bims-mimbat Biomed News
on Mitochondrial metabolism in brown adipose tissue
Issue of 2022‒12‒25
six papers selected by
José Carlos de Lima-Júnior
Washington University
  1. Membrane Lipid Reshaping Underlies Oxidative Stress Sensing by the Mitochondrial Proteins UCP1 and ANT1.
  2. Prostaglandin EP3 receptor-expressing preoptic neurons bidirectionally control body temperature via tonic GABAergic signaling.
  3. DEPTOR loss impairs brown adipocyte development in vitro but has limited impacts in mice.
  4. Contribution of the Collective Excitations to the Coupled Proton and Energy Transport along Mitochondrial Cristae Membrane in Oxidative Phosphorylation System.
  5. Futile cycle of β-oxidation and de novo lipogenesis are associated with essential fatty acids depletion in lipoatrophy.
  6. Multi-color live-cell STED nanoscopy of mitochondria with a gentle inner membrane stain.
  1. Antioxidants (Basel). 2022 Nov 23. pii: 2314. [Epub ahead of print]11(12):
    Membrane Lipid Reshaping Underlies Oxidative Stress Sensing by the Mitochondrial Proteins UCP1 and ANT1.
    Olga Jovanović, Ksenia Chekashkina, Sanja Škulj, Kristina Žuna, Mario Vazdar, Pavel V Bashkirov, Elena E Pohl.
      Oxidative stress and ROS are important players in the pathogenesis of numerous diseases. In addition to directly altering proteins, ROS also affects lipids with negative intrinsic curvature such as phosphatidylethanolamine (PE), producing PE adducts and lysolipids. The formation of PE adducts potentiates the protonophoric activity of mitochondrial uncoupling proteins, but the molecular mechanism remains unclear. Here, we linked the ROS-mediated change in lipid shape to the mechanical properties of the membrane and the function of uncoupling protein 1 (UCP1) and adenine nucleotide translocase 1 (ANT1). We show that the increase in the protonophoric activity of both proteins occurs due to the decrease in bending modulus in lipid bilayers in the presence of lysophosphatidylcholines (OPC and MPC) and PE adducts. Moreover, MD simulations showed that modified PEs and lysolipids change the lateral pressure profile of the membrane in the same direction and by the similar amplitude, indicating that modified PEs act as lipids with positive intrinsic curvature. Both results indicate that oxidative stress decreases stored curvature elastic stress (SCES) in the lipid bilayer membrane. We demonstrated that UCP1 and ANT1 sense SCES and proposed a novel regulatory mechanism for the function of these proteins. The new findings should draw the attention of the scientific community to this important and unexplored area of redox biochemistry.
    Keywords:  bending moduli; lateral pressure profile; lipid shape; lipid–protein interaction; mitochondrial membrane protein; protonophoric function; reactive aldehydes; stored curvature elastic stress
    DOI:  https://doi.org/10.3390/antiox11122314
  2. Sci Adv. 2022 Dec 23. 8(51): eadd5463
    Prostaglandin EP3 receptor-expressing preoptic neurons bidirectionally control body temperature via tonic GABAergic signaling.
    Yoshiko Nakamura, Takaki Yahiro, Akihiro Fukushima, Naoya Kataoka, Hiroyuki Hioki, Kazuhiro Nakamura.
      The bidirectional controller of the thermoregulatory center in the preoptic area (POA) is unknown. Using rats, here, we identify prostaglandin EP3 receptor-expressing POA neurons (POAEP3R neurons) as a pivotal bidirectional controller in the central thermoregulatory mechanism. POAEP3R neurons are activated in response to elevated ambient temperature but inhibited by prostaglandin E2, a pyrogenic mediator. Chemogenetic stimulation of POAEP3R neurons at room temperature reduces body temperature by enhancing heat dissipation, whereas inhibition of them elicits hyperthermia involving brown fat thermogenesis, mimicking fever. POAEP3R neurons innervate sympathoexcitatory neurons in the dorsomedial hypothalamus (DMH) via tonic (ceaseless) inhibitory signaling. Although many POAEP3R neuronal cell bodies express a glutamatergic messenger RNA marker, their axons in the DMH predominantly release γ-aminobutyric acid (GABA), and their GABAergic terminals are increased by chronic heat exposure. These findings demonstrate that tonic GABAergic inhibitory signaling from POAEP3R neurons is a fundamental determinant of body temperature for thermal homeostasis and fever.
    DOI:  https://doi.org/10.1126/sciadv.add5463
  3. Mol Metab. 2022 Dec 16. pii: S2212-8778(22)00229-0. [Epub ahead of print] 101660
    DEPTOR loss impairs brown adipocyte development in vitro but has limited impacts in mice.
    Charles Colas, Mathilde Mouchiroud, Manal Al Dow, Alona Kolnohuz, Yves Gélinas, Alexandre Caron, Mathieu Laplante.
      OBJECTIVES: The mechanistic target of rapamycin (mTOR) is a serine/threonine kinase that regulates growth and metabolism. In mice, activation of mTOR controls cold adaptation by promoting the recruitment and the activation of brown adipose tissue (BAT). DEP-domain containing mTOR-interacting protein (DEPTOR) interacts with mTOR to modulate its activity. Whether DEPTOR levels are modulated by cold in BAT and whether this protein regulates brown adipocyte development and thermogenic activation has never been tested.METHODS: DEPTOR levels were measured in mouse tissues upon cold exposure and in brown preadipocytes following the induction of adipogenesis. Lentiviruses expressing short-hairpin RNA were used to repress DEPTOR expression in brown preadipocytes in vitro. Conditional deletion of DEPTOR in brown preadipocytes and in mature brown fat cells was achieved by crossing DEPTOR floxed mice with either Myf5-Cre or Ucp1-CreERT2 mice. These animals were exposed to cold and extensively phenotyped.
    RESULTS: DEPTOR is highly expressed in BAT and its levels are induced by chronic cold exposure, a condition that triggers BAT expansion and activation. Supporting a role for DEPTOR in brown fat cell recruitment, we found that DEPTOR is induced during brown adipocyte development and that its depletion impairs adipogenesis in vitro. This adipogenic lesion was associated with defects in both Akt activation and the expression of key adipogenic regulators. Conditional deletion of DEPTOR in brown preadipocytes or mature brown fat cells did not impact BAT recruitment and thermogenesis in mice but slightly reduced the expression of adipogenic and lipogenic genes.
    CONCLUSIONS: DEPTOR is highly expressed in BAT and its levels are dynamically regulated during brown fat cell development and upon cold exposure. Although DEPTOR depletion severely represses brown fat adipogenesis in vitro, its deletion is dispensable for BAT development, recruitment, and thermogenic activation in mice.
    Keywords:  Adipogenesis; Cold exposure; DEPTOR; Thermogenesis; brown adipocyte; brown adipose tissue; mTOR
    DOI:  https://doi.org/10.1016/j.molmet.2022.101660
  4. Entropy (Basel). 2022 Dec 13. pii: 1813. [Epub ahead of print]24(12):
    Contribution of the Collective Excitations to the Coupled Proton and Energy Transport along Mitochondrial Cristae Membrane in Oxidative Phosphorylation System.
    Semen V Nesterov, Lev S Yaguzhinsky, Raif G Vasilov, Vasiliy N Kadantsev, Alexey N Goltsov.
      The results of many experimental and theoretical works indicate that after transport of protons across the mitochondrial inner membrane (MIM) in the oxidative phosphorylation (OXPHOS) system, they are retained on the membrane-water interface in nonequilibrium state with free energy excess due to low proton surface-to-bulk release. This well-established phenomenon suggests that proton trapping on the membrane interface ensures vectorial lateral transport of protons from proton pumps to ATP synthases (proton acceptors). Despite the key role of the proton transport in bioenergetics, the molecular mechanism of proton transfer in the OXPHOS system is not yet completely established. Here, we developed a dynamics model of long-range transport of energized protons along the MIM accompanied by collective excitation of localized waves propagating on the membrane surface. Our model is based on the new data on the macromolecular organization of the OXPHOS system showing the well-ordered structure of respirasomes and ATP synthases on the cristae membrane folds. We developed a two-component dynamics model of the proton transport considering two coupled subsystems: the ordered hydrogen bond (HB) chain of water molecules and lipid headgroups of MIM. We analytically obtained a two-component soliton solution in this model, which describes the motion of the proton kink, corresponding to successive proton hops in the HB chain, and coherent motion of a compression soliton in the chain of lipid headgroups. The local deformation in a soliton range facilitates proton jumps due to water molecules approaching each other in the HB chain. We suggested that the proton-conducting structures formed along the cristae membrane surface promote direct lateral proton transfer in the OXPHOS system. Collective excitations at the water-membrane interface in a form of two-component soliton ensure the coupled non-dissipative transport of charge carriers and elastic energy of MIM deformation to ATP synthases that may be utilized in ATP synthesis providing maximal efficiency in mitochondrial bioenergetics.
    Keywords:  collective excitations; mitochondrial cristae membrane; oxidative phosphorylation system; proton conducting networks; proton transport; soliton dynamics
    DOI:  https://doi.org/10.3390/e24121813
  5. Biochim Biophys Acta Mol Cell Biol Lipids. 2022 Dec 17. pii: S1388-1981(22)00154-8. [Epub ahead of print]1868(3): 159264
    Futile cycle of β-oxidation and de novo lipogenesis are associated with essential fatty acids depletion in lipoatrophy.
    Adriano B Chaves-Filho, Albert S Peixoto, Érique Castro, Tiago E Oliveira, Luiz A Perandini, Rafael J Moreira, Railmara P da Silva, Beatriz P da Silva, Eduardo H Moretti, Alexandre A Steiner, Sayuri Miyamoto, Marcos Y Yoshinaga, William T Festuccia.
      Total absence of adipose tissue (lipoatrophy) is associated with the development of severe metabolic disorders including hepatomegaly and fatty liver. Here, we sought to investigate the impact of severe lipoatrophy induced by deletion of peroxisome proliferator-activated receptor gamma (PPARγ) exclusively in adipocytes on lipid metabolism in mice. Untargeted lipidomics of plasma, gastrocnemius and liver uncovered a systemic depletion of the essential linoleic (LA) and α-linolenic (ALA) fatty acids from several lipid classes (storage lipids, glycerophospholipids, free fatty acids) in lipoatrophic mice. Our data revealed that such essential fatty acid depletion was linked to increased: 1) capacity for liver mitochondrial fatty acid β-oxidation (FAO), 2) citrate synthase activity and coenzyme Q content in the liver, 3) whole-body oxygen consumption and reduced respiratory exchange rate in the dark period, and 4) de novo lipogenesis and carbon flux in the TCA cycle. The key role of de novo lipogenesis in hepatic steatosis was evidenced by an accumulation of stearic, oleic, sapienic and mead acids in liver. Our results thus indicate that the simultaneous activation of the antagonic processes FAO and de novo lipogenesis in liver may create a futile metabolic cycle leading to a preferential depletion of LA and ALA. Noteworthy, this previously unrecognized cycle may also explain the increased energy expenditure displayed by lipoatrophic mice, adding a new piece to the metabolic regulation puzzle in lipoatrophies.
    Keywords:  Fatty acid oxidation; Linoleic acid; Lipoatrophy; Peroxisome proliferator-activated receptor gamma (PPARγ); de novo lipogenesis; α-Linolenic acid
    DOI:  https://doi.org/10.1016/j.bbalip.2022.159264
  6. Proc Natl Acad Sci U S A. 2022 Dec 27. 119(52): e2215799119
    Multi-color live-cell STED nanoscopy of mitochondria with a gentle inner membrane stain.
    Tianyan Liu, Till Stephan, Peng Chen, Jan Keller-Findeisen, Jingting Chen, Dietmar Riedel, Zhongtian Yang, Stefan Jakobs, Zhixing Chen.
      Capturing mitochondria's intricate and dynamic structure poses a daunting challenge for optical nanoscopy. Different labeling strategies have been demonstrated for live-cell stimulated emission depletion (STED) microscopy of mitochondria, but orthogonal strategies are yet to be established, and image acquisition has suffered either from photodamage to the organelles or from rapid photobleaching. Therefore, live-cell nanoscopy of mitochondria has been largely restricted to two-dimensional (2D) single-color recordings of cancer cells. Here, by conjugation of cyclooctatetraene (COT) to a benzo-fused cyanine dye, we report a mitochondrial inner membrane (IM) fluorescent marker, PK Mito Orange (PKMO), featuring efficient STED at 775 nm, strong photostability, and markedly reduced phototoxicity. PKMO enables super-resolution (SR) recordings of IM dynamics for extended periods in immortalized mammalian cell lines, primary cells, and organoids. Photostability and reduced phototoxicity of PKMO open the door to live-cell three-dimensional (3D) STED nanoscopy of mitochondria for 3D analysis of the convoluted IM. PKMO is optically orthogonal with green and far-red markers, allowing multiplexed recordings of mitochondria using commercial STED microscopes. Using multi-color STED microscopy, we demonstrate that imaging with PKMO can capture interactions of mitochondria with different cellular components such as the endoplasmic reticulum (ER) or the cytoskeleton, Bcl-2-associated X protein (BAX)-induced apoptotic process, or crista phenotypes in genetically modified cells, all at sub-100 nm resolution. Thereby, this work offers a versatile tool for studying mitochondrial IM architecture and dynamics in a multiplexed manner.
    Keywords:  STED nanoscopy; cristae; mitochondria
    DOI:  https://doi.org/10.1073/pnas.2215799119
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