during cold exposure.
    Keywords:  CP: Metabolism; CP: Molecular biology; PPARδ; VLDL; VLDL receptor; brown adipocyte; brown adipose tissue; mitochondrial respiration; thermogenesis; very-low-density lipoprotein
  2. Trends Cell Biol. 2022 Dec 12. pii: S0962-8924(22)00259-8. [Epub ahead of print]
      The mitochondrial calcium uniporter (MCU) controls mitochondrial bioenergetics, and its activity varies greatly between tissues. Here, we highlight a recently identified MCU-EMRE-UCP1 complex, named thermoporter, in the adaptive thermogenesis of brown adipose tissue (BAT). The thermoporter enhances MCU activity to promote thermogenic metabolism, demonstrating a BAT-specific regulation for MCU activity.
  3. Adv Exp Med Biol. 2022 ;1395 367-372
      In intact mitochondria, the transport of electrons, respiration and generation of proton gradients across the inner membrane (proton motive force) are mutually coupled, according to Peter Mitchell's hypothesis on oxidative phosphorylation. Thus, the inhibition of electron transport at either respiratory complex III or IV in the electron transport chain leads to failure in producing proton motive force along with the abolition of respiration. Here, we determined the mitochondrial membrane potential (MMP), as a measure of proton motive force, and cellular respiration in various cultured cells and demonstrated that inhibition of complex IV by KCN abolished mitochondrial respiration while MMP was sustained. These results are unexpected and appear incompatible with Mitchell's chemiosmotic hypothesis.
    Keywords:  Electron transport; Mitchell’s chemiosmotic hypothesis; Mitochondria; Proton motive force
  4. Nat Commun. 2022 Dec 12. 13(1): 7439
      Brown adipose tissue plays a central role in the regulation of the energy balance by expending energy to produce heat. NAD+-dependent deacylase sirtuins have widely been recognized as positive regulators of brown adipose tissue thermogenesis. However, here we reveal that SIRT7, one of seven mammalian sirtuins, suppresses energy expenditure and thermogenesis by regulating brown adipose tissue functions. Whole-body and brown adipose tissue-specific Sirt7 knockout mice have higher body temperature and energy expenditure. SIRT7 deficiency increases the protein level of UCP1, a key regulator of brown adipose tissue thermogenesis. Mechanistically, we found that SIRT7 deacetylates insulin-like growth factor 2 mRNA-binding protein 2, an RNA-binding protein that inhibits the translation of Ucp1 mRNA, thereby enhancing its inhibitory action on Ucp1. Furthermore, SIRT7 attenuates the expression of batokine genes, such as fibroblast growth factor 21. In conclusion, we propose that SIRT7 serves as an energy-saving factor by suppressing brown adipose tissue functions.
  5. Nat Commun. 2022 Dec 10. 13(1): 7633
      The signaling mechanisms underlying adipose thermogenesis have not been fully elucidated. Particularly, the involvement of adipokines that are selectively expressed in brown adipose tissue (BAT) and beige adipocytes remains to be investigated. Here we show that a previously uncharacterized adipokine (UPF0687 protein / human C20orf27 homolog) we named as Adissp (Adipose-secreted signaling protein) is a key regulator for white adipose tissue (WAT) thermogenesis and glucose homeostasis. Adissp expression is adipose-specific and highly BAT-enriched, and its secretion is stimulated by β3-adrenergic activation. Gain-of-functional studies collectively showed that secreted Adissp promotes WAT thermogenesis, improves glucose homeostasis, and protects against obesity. Adipose-specific Adissp knockout mice are defective in WAT browning, and are susceptible to high fat diet-induced obesity and hyperglycemia. Mechanistically, Adissp binds to a putative receptor on adipocyte surface and activates protein kinase A independently of β-adrenergic signaling. These results establish BAT-enriched Adissp as a major upstream signaling component in thermogenesis and offer a potential avenue for the treatment of obesity and diabetes.
  6. Sci Rep. 2022 Dec 10. 12(1): 21383
      Brown adipose tissue (BAT) is a fat tissue specialized in heat production (non-shivering thermogenesis) and used by mammals to defend core body temperature when exposed to cold. Several studies have shown that during non-shivering thermogenesis the increase in BAT oxygen demand is met by a local and specific increase in tissue's blood flow. While the vasculature of BAT has been extensively studied postmortem in rodents using histology, optical and CT imaging techniques, vasculature changes during stimulation of non-shivering thermogenesis have never been directly detected in vivo. Here, by using computed tomography (CT) angiography with gold nanoparticles we investigate, non-invasively, changes in BAT vasculature during adrenergic stimulation of non-shivering thermogenesis by norepinephrine, a vasoconstrictor known to mediate brown fat heat production, and by CL 316,243, a specific β3-adrenergic agonist also known to elicit BAT thermogenesis in rodents. We found that while CL 316,243 causes local vasodilation in BAT, with little impact on the rest of the vasculature throughout the body, norepinephrine leads to local vasodilation in addition to peripheral vasoconstriction. As a result, a significantly greater relative increase in BAT perfusion is observed following the injection of NE compared to CL. This study demonstrates the use of in vivo CT angiography as an effective tool in assessing vascular reactivity in BAT both qualitatively and quantitatively in preclinical studies.
  7. Biochim Biophys Acta Bioenerg. 2022 Dec 09. pii: S0005-2728(22)00421-2. [Epub ahead of print]1864(2): 148951
      Respiratory complex I in mitochondria and bacteria catalyzes the transfer of electrons from NADH to quinone (Q). The free energy available from the reaction is used to pump protons and to establish a membrane proton electrochemical gradient, which drives ATP synthesis. Even though several high-resolution structures of complex I have been resolved, how Q reduction is linked with proton pumping, remains unknown. Here, microsecond long molecular dynamics (MD) simulations were performed on Yarrowia lipolytica complex I structures where Q molecules have been resolved in the ~30 Å long Q tunnel. MD simulations of several different redox/protonation states of Q reveal the coupling between the Q dynamics and the restructuring of conserved loops and ion pairs. Oxidized quinone stabilizes towards the N2 FeS cluster, a binding mode not previously described in Yarrowia lipolytica complex I structures. On the other hand, reduced (and protonated) species tend to diffuse towards the Q binding sites closer to the tunnel entrance. Mechanistic and physiological relevance of these results are discussed.
    Keywords:  Bioenergetics; Electron transfer; Molecular dynamics simulations; Proton pumping; Semiquinone
  8. EMBO J. 2022 Dec 16. e111348
      Moderate coolness is sensed by TRPM8 ion channels in peripheral sensory nerves, but the mechanism by which noxious cold is detected remains elusive. Here, we show that somatosensory and sympathetic neurons express two distinct mechanisms to detect noxious cold. In the first, inhibition by cold of a background outward current causes membrane depolarization that activates an inward current through voltage-dependent calcium (CaV ) channels. A second cold-activated mechanism is independent of membrane voltage, is inhibited by blockers of ORAI ion channels and by downregulation of STIM1, and is recapitulated in HEK293 cells by co-expression of ORAI1 and STIM1. Using total internal reflection fluorescence microscopy we found that cold causes STIM1 to aggregate with and activate ORAI1 ion channels, in a mechanism similar to that underlying store-operated calcium entry (SOCE), but directly activated by cold and not by emptying of calcium stores. This novel mechanism may explain the phenomenon of cold-induced vasodilation (CIVD), in which extreme cold increases blood flow in order to preserve the integrity of peripheral tissues.
    Keywords:  ORAI; STIM; calcium influx; cold sensation; sensory neuron
  9. Chem Sci. 2022 Nov 23. 13(45): 13489-13498
      The mitochondrial electron transport chain comprises a series of protein complexes embedded in the inner mitochondrial membrane that generate a proton motive force via oxidative phosphorylation, ultimately generating ATP. These protein complexes can oligomerize to form larger structures called supercomplexes. Cardiolipin (CL), a conical lipid, unique within eukaryotes to the inner mitochondrial membrane, has proven essential in maintaining the stability and function of supercomplexes. Monolysocardiolipin (MLCL) is a CL variant that accumulates in people with Barth syndrome (BTHS). BTHS is caused by defects in CL biosynthesis and characterised by abnormal mitochondrial bioenergetics and destabilised supercomplexes. However, the mechanisms by which MLCL causes pathogenesis remain unclear. Here, multiscale molecular dynamics characterise the interactions of CL and MLCL with yeast and mammalian mitochondrial supercomplexes containing complex III (CIII) and complex IV (CIV). Coarse-grained simulations reveal that both CL and MLCL bind to sites at the interface between CIII and CIV of the supercomplex. Free energy perturbation calculations show that MLCL interaction is weaker than that of CL and suggest that interaction with CIV drives this difference. Atomistic contact analyses show that, although interaction with CIII is similar for CL and MLCL, CIV makes more contacts with CL than MLCL, demonstrating that CL is a more successful "glue" between the two complexes. Simulations of the human CIII2CIV supercomplex show that this interface site is maintained between species. Our study suggests that MLCL accumulation in people with BTHS disrupts supercomplex stability by formation of relatively weak interactions at the interface lipid binding site.
  10. J Biol Chem. 2022 Dec 07. pii: S0021-9258(22)01223-6. [Epub ahead of print] 102780
      Ischemia and reperfusion affect multiple elements of cardiomyocyte electrophysiology, especially within the mitochondria. We previously showed that in cardiac monolayers, upon reperfusion after coverslip-induced ischemia, mitochondrial inner membrane potential (ΔΨ) unstably oscillates between polarized and depolarized states, and ΔΨ instability corresponds with arrhythmias. Here, through confocal microscopy of compartment-specific molecular probes, we investigate the mechanisms underlying the post-ischemic ΔΨ oscillations, focusing on the role of Ca2+ and oxidative stress. During reperfusion, transient ΔΨ depolarizations occurred concurrently with periods of increased mitochondrial oxidative stress (5.07 ± 1.71 oscillations/15 min, N = 100). Supplementing the antioxidant system with glutathione monoethyl ester suppressed ΔΨ oscillations (1.84 ± 1.07 oscillations/15 min, N = 119, t-test P = 0.027) with 37% of mitochondrial clusters showing no ΔΨ oscillations (vs. 4% in control, odds ratio = 14.08, Fisher's exact test P < 0.001). We found that limiting the production of reactive oxygen species using cyanide inhibited post-ischemic ΔΨ oscillations (N = 15, t-test P < 10-5). Furthermore, ΔΨ oscillations were not associated with any discernable pattern in cell-wide oxidative stress, nor with the changes in cytosolic or mitochondrial Ca2+. Sustained ΔΨ depolarization followed cytosolic and mitochondrial Ca2+ increase and was associated with increased cell-wide oxidative stress. Collectively, these findings suggest that transient bouts of increased mitochondrial oxidative stress underlie post-ischemic ΔΨ oscillations, regardless of Ca2+ dynamics.
    Keywords:  calcium imaging; cardiac monolayers; coverslip-induced ischemia; glutathione redox potential; inner membrane potential oscillations; neonatal rat ventricular myocytes; optical mapping; reactive oxygen species (ROS); reentry arrhythmias; reperfusion
  11. J Am Chem Soc. 2022 Dec 15.
      Unassisted ion transport through lipid membranes plays a crucial role in many cell functions without which life would not be possible, yet the precise mechanism behind the process remains unknown due to its molecular complexity. Here, we demonstrate a direct link between membrane potential fluctuations and divalent ion transport. High-throughput wide-field non-resonant second harmonic (SH) microscopy of membrane water shows that membrane potential fluctuations are universally found in lipid bilayer systems. Molecular dynamics simulations reveal that such variations in membrane potential reduce the free energy cost of transient pore formation and increase the ion flux across an open pore. These transient pores can act as conduits for ion transport, which we SH image for a series of divalent cations (Cu2+, Ca2+, Ba2+, Mg2+) passing through giant unilamellar vesicle (GUV) membranes. Combining the experimental and computational results, we show that permeation through pores formed via an ion-induced electrostatic field is a viable mechanism for unassisted ion transport.
  12. Commun Biol. 2022 Dec 14. 5(1): 1372
      Anion exchanger 1 (AE1, band 3) is a major membrane protein of red blood cells and plays a key role in acid-base homeostasis, urine acidification, red blood cell shape regulation, and removal of carbon dioxide during respiration. Though structures of the transmembrane domain (TMD) of three SLC4 transporters, including AE1, have been resolved previously in their outward-facing (OF) state, no mammalian SLC4 structure has been reported in the inward-facing (IF) conformation. Here we present the cryoEM structures of full-length bovine AE1 with its TMD captured in both IF and OF conformations. Remarkably, both IF-IF homodimers and IF-OF heterodimers were detected. The IF structures feature downward movement in the core domain with significant unexpected elongation of TM11. Molecular modeling and structure guided mutagenesis confirmed the functional significance of residues involved in TM11 elongation. Our data provide direct evidence for an elevator-like mechanism of ion transport by an SLC4 family member.