bims-mimbat Biomed News
on Mitochondrial metabolism in brown adipose tissue
Issue of 2022‒10‒23
ten papers selected by
José Carlos de Lima-Júnior
University of California San Francisco

  1. Adipocyte. 2022 Dec;11(1): 616-629
      Brown adipose tissue (BAT) generates heat through non-shivering thermogenesis, and increasing BAT amounts or activity could facilitate obesity treatment and provide metabolic benefits. In mice, BAT has been reported in perirenal, thoracic and cranial sites. Here, we describe new pelvic and lower abdominal BAT depots located around the urethra, internal reproductive and urinary tract organs and major lower pelvic blood vessels, as well as between adjacent muscles where the upper hind leg meets the abdominal cavity. Immunohistochemical, western blot and PCR analyses revealed that these tissues expressed BAT markers such as uncoupling protein 1 (UCP1) and CIDEA, but not white adipose markers, and β3-adrenergic stimulation increased UCP1 amounts, a classic characteristic of BAT tissue. The newly identified BAT stores contained extensive sympathetic innervation with high mitochondrial density and multilocular lipid droplets similar to interscapular BAT. BAT repositories were present and functional neonatally, and showed developmental changes between the neonatal and adult periods. In summary, several new depots showing classical BAT characteristics are reported and characterized in the lower abdominal/pelvic region of mice. These BAT stores are likely significant metabolic regulators in the mouse and some data suggests that similar BAT depots may also exist in humans.
    Keywords:  UCP1; muscle; thermogenesis; ureter; uterus
  2. FEBS Lett. 2022 Oct 17.
      Complex I is a key proton-pumping enzyme in bacterial and mitochondrial respiratory electron transport chains. Using quantum chemistry and electrostatic calculations, we have examined the pKa of the reduced quinone QH-/QH2 in the catalytic cavity of complex I. We find that pKa(QH-/QH2) is very high, above 20. This means that the energy of a single protonation reaction of the doubly reduced quinone (i.e. the reduced semiquinone QH-) is sufficient to drive four protons across the membrane with a potential of 180mV. Based on these calculations, we propose a possible scheme of redox-linked proton pumping by complex I. The model explains how the energy of the protonation reaction can be divided equally between four pumping units of the pump, and how a single proton can drive translocation of four additional protons in multiple pumping blocks.
    Keywords:  Mitochondria; NADH dehydrogenase; coupled electron-proton transfer; proton pumping; proton translocation; respiratory complex I
  3. Nat Metab. 2022 Oct;4(10): 1352-1368
      Cysteine dioxygenase 1 (Cdo1) is a key enzyme in taurine synthesis. Here we show that Cdo1 promotes lipolysis in adipose tissue. Adipose-specific knockout of Cdo1 in mice impairs energy expenditure, cold tolerance and lipolysis, exacerbates diet-induced obesity (DIO) and decreases adipose expression of the key lipolytic genes encoding ATGL and HSL, with little effect on adipose taurine levels. White-adipose-specific overexpression of ATGL and HSL blunts the role of adipose Cdo1 deficiency in promoting DIO. Mechanistically, Cdo1 interacts with PPARγ and facilitates the recruitment of Med24, the core subunit of mediator complex, to ATGL and HSL gene promoters, thereby transactivating their expression. Further, mice with transgenic overexpression of Cdo1 show better cold tolerance, ameliorated DIO and higher lipolysis capacity. Thus, we uncover an unexpected and important role of Cdo1 in regulating adipose lipolysis.
  4. Science. 2022 Oct 21. 378(6617): 276-284
      Misalignment of feeding rhythms with the light-dark cycle leads to disrupted peripheral circadian clocks and obesity. Conversely, restricting feeding to the active period mitigates metabolic syndrome through mechanisms that remain unknown. We found that genetic enhancement of adipocyte thermogenesis through ablation of the zinc finger protein 423 (ZFP423) attenuated obesity caused by consumption of a high-fat diet during the inactive (light) period by increasing futile creatine cycling in mice. Circadian control of adipocyte creatine metabolism underlies the timing of diet-induced thermogenesis, and enhancement of adipocyte circadian rhythms through overexpression of the clock activator brain and muscle Arnt-like protein-1 (BMAL1) ameliorated metabolic complications during diet-induced obesity. These findings uncover rhythmic creatine-mediated thermogenesis as an essential mechanism that drives metabolic benefits during time-restricted feeding.
  5. J Exp Biol. 2022 Oct 21. pii: jeb.244659. [Epub ahead of print]
      The metabolic rate (ṀO2) of eurythermal fishes changes in response to temperature, yet it is unclear how changes in mitochondrial function contribute to changes in ṀO2. We hypothesized that ṀO2 would increase with acclimation temperature in the threespine stickleback (Gasterosteus aculeatus) in parallel with metabolic remodeling at the cellular level but that changes in metabolism in some tissues and organs, such as liver, would contribute more to changes in ṀO2 than others. Threespine stickleback were acclimated to 5, 12 and 20°C for 7 to 21 weeks. At each temperature, standard and maximum metabolic rate (SMR and MMR, respectively), and absolute aerobic scope (AAS) were quantified, along with mitochondrial respiration rates in liver, oxidative skeletal, and cardiac muscles, and the maximal activity of citrate synthase (CS) and lactate dehydrogenase (LDH) in liver, and oxidative and glycolytic skeletal muscles. SMR, MMR and AAS increased with acclimation temperature, along with rates of mitochondrial phosphorylating respiration in all tissues. Low SMR and MMR at 5°C were associated with low or undetectable rates of mitochondrial complex II activity and a greater reliance on complex I activity in liver, oxidative skeletal muscle, and heart. SMR was positively correlated with cytochrome c oxidase (CCO) activity in liver and oxidative muscle but not mitochondrial proton leak, while MMR was positively correlated with CCO in liver. Overall, the results suggest that changes in ṀO2 in response to temperature are driven by changes in some aspects of mitochondrial function in some, but not all tissues of threespine stickleback.
    Keywords:  Acclimation; Aerobic scope; Mitochondria; Stickleback; Temperature
  6. Science. 2022 Oct 21. 378(6617): 251-252
      Synchronizing food intake with the body clock boosts thermogenesis and limits obesity.
  7. J Exp Biol. 2022 Oct 21. pii: jeb.244934. [Epub ahead of print]
      For ectothermic species, adaptation to thermal changes is of critical importance. Mitochondrial oxidative phosphorylation (OXPHOS), which leverages multiple electron pathways to produce energy needed for survival, is among the crucial metabolic processes impacted by temperature. Our aim in this study was to identify how changes in temperature affect the less-studied electron transferring flavoprotein pathway, fed by fatty acid substrates. We used the planarian, Dugesia tigrina, acclimated for four weeks at 10 (cold-acclimated) or 20°C (normothermic). Respirometry experiments were conducted at either 10 or 20°C assay temperatures to study specific states of the OXPHOS process using the fatty acid substrates palmitoylcarnitine (long-chain), octanoylcarnitine (medium-chain), or acetylcarnitine (short-chain). Following cold acclimation, octanoylcarnitine exhibited increases in both the OXPHOS and ET (electron transfer, noncoupled) states, indicating that the pathway involved in medium-chain length fatty acids adjusts to cold temperatures. Acetylcarnitine only showed an increase in the OXPHOS state due to cold acclimation, but not in the ET state, indicative of a change in phosphorylation system capacity rather than fatty acid β-oxidation. Palmitoylcarnitine oxidation was unaffected. Our results show that cold acclimation in D. tigrina caused a specific adjustment in the capacity to metabolize medium-chain fatty acid rather than an adjustment in the activity of enzymes carnitine-acylcarnitine translocase, carnitine acyltransferase, and carnitine palmitoyltransferase-2. Here, we provide novel evidence of the alterations in fatty acid β-oxidation during cold acclimation in D. tigrina.
    Keywords:  Fatty acid oxidation; Mitochondrial respiration; Thermal acclimation
  8. Mitochondrion. 2022 Oct 16. pii: S1567-7249(22)00085-X. [Epub ahead of print]
      TRPV4 is associated with the development of neuropathic pain, sensory defects, muscular dystrophies, neurodegenerative disorders, Charcot Marie Tooth and skeletal dysplasia. In all these cases, mitochondrial abnormalities are prominent. Here, we demonstrate that TRPV4, localizes to a subpopulation of mitochondria in various cell lines. Improper expression and/or function of TRPV4 induces several mitochondrial abnormalities. TRPV4 is also involved in the regulation of mitochondrial numbers, Ca2+-levels and mitochondrial temperature. Accordingly, several naturally occurring TRPV4 mutations affect mitochondrial morphology and distribution. These findings may help in understanding the significance of mitochondria in TRPV4-mediated channelopathies possibly classifying them as mitochondrial diseases.
    Keywords:  Mitochondrial Ca(2+); Neuro-Muscular Dystrophies Mitochondrial diseases; TRP channels; mitochondrial dynamics; mitochondrial temperature
  9. Nat Commun. 2022 Oct 17. 13(1): 6113
      TRP channels sense temperatures ranging from noxious cold to noxious heat. Whether specialized TRP thermosensor modules exist and how they control channel pore gating is unknown. We studied purified human TRPA1 (hTRPA1) truncated proteins to gain insight into the temperature gating of hTRPA1. In patch-clamp bilayer recordings, ∆1-688 hTRPA1, without the N-terminal ankyrin repeat domain (N-ARD), was more sensitive to cold and heat, whereas ∆1-854 hTRPA1, also lacking the S1-S4 voltage sensing-like domain (VSLD), gained sensitivity to cold but lost its heat sensitivity. In hTRPA1 intrinsic tryptophan fluorescence studies, cold and heat evoked rearrangement of VSLD and the C-terminus domain distal to the transmembrane pore domain S5-S6 (CTD). In whole-cell electrophysiology experiments, replacement of the CTD located cysteines 1021 and 1025 with alanine modulated hTRPA1 cold responses. It is proposed that hTRPA1 CTD harbors cold and heat sensitive domains allosterically coupled to the S5-S6 pore region and the VSLD, respectively.
  10. Nat Metab. 2022 Oct;4(10): 1336-1351
      Mitochondrial respiratory complexes form superassembled structures called supercomplexes. COX7A2L is a supercomplex-specific assembly factor in mammals, although its implication for supercomplex formation and cellular metabolism remains controversial. Here we identify a role for COX7A2L for mitochondrial supercomplex formation in humans. By using human cis-expression quantitative trait loci data, we highlight genetic variants in the COX7A2L gene that affect its skeletal muscle expression specifically. The most significant cis-expression quantitative trait locus is a 10-bp insertion in the COX7A2L 3' untranslated region that increases messenger RNA stability and expression. Human myotubes harboring this insertion have more supercomplexes and increased respiration. Notably, increased COX7A2L expression in the muscle is associated with lower body fat and improved cardiorespiratory fitness in humans. Accordingly, specific reconstitution of Cox7a2l expression in C57BL/6J mice leads to higher maximal oxygen consumption, increased lean mass and increased energy expenditure. Furthermore, Cox7a2l expression in mice is induced specifically in the muscle upon exercise. These findings elucidate the genetic basis of mitochondrial supercomplex formation and function in humans and show that COX7A2L plays an important role in cardiorespiratory fitness, which could have broad therapeutic implications in reducing cardiovascular mortality.