bims-mimbat Biomed News
on Mitochondrial metabolism in brown adipose tissue
Issue of 2024‒04‒14
ten papers selected by
José Carlos de Lima-Júnior, Washington University
  1. Glucose regulation of adipose tissue browning by CBP/p300- and HDAC3-mediated reversible acetylation of CREBZF.
  2. Terrestrial birth and body size tune UCP1 functionality in seals.
  3. Statin-mediated reduction in mitochondrial cholesterol primes an anti-inflammatory response in macrophages by upregulating Jmjd3.
  4. Fatty acyl-coenzyme A activates mitochondrial division through oligomerization of MiD49 and MiD51.
  5. Mrs2-mediated mitochondrial magnesium uptake is essential for the regulation of MCU-mediated mitochondrial Ca2+ uptake and viability.
  6. The interplay between sodium/glucose cotransporter type 2 and mitochondrial ionic environment.
  7. Adipose tissue macrophages secrete small extracellular vesicles that mediate rosiglitazone-induced insulin sensitization.
  8. Mitochondrial respiration atlas reveals differential changes in mitochondrial function across sex and age.
  9. Coenzyme Q4 is a functional substitute for coenzyme Q10 and can be targeted to the mitochondria.
  10. Perilipin membrane integration determines lipid droplet heterogeneity in differentiating adipocytes.
  1. Proc Natl Acad Sci U S A. 2024 Apr 16. 121(16): e2318935121
    Glucose regulation of adipose tissue browning by CBP/p300- and HDAC3-mediated reversible acetylation of CREBZF.
    Aoyuan Cui, Yaqian Xue, Weitong Su, Jing Lin, Yuxiao Liu, Genxiang Cai, Qin Wan, Yang Jiang, Dong Ding, Zengpeng Zheng, Shuang Wei, Wenjing Li, Jiaxin Shen, Jian Wen, Mengyao Huang, Jiuxiang Zhao, Xiaojie Zhang, Yuwu Zhao, Hong Li, Hao Ying, Haibing Zhang, Yan Bi, Yan Chen, Aimin Xu, Yong Xu, Yu Li.
      Glucose is required for generating heat during cold-induced nonshivering thermogenesis in adipose tissue, but the regulatory mechanism is largely unknown. CREBZF has emerged as a critical mechanism for metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as nonalcoholic fatty liver disease (NAFLD). We investigated the roles of CREBZF in the control of thermogenesis and energy metabolism. Glucose induces CREBZF in human white adipose tissue (WAT) and inguinal WAT (iWAT) in mice. Lys208 acetylation modulated by transacetylase CREB-binding protein/p300 and deacetylase HDAC3 is required for glucose-induced reduction of proteasomal degradation and augmentation of protein stability of CREBZF. Glucose induces rectal temperature and thermogenesis in white adipose of control mice, which is further potentiated in adipose-specific CREBZF knockout (CREBZF FKO) mice. During cold exposure, CREBZF FKO mice display enhanced thermogenic gene expression, browning of iWAT, and adaptive thermogenesis. CREBZF associates with PGC-1α to repress thermogenic gene expression. Expression levels of CREBZF are negatively correlated with UCP1 in human adipose tissues and increased in WAT of obese ob/ob mice, which may underscore the potential role of CREBZF in the development of compromised thermogenic capability under hyperglycemic conditions. Our results reveal an important mechanism of glucose sensing and thermogenic inactivation through reversible acetylation.
    Keywords:  CREBZF; adipose tissue; glucose-sensing pathway; reversible acetylation; thermogenesis
    DOI:  https://doi.org/10.1073/pnas.2318935121
  2. Mol Biol Evol. 2024 Apr 12. pii: msae075. [Epub ahead of print]
    Terrestrial birth and body size tune UCP1 functionality in seals.
    Michael J Gaudry, Jane Khudyakov, Laura Pirard, Cathy Debier, Daniel Crocker, Paul G Crichton, Martin Jastroch.
      The molecular evolution of the mammalian heater protein UCP1 is a powerful biomarker to understand thermoregulatory strategies during species radiation into extreme climates, such as aquatic life with high thermal conductivity. While fully aquatic mammals lost UCP1, most semi-aquatic seals display intact UCP1 genes, apart from large elephant seals. Here, we show that UCP1 thermogenic activity of the small-bodied harbor seal is equally potent compared to terrestrial orthologues, emphasizing its importance for neonatal survival on land. In contrast, elephant seal UCP1 does not display thermogenic activity, not even when translating a repaired or a recently highlighted truncated version. Thus, the thermogenic benefits for neonatal survival during terrestrial birth in semi-aquatic pinnipeds maintained evolutionary selection pressure on UCP1 function, and were only outweighed by extreme body sizes among elephant seals, fully eliminating UCP1-dependent thermogenesis.
    DOI:  https://doi.org/10.1093/molbev/msae075
  3. Elife. 2024 Apr 11. pii: e85964. [Epub ahead of print]13
    Statin-mediated reduction in mitochondrial cholesterol primes an anti-inflammatory response in macrophages by upregulating Jmjd3.
    Zeina Salloum, Kristin Dauner, Yun-Fang Li, Neha Verma, David Valdivieso-González, Víctor G Almendro-Vedia, John D Zhang, Kiran Nakka, Mei Xi Chen, Jeffrey G McDonald, Chase D Corley, Alexander Sorisky, Bao-Liang Song, Iván López-Montero, Jie Luo, Jeffrey F Dilworth, Xiaohui Zha.
      Stains are known to be anti-inflammatory, but the mechanism remains poorly understood. Here we show that macrophages, either treated with statin in vitro or from statin-treated mice, have reduced cholesterol levels and higher expression of Jmjd3, a H3K27me3 demethylase. We provide evidence that lowering cholesterol levels in macrophages suppresses the ATP synthase in the inner mitochondrial membrane (IMM) and changes the proton gradient in the mitochondria. This activates NFkB and Jmjd3 expression to remove the repressive marker H3K27me3. Accordingly, the epigenome is altered by the cholesterol reduction. When subsequently challenged by the inflammatory stimulus LPS (M1), both macrophages treated with statins in vitro or isolated from statin-treated mice in vivo, express lower levels pro-inflammatory cytokines than controls, while augmenting anti-inflammatory Il10 expression. On the other hand, when macrophages are alternatively activated by IL4 (M2), statins promote the expression of Arg1, Ym1, and Mrc1. The enhanced expression is correlated with the statin-induced removal of H3K27me3 from these genes prior to activation. In addition, Jmjd3 and its demethylase activity are necessary for cholesterol to modulate both M1 and M2 activation. We conclude that upregulation of Jmjd3 is a key event for the anti-inflammatory function of statins on macrophages.
    Keywords:  cell biology; mouse
    DOI:  https://doi.org/10.7554/eLife.85964
  4. Nat Cell Biol. 2024 Apr 09.
    Fatty acyl-coenzyme A activates mitochondrial division through oligomerization of MiD49 and MiD51.
    Ao Liu, Frieda Kage, Asan F Abdulkareem, Mac Pholo Aguirre-Huamani, Gracie Sapp, Halil Aydin, Henry N Higgs.
      Mitochondrial fission occurs in many cellular processes, but the regulation of fission is poorly understood. We show that long-chain acyl-coenzyme A (LCACA) activates two related mitochondrial fission proteins, MiD49 and MiD51, by inducing their oligomerization, which activates their ability to stimulate the DRP1 GTPase. The 1:1 stoichiometry of LCACA:MiD in the oligomer suggests interaction in the previously identified nucleotide-binding pocket, and a point mutation in this pocket reduces LCACA binding and LCACA-induced oligomerization for MiD51. In cells, this LCACA binding mutant does not assemble into puncta on mitochondria or rescue MiD49/51 knockdown effects on mitochondrial length and DRP1 recruitment. Furthermore, cellular treatment with BSA-bound oleic acid, which causes increased LCACA, promotes mitochondrial fission in an MiD49/51-dependent manner. These results suggest that LCACA is an endogenous ligand for MiDs, inducing mitochondrial fission and providing a potential mechanism for fatty-acid-induced mitochondrial division. Finally, MiD49 or MiD51 oligomers synergize with Mff, but not with actin filaments, in DRP1 activation, suggesting distinct pathways for DRP1 activation.
    DOI:  https://doi.org/10.1038/s41556-024-01400-3
  5. Mitochondrion. 2024 Apr 08. pii: S1567-7249(24)00035-7. [Epub ahead of print] 101877
    Mrs2-mediated mitochondrial magnesium uptake is essential for the regulation of MCU-mediated mitochondrial Ca2+ uptake and viability.
    Thiruvelselvan Ponnusamy, Prema Velusamy, Santhanam Shanmughapriya.
      Mitochondrial Ca2+ uptake is essential in regulating bioenergetics, cell death, and cytosolic Ca2+ transients. Mitochondrial Calcium Uniporter (MCU) mediates the mitochondrial Ca2+ uptake. Though MCU regulation by MICUs is unequivocally established, there needs to be more knowledge of whether divalent cations regulate MCU. Here, we set out to understand the mitochondrial matrix Mg2+-dependent regulation of MCU activity. We showed that decreased matrix [Mg2+] is associated with increased MCU activity and significantly prompted mitochondrial permeability transition pore opening. Our findings support the critical role of mMg2+ in regulating MCU activity.
    Keywords:  Calcium; Cell death; MCU; Magnesium; Mitochondria; Mrs2; mPTP
    DOI:  https://doi.org/10.1016/j.mito.2024.101877
  6. Mitochondrion. 2024 Apr 08. pii: S1567-7249(24)00036-9. [Epub ahead of print]76 101878
    The interplay between sodium/glucose cotransporter type 2 and mitochondrial ionic environment.
    Gianmarco Borriello, Veronica Buonincontri, Antonio de Donato, Michele Della Corte, Ilenia Gravina, Pietro Iulianiello, Rashmi Joshi, Pasquale Mone, Giovanna Cacciola, Davide Viggiano.
      Mitochondrial volume is maintained through the permeability of the inner mitochondrial membrane by a specific aquaporin and the osmotic balance between the mitochondrial matrix and cellular cytoplasm. Various electrolytes, such as calcium and hydrogen ions, potassium, and sodium, as well as other osmotic substances, affect the swelling of mitochondria. Intracellular glucose levels may also affect mitochondrial swelling, although the relationship between mitochondrial ion homeostasis and intracellular glucose is poorly understood. This article reviews what is currently known about how the Sodium-Glucose transporter (SGLT) may impact mitochondrial sodium (Na+) homeostasis. SGLTs regulate intracellular glucose and sodium levels and, therefore, interfere with mitochondrial ion homeostasis because mitochondrial Na+ is closely linked to cytoplasmic calcium and sodium dynamics. Recently, a large amount of data has been available on the effects of SGLT2 inhibitors on mitochondria in different cell types, including renal proximal tubule cells, endothelial cells, mesangial cells, podocytes, neuronal cells, and cardiac cells. The current evidence suggests that SGLT inhibitors (SGLTi) may affect mitochondrial dynamics regarding intracellular Sodium and hydrogen ions. Although the regulation of mitochondrial ion channels by SGLTs is still in its infancy, the evidence accumulated thus far of the effect of SGLTi on mitochondrial functions certainly will foster further research in this direction.
    Keywords:  Endothelium; Gliflozins; Proximal tubule; SGLT2; Sodium; Swelling
    DOI:  https://doi.org/10.1016/j.mito.2024.101878
  7. Nat Metab. 2024 Apr 11.
    Adipose tissue macrophages secrete small extracellular vesicles that mediate rosiglitazone-induced insulin sensitization.
    Theresa V Rohm, Felipe Castellani Gomes Dos Reis, Roi Isaac, Cairo Murphy, Karina Cunha E Rocha, Gautam Bandyopadhyay, Hong Gao, Avraham M Libster, Rizaldy C Zapata, Yun Sok Lee, Wei Ying, Charlene Miciano, Allen Wang, Jerrold M Olefsky.
      The obesity epidemic continues to worsen worldwide, driving metabolic and chronic inflammatory diseases. Thiazolidinediones, such as rosiglitazone (Rosi), are PPARγ agonists that promote 'M2-like' adipose tissue macrophage (ATM) polarization and cause insulin sensitization. As ATM-derived small extracellular vesicles (ATM-sEVs) from lean mice are known to increase insulin sensitivity, we assessed the metabolic effects of ATM-sEVs from Rosi-treated obese male mice (Rosi-ATM-sEVs). Here we show that Rosi leads to improved glucose and insulin tolerance, transcriptional repolarization of ATMs and increased sEV secretion. Administration of Rosi-ATM-sEVs rescues obesity-induced glucose intolerance and insulin sensitivity in vivo without the known thiazolidinedione-induced adverse effects of weight gain or haemodilution. Rosi-ATM-sEVs directly increase insulin sensitivity in adipocytes, myotubes and primary mouse and human hepatocytes. Additionally, we demonstrate that the miRNAs within Rosi-ATM-sEVs, primarily miR-690, are responsible for these beneficial metabolic effects. Thus, using ATM-sEVs with specific miRNAs may provide a therapeutic path to induce insulin sensitization.
    DOI:  https://doi.org/10.1038/s42255-024-01023-w
  8. bioRxiv. 2024 Mar 29. pii: 2024.03.26.586781. [Epub ahead of print]
    Mitochondrial respiration atlas reveals differential changes in mitochondrial function across sex and age.
    Dylan C Sarver, Muzna Saqib, Fangluo Chen, G William Wong.
      Organ function declines with age, and large-scale transcriptomic analyses have highlighted differential aging trajectories across tissues. The mechanisms underlying shared and organ-selective functional changes across the lifespan, however, still remains poorly understood. Given the central role of mitochondria in powering cellular processes needed to maintain tissue health, we therefore undertook a systematic assessment of respiratory activity across 33 different tissues in young (2.5 months) and old (20 months) mice of both sexes. Our high-resolution mitochondrial respiration atlas reveals: 1) within any group of mice, mitochondrial activity varies widely across tissues, with the highest values consistently seen in heart, brown fat, and kidney; 2) biological sex is a significant but minor contributor to mitochondrial respiration, and its contributions are tissue-specific, with major differences seen in the pancreas, stomach, and white adipose tissue; 3) age is a dominant factor affecting mitochondrial activity, especially across different fat depots and skeletal muscle groups, and most brain regions; 4) age-effects can be sex- and tissue-specific, with some of the largest effects seen in pancreas, heart, adipose tissue, and skeletal muscle; and 5) while aging alters the functional trajectories of mitochondria in a majority of tissues, some are remarkably resilient to age-induced changes. Altogether, our data provide the most comprehensive compendium of mitochondrial respiration and illuminate functional signatures of aging across diverse tissues and organ systems.
    DOI:  https://doi.org/10.1101/2024.03.26.586781
  9. J Biol Chem. 2024 Apr 06. pii: S0021-9258(24)01770-8. [Epub ahead of print] 107269
    Coenzyme Q4 is a functional substitute for coenzyme Q10 and can be targeted to the mitochondria.
    Laura H Steenberge, Sean Rogers, Andrew Y Sung, Jing Fan, David J Pagliarini.
      Coenzyme Q10 (CoQ10) is an important cofactor and antioxidant for numerous cellular processes, and its deficiency has been linked to human disorders including mitochondrial disease, heart failure, Parkinson's disease, and hypertension. Unfortunately, treatment with exogenous CoQ10 is often ineffective, likely due to the extreme hydrophobicity and high molecular weight of CoQ10. Here, we show that less hydrophobic CoQ species with shorter isoprenoid tails can serve as viable substitutes for CoQ10 in human cells. We demonstrate that CoQ4 can perform multiple functions of CoQ10 in CoQ-deficient cells at markedly lower treatment concentrations, motivating further investigation of CoQ4 as a supplement for CoQ10 deficiencies. In addition, we describe the synthesis and evaluation of an initial set of compounds designed to target CoQ4 selectively to mitochondria using triphenylphosphonium (TPP). Our results indicate that select versions of these compounds can successfully be delivered to mitochondria in a cell model and be cleaved to produce CoQ4, laying the groundwork for further development.
    Keywords:  Antioxidant; Bioenergetics; Coenzyme Q10 (CoQ10); Ferroptosis; Membrane lipid; Mitochondrial respiratory chain complex; Mitochondrial therapeutics; Pyrimidine biosynthesis; Ubiquinone
    DOI:  https://doi.org/10.1016/j.jbc.2024.107269
  10. Cell Rep. 2024 Apr 09. pii: S2211-1247(24)00421-2. [Epub ahead of print]43(4): 114093
    Perilipin membrane integration determines lipid droplet heterogeneity in differentiating adipocytes.
    Mario Majchrzak, Ozren Stojanović, Dalila Ajjaji, Kalthoum Ben M'barek, Mohyeddine Omrane, Abdou Rachid Thiam, Robin W Klemm.
      The storage of fat within lipid droplets (LDs) of adipocytes is critical for whole-body health. Acute fatty acid (FA) uptake by differentiating adipocytes leads to the formation of at least two LD classes marked by distinct perilipins (PLINs). How this LD heterogeneity arises is an important yet unresolved cell biological problem. Here, we show that an unconventional integral membrane segment (iMS) targets the adipocyte specific LD surface factor PLIN1 to the endoplasmic reticulum (ER) and facilitates high-affinity binding to the first LD class. The other PLINs remain largely excluded from these LDs until FA influx recruits them to a second LD population. Preventing ER targeting turns PLIN1 into a soluble, cytoplasmic LD protein, reduces its LD affinity, and switches its LD class specificity. Conversely, moving the iMS to PLIN2 leads to ER insertion and formation of a separate LD class. Our results shed light on how differences in organelle targeting and disparities in lipid affinity of LD surface factors contribute to formation of LD heterogeneity.
    Keywords:  CP: Cell biology; CP: Metabolism; CYTOLD; ERTOLD; LD affinity; LD heterogeneity; LD targeting; PLIN1
    DOI:  https://doi.org/10.1016/j.celrep.2024.114093
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