bims-mimbat Biomed News
on Mitochondrial metabolism in brown adipose tissue
Issue of 2024–12–01
ten papers selected by
José Carlos de Lima-Júnior, Washington University
  1. Structure and function of the human mitochondrial MRS2 channel.
  2. When brown fat sparked fire.
  3. Cold-inducible GOT1 activates the malate-aspartate shuttle in brown adipose tissue to support fuel preference for fatty acids.
  4. Ablation of FAM210A in brown adipocytes of mice exacerbates high fat diet induced metabolic dysfunction.
  5. Human mitochondrial peroxiredoxin Prdx3 is dually localized in the intermembrane space and matrix subcompartments.
  6. Mitochondrial calcium uptake declines during aging and is directly activated by oleuropein to boost energy metabolism and skeletal muscle performance.
  7. PPARγ-dependent remodeling of translational machinery in adipose progenitors is impaired in obesity.
  8. Plasma membrane remodeling determines adipocyte expansion and mechanical adaptability.
  9. Genetic evidence against involvement of TRPC proteins in SOCE, ROCE, and CRAC channel function.
  10. Suppression of neurons in circumventricular organs enables months-long survival without water in thirteen-lined ground squirrels.
  1. Nat Struct Mol Biol. 2024 Nov 28.
    Structure and function of the human mitochondrial MRS2 channel.
    Zhihui He, Yung-Chi Tu, Chen-Wei Tsai, Jonathan Mount, Jingying Zhang, Ming-Feng Tsai, Peng Yuan.
      The human mitochondrial RNA splicing 2 protein (MRS2) has been implicated in Mg2+ transport across mitochondrial inner membranes, thus having an important role in Mg2+ homeostasis critical for mitochondrial integrity and function. However, the molecular mechanisms underlying its fundamental channel properties such as ion selectivity and regulation remain unclear. Here we present a structural and functional investigation of MRS2. Cryo-electron microscopy structures in various ionic conditions reveal a pentameric channel architecture and the molecular basis of ion permeation and potential regulation mechanisms. Electrophysiological analyses demonstrate that MRS2 is a Ca2+-regulated, nonselective channel permeable to Mg2+, Ca2+, Na+ and K+, which contrasts with its prokaryotic ortholog, CorA, operating as a Mg2+-gated Mg2+ channel. Moreover, a conserved arginine ring within the pore of MRS2 functions to restrict cation movements, thus preventing the channel from collapsing the proton motive force that drives mitochondrial adenosine triphosphate synthesis. Together, our results provide a molecular framework for further understanding MRS2 in mitochondrial function and disease.
    DOI:  https://doi.org/10.1038/s41594-024-01420-5
  2. Temperature (Austin). 2024 ;11(4): 305-308
    When brown fat sparked fire.
    Martin Jastroch, Michael J Gaudry.
      
    DOI:  https://doi.org/10.1080/23328940.2024.2422699
  3. bioRxiv. 2024 Nov 18. pii: 2024.11.18.623867. [Epub ahead of print]
    Cold-inducible GOT1 activates the malate-aspartate shuttle in brown adipose tissue to support fuel preference for fatty acids.
    Chul-Hong Park, Minsung Park, Miranda E Kelly, Helia Cheng, Sang Ryeul Lee, Cholsoon Jang, Ji Suk Chang.
      Brown adipose tissue (BAT) simultaneously metabolizes fatty acids (FA) and glucose under cold stress but favors FA as the primary fuel for heat production. It remains unclear how BAT steer fuel preference toward FA over glucose. Here we show that the malate-aspartate shuttle (MAS) is activated by cold in BAT and plays a crucial role in promoting mitochondrial FA utilization. Mechanistically, cold stress selectively induces glutamic-oxaloacetic transaminase (GOT1), a key MAS enzyme, via the β-adrenergic receptor-PKA-PGC-1α axis. The increase in GOT1 activates MAS, transferring reducing equivalents from the cytosol to mitochondria. This process enhances FA oxidation in mitochondria while limiting glucose oxidation. In contrast, loss of MAS activity by GOT1 deficiency reduces FA oxidation, leading to increased glucose oxidation. Together, our work uncovers a unique regulatory mechanism and role for MAS in mitochondrial fuel selection and advances our understanding of how BAT maintains fuel preference for FA under cold conditions.
    Highlights: Got1 is markedly induced by cold in BAT via a β-adrenergic receptor-PKA-PGC-1α axis The increase in cytosolic GOT1 activates the malate-aspartate shuttle (MAS)MAS activation promotes fatty acid oxidation while reducing glucose oxidation Loss of MAS activity in BAT by Got1 deletion shifts the fuel preference to glucose.
    DOI:  https://doi.org/10.1101/2024.11.18.623867
  4. Diabetes. 2024 Nov 27. pii: db240294. [Epub ahead of print]
    Ablation of FAM210A in brown adipocytes of mice exacerbates high fat diet induced metabolic dysfunction.
    Jiamin Qiu, Mennatallah A Khedr, Meijin Pan, Christina R Ferreira, Jingjuan Chen, Madigan M Snyder, Kolapo M Ajuwon, Feng Yue, Shihuan Kuang.
      Thermogenesis of brown adipose tissues (BAT) provides metabolic benefits against pathological conditions such as Type 2 diabetes, obesity, cardiovascular diseases, and cancer. The thermogenic function of BAT relies on mitochondria, but whether mitochondrial remodeling is required for the beneficial effects of BAT remains unclear. We have recently identified FAM210A as a BAT-enriched mitochondrial protein essential for cold-induced thermogenesis through the modulation of OPA1-dependent cristae remodeling. Here we report a key role of FAM210A in the systemic response to high-fat diet (HFD). We discovered that HFD suppressed FAM210A expression, associated with excessive OPA1 cleavage in BAT. Ucp1-Cre-driven BAT-specific Fam210a knockout (Fam210aUKO) similarly elevates OPA1 cleavage, accompanied by whitening of BAT. When subjected to HFD, the Fam210aUKO mice gained similar fat mass as sibling control mice, but developed glucose intolerance, insulin resistance, and liver steatosis. The metabolic dysfunction was associated with an overall increased lipid content in both liver and BAT. Additionally, Fam210aUKO leads to inflammation in white adipose tissues. These data demonstrate that FAM210A in BAT is necessary for counteracting HFD-induced metabolic dysfunction but not obesity.
    DOI:  https://doi.org/10.2337/db24-0294
  5. Redox Biol. 2024 Nov 21. pii: S2213-2317(24)00414-2. [Epub ahead of print]78 103436
    Human mitochondrial peroxiredoxin Prdx3 is dually localized in the intermembrane space and matrix subcompartments.
    Fernando Gomes, Helena Turano, Luciana A Haddad, Luis E S Netto.
      Peroxiredoxin 3 (Prdx3) is the major sink for H2O2 and other hydroperoxides within mitochondria, yet the mechanisms guiding the import of its cytosolic precursor into mitochondrial sub-compartments remain elusive. Prdx3 is synthesized in the cytosol as a precursor with an N-terminal cleavable presequence, which is frequently proposed to target the protein exclusively to the mitochondrial matrix. Here, we present a comprehensive analysis of the human Prdx3 biogenesis, using highly purified mitochondria from HEK293T cells. Subfractionation and probing for specific mitochondrial markers confirmed Prdx3 localization in the matrix, while unexpectedly revealed its presence in the mitochondrial intermembrane space (IMS). Both matrix and IMS isoforms were found to be soluble proteins, as demonstrated by alkaline carbonate extraction. By combining in silico analysis, in organello import assays and heterologous expression in yeast, we found that Prdx3 undergoes sequential proteolytic processing steps by mitochondrial processing peptidase (MPP) and mitochondrial intermediate peptidase (MIP) during its import into the matrix. Additionally, heterologous expression of Prdx3 in yeast revealed that its sorting to the IMS is dependent on the inner membrane peptidase (IMP) complex. Collectively, these findings uncover a complex submitochondrial distribution of Prdx3, supporting its multifaceted role in mitochondrial H2O2 metabolism.
    Keywords:  Intermembrane space (IMS); Matrix; Mitochondria; Peroxiredoxin; Prdx3
    DOI:  https://doi.org/10.1016/j.redox.2024.103436
  6. Cell Metab. 2024 Nov 23. pii: S1550-4131(24)00417-0. [Epub ahead of print]
    Mitochondrial calcium uptake declines during aging and is directly activated by oleuropein to boost energy metabolism and skeletal muscle performance.
    Gaia Gherardi, Anna Weiser, Flavien Bermont, Eugenia Migliavacca, Benjamin Brinon, Guillaume E Jacot, Aurélie Hermant, Mattia Sturlese, Leonardo Nogara, Filippo Vascon, Agnese De Mario, Andrea Mattarei, Emma Garratt, Mark Burton, Karen Lillycrop, Keith M Godfrey, Laura Cendron, Denis Barron, Stefano Moro, Bert Blaauw, Rosario Rizzuto, Jerome N Feige, Cristina Mammucari, Umberto De Marchi.
      Mitochondrial calcium (mtCa2+) uptake via the mitochondrial calcium uniporter (MCU) couples calcium homeostasis and energy metabolism. mtCa2+ uptake via MCU is rate-limiting for mitochondrial activation during muscle contraction, but its pathophysiological role and therapeutic application remain largely uncharacterized. By profiling human muscle biopsies, patient-derived myotubes, and preclinical models, we discovered a conserved downregulation of mitochondrial calcium uniporter regulator 1 (MCUR1) during skeletal muscle aging that associates with human sarcopenia and impairs mtCa2+ uptake and mitochondrial respiration. Through a screen of 5,000 bioactive molecules, we identify the natural polyphenol oleuropein as a specific MCU activator that stimulates mitochondrial respiration via mitochondrial calcium uptake 1 (MICU1) binding. Oleuropein activates mtCa2+ uptake and energy metabolism to enhance endurance and reduce fatigue in young and aged mice but not in muscle-specific MCU knockout (KO) mice. Our work demonstrates that impaired mtCa2+ uptake contributes to mitochondrial dysfunction during aging and establishes oleuropein as a novel food-derived molecule that specifically targets MCU to stimulate mitochondrial bioenergetics and muscle performance.
    Keywords:  MCU; MCUR1; aging; calcium signaling; endurance; energy; fatigue; mitochondria; polyphenols; sarcopenia; skeletal muscle
    DOI:  https://doi.org/10.1016/j.cmet.2024.10.021
  7. Cell Rep. 2024 Nov 07. pii: S2211-1247(24)01296-8. [Epub ahead of print] 114945
    PPARγ-dependent remodeling of translational machinery in adipose progenitors is impaired in obesity.
    Mirian Krystel De Siqueira, Gaoyan Li, Yutian Zhao, Siqi Wang, In Sook Ahn, Mikayla Tamboline, Andrew D Hildreth, Jakeline Larios, Alejandro Schcolnik-Cabrera, Zaynab Nouhi, Zhengyi Zhang, Marcus J Tol, Vijaya Pandey, Shili Xu, Timothy E O'Sullivan, Julia J Mack, Peter Tontonoz, Tamer Sallam, James A Wohlschlegel, Laura Hulea, Xinshu Xiao, Xia Yang, Claudio J Villanueva.
      Adipose tissue regulates energy homeostasis and metabolic function, but its adaptability is impaired in obesity. In this study, we investigate the impact of acute PPARγ agonist treatment in obese mice and find significant transcriptional remodeling of cells in the stromal vascular fraction (SVF). Using single-cell RNA sequencing, we profile the SVF of inguinal and epididymal adipose tissue of obese mice following rosiglitazone treatment and find an induction of ribosomal factors in both progenitor and preadipocyte populations, while expression of ribosomal factors is reduced with obesity. Notably, the expression of a subset of ribosomal factors is directly regulated by PPARγ. Polysome profiling of the epididymal SVF shows that rosiglitazone promotes translational selectivity of mRNAs that encode pathways involved in adipogenesis and lipid metabolism. Inhibition of translation using a eukaryotic translation initiation factor 4A (eIF4A) inhibitor is sufficient in blocking adipogenesis. Our findings shed light on how PPARγ agonists promote adipose tissue plasticity in obesity.
    Keywords:  CP: Metabolism; adipocytes; adipose progenitors; adipose stem cells; diabetes; glucose; obesity; ribosomes; rosiglitazone; translation
    DOI:  https://doi.org/10.1016/j.celrep.2024.114945
  8. Nat Commun. 2024 Nov 28. 15(1): 10102
    Plasma membrane remodeling determines adipocyte expansion and mechanical adaptability.
    María C M Aboy-Pardal, Marta C Guadamillas, Carlos R Guerrero, Mauro Català-Montoro, Mónica Toledano-Donado, Sara Terrés-Domínguez, Dácil M Pavón, Víctor Jiménez-Jiménez, Daniel Jimenez-Carretero, Moreno Zamai, Cintia Folgueira, Ana Cerezo, Fidel-Nicolás Lolo, Rubén Nogueiras, Guadalupe Sabio, Miguel Sánchez-Álvarez, Asier Echarri, Ricardo Garcia, Miguel A Del Pozo.
      Adipocytes expand massively to accommodate excess energy stores and protect the organism from lipotoxicity. Adipose tissue expandability is at the center of disorders such as obesity and lipodystrophy; however, little is known about the relevance of adipocyte biomechanics on the etiology of these conditions. Here, we show in male mice in vivo that the adipocyte plasma membrane undergoes caveolar domain reorganization upon lipid droplet expansion. As the lipid droplet grows, caveolae disassemble to release their membrane reservoir and increase cell surface area, and transfer specific caveolar components to the LD surface. Adipose tissue null for caveolae is stiffer, shows compromised deformability, and is prone to rupture under mechanical compression. Mechanistically, phosphoacceptor Cav1 Tyr14 is required for caveolae disassembly: adipocytes bearing a Tyr14Phe mutation at this residue are stiffer and smaller, leading to decreased adiposity in vivo; exhibit deficient transfer of Cav1 and EHD2 to the LD surface, and show distinct Cav1 molecular dynamics and tension adaptation. These results indicate that Cav1 phosphoregulation modulates caveolar dynamics as a relevant component of the homeostatic mechanoadaptation of the differentiated adipocyte.
    DOI:  https://doi.org/10.1038/s41467-024-54224-y
  9. Proc Natl Acad Sci U S A. 2024 Dec 03. 121(49): e2411389121
    Genetic evidence against involvement of TRPC proteins in SOCE, ROCE, and CRAC channel function.
    Sebastian Susperreguy, Megumi Yamashita, Chan-Il Choi, Yanhong Liao, Lauranell H Burch, Terry L Blankenship, Erika Hayes, Thomas Sliwa, Yingpei Zhang, Dagoberto Grenet, Mitzie Walker, Nicholas W Plummer, Joel Abramowitz, Jean Pierre Kinet, Karina Formoso, Brandon E Johnson, Andrea Fleig, Lori Hazlehurst, Reinhold Penner, Marc Freichel, Veit Flockerzi, Murali Prakriya, Lutz Birnbaumer.
      Using genetically engineered mice and cell lines derived from genetically engineered mice we show that depletion of ER delimited Ca2+ stores activates heteromeric Ca2+ entry (SOCE) channels formed obligatorily, but not exclusively by Orai1 molecules. Comparison of Orai-dependent Ca2+ entries revealed Orai1 to be dominant when compared to Orai2 and Orai3. Unexpectedly, we found that store-depletion-activated Ca2+ entry does not depend obligatorily on functionally intact TRPC molecules, as SOCE monitored with the Fura2 Ca2+ reporter dye is unaffected in cells in which all seven TRPC coding genes have been structurally and functionally inactivated. Unexpectedly as well, we found that TRPC-independent Gq-coupled receptor-operated Ca2+ entry (ROCE) also depends on Orai1. Biophysical measurements of Ca2+ release activated Ca2+ currents (Icrac) are likewise unaffected by ablation of all seven TRPC genes. We refer to mice and cells carrying the seven-fold disruption of TRPC genes as TRPC heptaKO mice and cells. TRPC heptaKO mice are fertile allowing the creation of a new homozygous inbred strain.
    Keywords:  Orai; ROCE; SOCE; TRPC
    DOI:  https://doi.org/10.1073/pnas.2411389121
  10. Science. 2024 Nov 29. 386(6725): 1048-1055
    Suppression of neurons in circumventricular organs enables months-long survival without water in thirteen-lined ground squirrels.
    Madeleine S Junkins, Ni Y Feng, Dana K Merriman, Sviatoslav N Bagriantsev, Elena O Gracheva.
      Water deprivation is a life-threatening condition that engages a protective physiological response to couple osmolyte retention with potentiation of thirst. This response, typical for most mammals, safeguards against short-term water deprivation but fails in the long term. Thirteen-lined ground squirrels (Ictidomys tridecemlineatus) use the short-term response during summer, whereas during winter, they lack thirst and survive without water for months. In this work, we show that long-term thirst suppression occurs despite hormonal and behavioral signs of a substantial fluid deficit and originates from hypoactivity of neurons in the circumventricular organs, which exhibit marked functional suppression during winter that blunts their sensitivity to thirst cues. Our work reveals a notable capacity of the evolutionarily conserved brain regions that control fluid homeostasis in mammals to enable long-term survival without water.
    DOI:  https://doi.org/10.1126/science.adp8358
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