bims-mimbat Biomed News
on Mitochondrial metabolism in brown adipose tissue
Issue of 2022‒08‒14
fourteen papers selected by
José Carlos de Lima-Júnior
University of California San Francisco

  1. Proc Natl Acad Sci U S A. 2022 Aug 16. 119(33): e2205276119
      Brown adipose tissue (BAT) is a key thermogenic organ whose expression of uncoupling protein 1 (UCP1) and ability to maintain body temperature in response to acute cold exposure require histone deacetylase 3 (HDAC3). HDAC3 exists in tight association with nuclear receptor corepressors (NCoRs) NCoR1 and NCoR2 (also known as silencing mediator of retinoid and thyroid receptors [SMRT]), but the functions of NCoR1/2 in BAT have not been established. Here we report that as expected, genetic loss of NCoR1/2 in BAT (NCoR1/2 BAT-dKO) leads to loss of HDAC3 activity. In addition, HDAC3 is no longer bound at its physiological genomic sites in the absence of NCoR1/2, leading to a shared deregulation of BAT lipid metabolism between NCoR1/2 BAT-dKO and HDAC3 BAT-KO mice. Despite these commonalities, loss of NCoR1/2 in BAT does not phenocopy the cold sensitivity observed in HDAC3 BAT-KO, nor does loss of either corepressor alone. Instead, BAT lacking NCoR1/2 is inflamed, particularly with respect to the interleukin-17 axis that increases thermogenic capacity by enhancing innervation. Integration of BAT RNA sequencing and chromatin immunoprecipitation sequencing data revealed that NCoR1/2 directly regulate Mmp9, which integrates extracellular matrix remodeling and inflammation. These findings reveal pleiotropic functions of the NCoR/HDAC3 corepressor complex in BAT, such that HDAC3-independent suppression of BAT inflammation counterbalances stimulation of HDAC3 activity in the control of thermogenesis.
    Keywords:  brown adipose tissue; corepressor; inflammation; thermogenesis; transcription
  2. Autophagy. 2022 Aug 10.
      Brown adipose tissue (BAT) thermogenesis affects energy balance, and thereby it has the potential to induce weight loss and to prevent obesity. Here we document a macroautophagic/autophagic-dependent mechanism of PPARG activity regulation that induces brown adipose differentiation and thermogenesis, and that is mediated by TP53INP2. Disruption of TP53INP2-dependent autophagy reduced brown adipogenesis in cultured cells. In vivo specific-tp53inp2 ablation in brown precursor cells or in adult mice decreased the expression of thermogenic and mature adipocytes genes in BAT. As a result, TP53INP2-deficient mice had reduced UCP1 content in BAT and impaired maximal thermogenic capacity, leading to lipid accumulation and to positive energy balance. Mechanistically, TP53INP2 stimulates PPARG activity and adipogenesis in brown adipose cells by promoting the autophagic degradation of NCOR1, a PPARG co-repressor. Moreover, the modulation of TP53INP2 expression in BAT and in human brown adipocytes suggest that this protein increases PPARG activity during metabolic activation of brown fat. In all, we have identified a novel molecular explanation to the contribution of autophagy to BAT energy metabolism that could facilitate the design of therapeutic strategies against obesity and its metabolic complications.
    Keywords:  Autophagy; brown adipose tissue; metabolism; obesity; thermogenesis
  3. Cardiovasc Res. 2022 Aug 10. pii: cvac131. [Epub ahead of print]
      Brown adipocytes within brown adipose tissue (BAT) and beige adipocytes within white adipose tissue dissipate nutritional energy as heat. Studies in mice have shown that activation of thermogenesis in brown and beige adipocytes enhances the lipolytic processing of triglyceride-rich lipoproteins (TRLs) in plasma to supply these adipocytes with fatty acids for oxidation. This process results in formation of TRL remnants that are removed from the circulation through binding of apolipoprotein E (ApoE) on their surface to the low-density lipoprotein receptor (LDLR) on hepatocytes, followed by internalization. Concomitantly, lipolytic processing of circulating TRLs leads to generation of excess surface phospholipids that are transferred to nascent high-density lipoproteins (HDL), increasing their capacity for reverse cholesterol transport. Activation of thermogenic adipocytes thus lowers circulating triglycerides and non-HDL-cholesterol, while it increases HDL-cholesterol. The combined effect is protection from atherosclerosis development, which becomes evident in humanized mouse models with an intact ApoE-LDLR clearance pathway only, and is additive to the effects of classical lipid-lowering drugs including statins and proprotein convertase subtilisin/kexin type 9 inhibitors. A large recent study revealed that the presence of metabolically active BAT in humans is associated with lower triglycerides, higher HDL-cholesterol and lower risk of cardiovascular diseases. This narrative review aims to provide leads for further exploration of thermogenic adipose tissue as a therapeutic target. To this end, we describe the latest knowledge on the role of BAT in lipoprotein metabolism and address, for example, the discovery of the β2-adrenergic receptor as the dominant adrenergic receptor in human thermogenic adipocytes.
    Keywords:  adipose tissue; atherosclerosis; cardiovascular disease; dyslipidemia; non-shivering thermogenesis
  4. Adipocyte. 2022 Dec;11(1): 463-476
      A large number of studies in recent years have aimed to devise novel therapeutic strategies to increase adipose tissue metabolic activity and fight the global obesity epidemics. Growing evidence suggests that cells are able to accept isolated mitochondria by a simple coincubation in a process known as mitochondrial transformation. Therefore, we aimed to test whether mitochondrial transformation occurs in mature adipocytes, and whether this phenomenon could be utilized as a therapeutic approach to increase adipose tissue mitochondrial content and improve metabolic control. We provide evidence that both brown and white adipocytes are able to rapidly accept a large amount of brown adipocyte-derived mitochondria, which remain functional for several days and significantly contribute to cellular respiration in vitro. However, we did not find any evidence that internalization of exogenous mitochondria would trigger transcriptional changes in the recipient cells. Moreover, injection of a large amount of brown adipocyte-derived mitochondria into the inguinal fat of C57BL/6 mice failed to increase whole-body energy expenditure, and reduce body weight gain under obesogenic conditions. This might be due to activation of immune response and rapid removal of administered mitochondria. Altogether, our study adds information on the usability of mitochondrial transformation in the treatment of metabolic disease.
    Keywords:  Adipocyte; energy expenditure; metabolism; mitochondria; mitochondrial respiration; mitochondrial transformation
  5. Biochim Biophys Acta Bioenerg. 2022 Aug 09. pii: S0005-2728(22)00378-4. [Epub ahead of print] 148908
      Mitochondria play an important role not only in producing energy for the cell but also for regulating mitochondrial and cell function depending on the cell's needs and environment. Uptake of cations, anions, and substrates requires a stable, polarized transmembrane charge potential (ΔΨm). Chemiosmosis requires ion exchangers to remove Na+, K+, Ca2+, PO43-, and other charged species, that enter mitochondria. Knowledge of the kinetics of mitochondrial (m) cation channels and exchangers is important to understand their roles in regulating mitochondrial chemiosmosis and bioenergetics. The influx/efflux of K+, the most abundant mitochondrial cation, alters mitochondrial volume and shape by bringing in anions and H2O by osmosis. The effects of K+ uptake through ligand-specific mK+ channels stimulated/inhibited by agonists/antagonists on mitochondrial volume (swelling/contraction) are well known. However, a more important role for K+ influx is likely its effects on H+ cycling and bioenergetics facilitated by mitochondrial (m) K+/H+ exchange (mKHE), though the kinetics and consequences of K+ efflux by KHE are not well described. We hypothesized that a major role of K+ influx/efflux is stimulation of respiration via the influx of H+ by KHE. We proposed to modulate KHE activity by energizing guinea pig heart isolated mitochondria and by altering the mK+ cycle to capture changes in mitochondrial volume, pHm, ΔΨm, and respiration that would reflect a role for H+ influx via KHE to regulate bioenergetics. To test this, mitochondria were suspended in a 150 mM K+ buffer at pH 6.9, or in a 140 mM Cs+ buffer at pH 7.6 or 6.9 with added 10 mM K+, minimal Ca2+ and free of Na+. O2 content was measured by a Clark electrode, and pHm, ΔΨm, and volume, were measured by fluorescence spectrophotometry and light-scattering. Adding pyruvic acid (PA) alone caused increases in volume and respiration and a rapid decrease in the transmembrane pH gradient (ΔpHm = pHin-pHext) at pHext 6.9> > 7.6, so that ΔΨm was charged and maintained. BKCa agonist NS1619 and antagonist paxilline modified these effects, and KHE inhibitor quinine, and K+ ionophore valinomycin depolarized ΔΨm. We postulate that K+ efflux-induced H+ influx via KHE causes an inward H+ leak that stimulates respiration, but at buffer pH 6.9 also utilizes the energy of ΔpHm, the smaller component of the overall proton motive force, ΔμH+. Thus ΔpHm establishes and maintains the ΔΨm required for utilization of substrates, entry of all cations, and for oxidative phosphorylation. Thus, K+ influx/efflux appears to play a pivotal role in regulating energetics while maintaining mitochondrial ionic balance and volume homeostasis.
    Keywords:  Bioenergetics; Membrane potential; Mitochondria; Potassium/hydrogen exchange; Volume; pH gradient
  6. Biochemistry. 2022 Aug 09.
      Biotin-dependent enzymes employ a carrier domain to efficiently transport reaction intermediates between distant active sites. The translocation of this carrier domain is critical to the interpretation of kinetic and structural studies, but there have been few direct attempts to investigate the dynamic interplay between ligand binding and carrier domain positioning in biotin-dependent enzymes. Pyruvate carboxylase (PC) catalyzes the MgATP-dependent carboxylation of pyruvate where the biotinylated carrier domain must translocate ∼70 Å from the biotin carboxylase domain to the carboxyltransferase domain. Many prior studies have assumed that carrier domain movement is governed by ligand-induced conformational changes, but the mechanism underlying this movement has not been confirmed. Here, we have developed a system to directly observe PC carrier domain positioning in both the presence and absence of ligands, independent of catalytic turnover. We have incorporated a cross-linking trap that reports on the interdomain conformation of the carrier domain when it is positioned in proximity to a neighboring carboxyltransferase domain. Cross-linking was monitored by gel electrophoresis, inactivation kinetics, and intrinsic tryptophan fluorescence. We demonstrate that the carrier domain positioning equilibrium is sensitive to substrate analogues and the allosteric activator acetyl-CoA. Notably, saturating concentrations of biotin carboxylase ligands do not prevent carrier domain trapping proximal to the neighboring carboxyltransferase domain, demonstrating that carrier domain positioning is governed by conformational selection. This model of carrier domain translocation in PC can be applied to other multi-domain enzymes that employ large-scale domain motions to transfer intermediates during catalysis.
  7. Adipocyte. 2022 Dec;11(1): 448-462
      Adipogenesis involves complex interactions between transcription and metabolic signalling. Exploration of the developmental characteristics of intramuscular adipocyte will provide targets for enhancing beef cattle marbling without increasing obesity. Few reports have compared bovine perirenal and intramuscular adipocyte transcriptomes using the combined analysis of transcriptomes and lipid metabolism to explore differences in adipogenic characteristics. We identified perirenal preadipocytes (PRA) and intramuscular preadipocytes (IMA) in Qinchuan cattle. We found that IMA were highly prolific in the early stages of adipogenesis, while PRA shows a stronger adipogenic ability in the terminal differentiation. Bovine perirenal and intramuscular adipocytes were detected through the combined analysis of the transcriptome and metabolome. More triglyceride was found to be upregulated in perirenal adipocytes; however, more types and amounts of unsaturated fatty acids were detected in intramuscular adipocytes, including eicosapentaenoic acid (20:5 n-3; EPA) and docosahexaenoic acid (22:6 n-3; DHA). Furthermore, differentially expressed genes in perirenal and intramuscular adipocytes were positively correlated with the eicosanoid, phosphatidylcholine (PC), phosphatidyl ethanolamine (PE), and sphingomyelin contents. Associated differential metabolic pathways included the glycerolipid and glycerophospholipid metabolisms. Our research findings provide a basis for the screening of key metabolic pathways or genes and metabolites involved in intramuscular fat production in cattle.
    Keywords:  Beef; adipogenic; lipid dynamics; marbling; transcriptome
  8. Plant Cell. 2022 Aug 08. pii: koac242. [Epub ahead of print]
      Ca2+ signaling is central to plant development and acclimation. While Ca2+-responsive proteins have been investigated intensely in plants, only a few Ca2+-permeable channels have been identified, and our understanding of how intracellular Ca2+ fluxes are facilitated remains limited. Arabidopsis thaliana homologues of the mammalian channel-forming mitochondrial calcium uniporter (MCU) protein showed Ca2+ transport activity in vitro. Yet, the evolutionary complexity of MCU proteins, as well as reports about alternative systems and unperturbed mitochondrial Ca2+ uptake in knockout lines of MCU genes, leave critical questions about the in vivo functions of the MCU protein family in plants unanswered. Here, we demonstrate that MCU proteins mediate mitochondrial Ca2+ transport in planta and that this mechanism is the major route for fast Ca2+ uptake. Guided by the subcellular localization, expression, and conservation of MCU proteins, we generated an mcu triple knockout line. Using Ca2+ imaging in living root tips and the stimulation of Ca2+ transients of different amplitudes, we demonstrated that mitochondrial Ca2+ uptake became limiting in the triple mutant. The drastic cell physiological phenotype of impaired subcellular Ca2+ transport coincided with deregulated jasmonate-related signaling and thigmomorphogenesis. Our findings establish MCUs as a major mitochondrial Ca2+ entry route in planta and link mitochondrial Ca2+ transport with phytohormone signaling.
  9. J Biol Chem. 2022 Aug 04. pii: S0021-9258(22)00745-1. [Epub ahead of print] 102303
      Many cell surface stimuli cause calcium release from endoplasmic reticulum (ER) stores to regulate cellular physiology. Upon ER calcium store depletion, the ER-resident protein stromal interaction molecule 1 (STIM1) physically interacts with plasma membrane protein Orai1 to induce calcium release-activated calcium (CRAC) currents that conduct calcium influx from the extracellular milieu. Although the physiological relevance of this process is well established, the mechanism supporting the assembly of these proteins is incompletely understood. Earlier we demonstrated a previously unknown post-translational modification of Orai1 with long-chain fatty acids, known as S-acylation. We found that S-acylation of Orai1 is dynamically regulated in a stimulus-dependent manner and essential for its function as a calcium channel. Here using the acyl-resin assisted capture (acyl-RAC) assay, we show that STIM1 is also rapidly S-acylated at cysteine 437 upon ER calcium store depletion. Using a combination of live cell imaging and electrophysiology approaches with a mutant STIM1 protein which could not be S-acylated, we determined that the S-acylation of STIM1 is required for the assembly of STIM1 into puncta with Orai1 and full CRAC channel function. Together with the S-acylation of Orai1, our data suggest that stimulus-dependent S-acylation of CRAC channel components Orai1 and STIM1 is a critical mechanism facilitating the CRAC channel assembly and function.
  10. Trends Endocrinol Metab. 2022 Aug 08. pii: S1043-2760(22)00140-0. [Epub ahead of print]
      Hexokinase (HK)-1 mitochondrial-binding mechanisms and consequential physiological relevance remain unclear. Recently, De Jesus et al. studied myeloid cells with HK1 carrying mutated mitochondrial-binding domains (MBDs) and provided evidence that HK1 localization controls glucose metabolic fate. Increases in cytosolic HK1 may also contribute to the inflammation associated with diabetes and aging.
    Keywords:  aging; deacetylation; diabetes; glucose metabolism; inflammation; nitrosylation
  11. Redox Biol. 2022 Aug 05. pii: S2213-2317(22)00201-4. [Epub ahead of print]55 102429
      Mitochondria-targeted H2S donors are thought to protect against acute ischemia-reperfusion (IR) injury by releasing H2S that decreases oxidative damage. However, the rate of H2S release by current donors is too slow to be effective upon administration following reperfusion. To overcome this limitation here we develop a mitochondria-targeted agent, MitoPerSulf that very rapidly releases H2S within mitochondria. MitoPerSulf is quickly taken up by mitochondria, where it reacts with endogenous thiols to generate a persulfide intermediate that releases H2S. MitoPerSulf is acutely protective against cardiac IR injury in mice, due to the acute generation of H2S that inhibits respiration at cytochrome c oxidase thereby preventing mitochondrial superoxide production by lowering the membrane potential. Mitochondria-targeted agents that rapidly generate H2S are a new class of therapy for the acute treatment of IR injury.
    Keywords:  Hydrogen sulfide donors; Ischemia-reperfusion injury; Mitochondria; Mitochondria targeting; Reverse electron transport (RET)
  12. Proc Natl Acad Sci U S A. 2022 Aug 16. 119(33): e2121040119
      Regulation of firing rate homeostasis constitutes a fundamental property of central neural circuits. While intracellular Ca2+ has long been hypothesized to be a feedback control signal, the molecular machinery enabling a network-wide homeostatic response remains largely unknown. We show that deletion of insulin-like growth factor-1 receptor (IGF-1R) limits firing rate homeostasis in response to inactivity, without altering the distribution of baseline firing rates. The deficient firing rate homeostatic response was due to disruption of both postsynaptic and intrinsic plasticity. At the cellular level, we detected a fraction of IGF-1Rs in mitochondria, colocalized with the mitochondrial calcium uniporter complex (MCUc). IGF-1R deletion suppressed transcription of the MCUc members and burst-evoked mitochondrial Ca2+ (mitoCa2+) by weakening mitochondria-to-cytosol Ca2+ coupling. Overexpression of either mitochondria-targeted IGF-1R or MCUc in IGF-1R-deficient neurons was sufficient to rescue the deficits in burst-to-mitoCa2+ coupling and firing rate homeostasis. Our findings indicate that mitochondrial IGF-1R is a key regulator of the integrated homeostatic response by tuning the reliability of burst transfer by MCUc. Based on these results, we propose that MCUc acts as a homeostatic Ca2+ sensor. Faulty activation of MCUc may drive dysregulation of firing rate homeostasis in aging and in brain disorders associated with aberrant IGF-1R/MCUc signaling.
    Keywords:  IGF-1 receptor; MCU; firing rate homeostasis; homeostatic plasticity; mitochonria
  13. Mol Cell. 2022 Aug 09. pii: S1097-2765(22)00708-0. [Epub ahead of print]
      Mitochondrial energetics and respiration have emerged as important factors in how cancer cells respond to or evade apoptotic signals. The study of the functional connection between these two processes may provide insight into following questions old and new: how might we target respiration or downstream signaling pathways to amplify apoptotic stress in the context of cancer therapy? Why are respiration and apoptotic regulation housed in the same organelle? Here, we briefly review mitochondrial respiration and apoptosis and then focus on how the intersection of these two processes is regulated by cytoplasmic signaling pathways such as the integrated stress response.
    Keywords:  CRISPR; apoptosis; cancer; electron transport chain; integrated stress response; leukemia; mitochondria; oncology; oxidative phosphorylation; respiration; stress; venetoclax
  14. Mol Metab. 2022 Aug 06. pii: S2212-8778(22)00129-6. [Epub ahead of print] 101560
      OBJECTIVE: Mitochondrial disorders are often characterized by muscle weakness and fatigue. Null mutations in the heart-muscle adenine nucleotide translocator isoform 1 (ANT1) of both humans and mice cause cardiomyopathy and myopathy associated with exercise intolerance and muscle weakness. Here we decipher the molecular underpinnings of ANT1-deficiency-mediated exercise intolerance.METHODS: This was achieved by correlating exercise physiology, mitochondrial function and metabolomics of mice deficient in ANT1 and comparing this to control mice.
    RESULTS: We demonstrate a peripheral limitation of skeletal muscle mitochondrial respiration and a reduced complex I respiration in ANT1-deficient mice. Upon exercise, this results in a lack of NAD+ leading to a substrate limitation and stalling of the TCA cycle and mitochondrial respiration, further limiting skeletal muscle mitochondrial respiration. Treatment of ANT1-deficient mice with nicotinamide riboside increased NAD+ levels in skeletal muscle and liver, which increased the exercise capacity and the mitochondrial respiration.
    CONCLUSION: Increasing NAD + levels with nicotinamide riboside can alleviate the exercise intolerance associated to ANT1-deficiency, indicating the therapeutic potential of NAD+-stimulating compounds in mitochondrial myopathies.
    Keywords:  Exercise; Mitochondrial disorder; NAD(+)/NADH; Nicotinamide riboside