bims-mimbat 2023-10-01 papers

bims-mimbat

Biomed News

on Mitochondrial metabolism in brown adipose tissue

Issue of 2023–10–01
ten papers selected by
José Carlos de Lima-Júnior, Washington University

TMEM135 links peroxisomes to the regulation of brown fat mitochondrial fission and energy homeostasis.
Sphingosine Kinase 1 is Involved in Triglyceride Breakdown by Maintaining Lysosomal Integrity in Brown Adipocytes.
All-optical spatiotemporal mapping of ROS dynamics across mitochondrial microdomains in situ.
Crystallographic cyanide-probing for cytochrome c oxidase reveals structural bases suggesting that a putative proton transfer H-pathway pumps protons.
Membrane Lipid Composition Influences the Hydration of Proton Half-Channels in FoF1-ATP Synthase.
A brown fat-enriched adipokine, ASRA, is a leptin receptor antagonist that stimulates appetite.
Regulators of mitonuclear balance link mitochondrial metabolism to mtDNA expression.
Enantioselective Total Syntheses of Cassane Furanoditerpenoids and Their Stimulation of Cellular Respiration in Brown Adipocytes.
Chloroquine attenuates diet-induced obesity and glucose intolerance through a mechanism that might involve FGF-21, but not UCP-1-mediated thermogenesis and inhibition of adipocyte autophagy.
Inhibition of fatty acid oxidation enables heart regeneration in adult mice.

Nat Commun. 2023 Sep 29. 14(1): 6099

TMEM135 links peroxisomes to the regulation of brown fat mitochondrial fission and energy homeostasis.

Donghua Hu, Min Tan, Dongliang Lu, Brian Kleiboeker, Xuejing Liu, Hongsuk Park, Alexxai V Kravitz, Kooresh I Shoghi, Yu-Hua Tseng, Babak Razani, Akihiro Ikeda, Irfan J Lodhi.

Mitochondrial morphology, which is controlled by mitochondrial fission and fusion, is an important regulator of the thermogenic capacity of brown adipocytes. Adipose-specific peroxisome deficiency impairs thermogenesis by inhibiting cold-induced mitochondrial fission due to decreased mitochondrial membrane content of the peroxisome-derived lipids called plasmalogens. Here, we identify TMEM135 as a critical mediator of the peroxisomal regulation of mitochondrial fission and thermogenesis. Adipose-specific TMEM135 knockout in mice blocks mitochondrial fission, impairs thermogenesis, and increases diet-induced obesity and insulin resistance. Conversely, TMEM135 overexpression promotes mitochondrial division, counteracts obesity and insulin resistance, and rescues thermogenesis in peroxisome-deficient mice. Mechanistically, thermogenic stimuli promote association between peroxisomes and mitochondria and plasmalogen-dependent localization of TMEM135 in mitochondria, where it mediates PKA-dependent phosphorylation and mitochondrial retention of the fission factor Drp1. Together, these results reveal a previously unrecognized inter-organelle communication regulating mitochondrial fission and energy homeostasis and identify TMEM135 as a potential target for therapeutic activation of BAT.

DOI: https://doi.org/10.1038/s41467-023-41849-8
J Lipid Res. 2023 Sep 24. pii: S0022-2275(23)00123-2. [Epub ahead of print] 100450

Sphingosine Kinase 1 is Involved in Triglyceride Breakdown by Maintaining Lysosomal Integrity in Brown Adipocytes.

Jun-Ichi Morishige, Kazuaki Yoshioka, Hiroki Nakata, Kazuhiro Ishimaru, Naoto Nagata, Tamotsu Tanaka, Yoh Takuwa, Hitoshi Ando.

  Sphingosine 1-phosphate (S1P) has been implicated in brown adipose tissue (BAT) formation and energy consumption; however, the mechanistic role of sphingolipids, including S1P, in BAT remains unclear. Here, we showed that, in mice, BAT activation by cold exposure upregulated mRNA and protein expression of the S1P-synthesizing enzyme sphingosine kinase 1 (SphK1), and S1P production in BAT. Treatment of wild-type brown adipocytes with exogenous S1P or S1P receptor subtype-selective agonists stimulated triglyceride (TG) breakdown only marginally, compared with noradrenaline. However, genetic deletion of Sphk1 resulted in hypothermia and diminished body weight loss upon cold exposure, suggesting that SphK1 is involved in thermogenesis through mechanisms different from receptor-mediated, extracellular action of S1P. In BAT of wild-type mice, SphK1 was localized largely in the lysosomes of brown adipocytes. In the brown adipocytes of Sphk1-/- mice, the number of lysosomes was reduced and lysosomal function, including proteolytic activity, acid esterase activity and motility, was impaired. Concordantly, nuclear translocation of transcription factor EB, a master transcriptional regulator of lysosome biogenesis, was reduced, leading to decreased mRNA expression of the lysosome-related genes in Sphk1-/- BAT. Moreover, BAT of Sphk1-/- mice showed greater TG accumulation with dominant larger lipid droplets in brown adipocytes. Inhibition of lysosomes with chloroquine resulted in a less extent of triglyceride accumulation in Sphk1-/- brown adipocytes compared with wild-type brown adipocytes, suggesting a reduced lysosome-mediated TG breakdown in Sphk1-/- mice. Our results indicate a novel role of SphK1 in lysosomal integrity, which is required for TG breakdown and thermogenesis in BAT.

Keywords:  Adipose tissue; Lipase; Lipid droplets; Lipolysis; Lysosome; Sphingolipids; Sphingosine kinase; Sphingosine phosphate; Thermogenesis; Triglyceride; brown

DOI:  https://doi.org/10.1016/j.jlr.2023.100450
Nat Commun. 2023 Sep 27. 14(1): 6036

All-optical spatiotemporal mapping of ROS dynamics across mitochondrial microdomains in situ.

Shon A Koren, Nada Ahmed Selim, Lizbeth De la Rosa, Jacob Horn, M Arsalan Farooqi, Alicia Y Wei, Annika Müller-Eigner, Jacen Emerson, Gail V W Johnson, Andrew P Wojtovich.

Hydrogen peroxide (H2O2) functions as a second messenger to signal metabolic distress through highly compartmentalized production in mitochondria. The dynamics of reactive oxygen species (ROS) generation and diffusion between mitochondrial compartments and into the cytosol govern oxidative stress responses and pathology, though these processes remain poorly understood. Here, we couple the H2O2 biosensor, HyPer7, with optogenetic stimulation of the ROS-generating protein KillerRed targeted into multiple mitochondrial microdomains. Single mitochondrial photogeneration of H2O2 demonstrates the spatiotemporal dynamics of ROS diffusion and transient hyperfusion of mitochondria due to ROS. This transient hyperfusion phenotype required mitochondrial fusion but not fission machinery. Measurement of microdomain-specific H2O2 diffusion kinetics reveals directionally selective diffusion through mitochondrial microdomains. All-optical generation and detection of physiologically-relevant concentrations of H2O2 between mitochondrial compartments provide a map of mitochondrial H2O2 diffusion dynamics in situ as a framework to understand the role of ROS in health and disease.

DOI: https://doi.org/10.1038/s41467-023-41682-z
J Biol Chem. 2023 Sep 22. pii: S0021-9258(23)02305-0. [Epub ahead of print] 105277

Crystallographic cyanide-probing for cytochrome c oxidase reveals structural bases suggesting that a putative proton transfer H-pathway pumps protons.

Atsuhiro Shimada, Jumpei Baba, Shuhei Nagao, Kyoko Shinzawa-Itoh, Eiki Yamashita, Kazumasa Muramoto, Tomitake Tsukihara, Shinya Yoshikawa.

  Cytochrome c oxidase (CcO) reduces O2 in the O2-reduction site by sequential four-electron donations through the low-potential metal sites (CuA and Fea). Redox-coupled X-ray crystal structural changes have been identified at five distinct sites including Asp51, Arg438, Glu198, the hydroxyfarnesyl ethyl group of heme a, and Ser382, respectively. These sites interact with the putative proton-pumping H-pathway. However, the metal sites responsible for each structural change have not been identified, since these changes were detected as structural differences between the fully reduced and fully oxidized CcOs. Thus, the roles of these structural changes in the CcO function are yet to be revealed. X-ray crystal structures of cyanide-bound CcOs under various oxidation states showed that the O2-reduction site controlled only the Ser382-including site, while the low potential metal sites induced the other changes. This finding indicates that these low-potential site-inducible structural changes are triggered by sequential electron-extraction from the low-potential sites by the O2-reduction site and that each structural change is insensitive to the oxidation and ligand-binding states of the O2-reduction site. Because the proton/electron coupling efficiency is constant (1:1), regardless of the reaction progress in the O2-reduction site, the structural changes induced by the low-potential sites are assignable to those critically involved in the proton-pumping, suggesting that the H-pathway, facilitating these low-potential site-inducible structural changes, pumps protons. Furthermore, a cyanide-bound CcO structure suggests that a hypoxia-inducible activator, Higd1a, activates the O2-reduction site without influencing the electron transfer mechanism through the low-potential sites, kinetically confirming that the low-potential sites facilitate proton-pump.

Keywords:  O(2)-reduction; X-ray crystallographic analysis; cyanide inhibition; cytochrome c oxidase; hemoprotein; proton pump

DOI:  https://doi.org/10.1016/j.jbc.2023.105277
Life (Basel). 2023 Aug 28. pii: 1816. [Epub ahead of print]13(9):

Membrane Lipid Composition Influences the Hydration of Proton Half-Channels in FoF1-ATP Synthase.

Leonid A Ivontsin, Elena V Mashkovtseva, Yaroslav R Nartsissov.

  The membrane lipid composition plays an important role in the regulation of membrane protein activity. To probe its influence on proton half-channels' structure in FoF1-ATP synthase, we performed molecular dynamics simulations with the bacterial protein complex (PDB ID: 6VWK) embedded in three types of membranes: a model POPC, a lipid bilayer containing 25% (in vivo), and 75% (bacterial stress) of cardiolipin (CL). The structure proved to be stable regardless of the lipid composition. The presence of CL increased the hydration of half-channels. The merging of two water cavities at the inlet half-channel entrance and a long continuous chain of water molecules directly to cAsp61 from the periplasm were observed. Minor conformational changes in half-channels with the addition of CL caused extremely rare direct transitions between aGlu219-aAsp119, aGlu219-aHis245, and aGln252-cAsp61. Deeper penetration of water molecules (W1-W3) also increased the proton transport continuity. Stable spatial positions of significant amino acid (AA) residue aAsn214 were found under all simulation conditions indicate a prevailing influence of AA-AA or AA-W interactions on the side-chain dynamics. These results allowed us to put forward a model of the proton movement in ATP synthases under conditions close to in vivo and to evaluate the importance of membrane composition in simulations.

Keywords:  FoF1-ATP synthase; cardiolipin; membrane proteins; molecular dynamics; proton transport

DOI:  https://doi.org/10.3390/life13091816
bioRxiv. 2023 Sep 12. pii: 2023.09.12.557454. [Epub ahead of print]

A brown fat-enriched adipokine, ASRA, is a leptin receptor antagonist that stimulates appetite.

Lei Huang, Pengpeng Liu, Yong Du, Dongning Pan, Alexandra Lee, Scot A Wolfe, Yong-Xu Wang.

The endocrine control of food intake remains incompletely understood, and whether the leptin receptor-mediated anorexigenic pathway in the hypothalamus is negatively regulated by a humoral factor is unknown. Here we identify an appetite-stimulating factor - ASRA - that acts as a leptin receptor antagonist. ASRA encodes an 8 kD protein that is abundantly and selectively expressed in adipose tissue and to a lesser extent, in liver, and is upregulated during fasting and cold. ASRA protein associates with autophagosomes and its secretion is induced by energy deficiency. Overexpression of ASRA in mice attenuates leptin receptor signaling leading to elevated blood glucose and development of severe hyperphagic obesity, whereas either adipose- or liver-specific ASRA knockout mice display increased leptin sensitivity, improved glucose homeostasis, reduced food intake, and resistance to high fat diet-induced obesity. Furthermore, ASRA is indispensable for cold-evoked feeding response. Recombinant ASRA (rASRA) protein binds to leptin receptor and suppresses leptin receptor signaling in cultured cells. In vivo, rASRA promotes food intake and increases blood glucose in a leptin receptor signaling-dependent manner. Our studies collectively show that ASRA, acting as a peripheral signal of energy deficit, stimulates appetite and regulates glucose metabolism by antagonizing leptin receptor signaling, thus revealing a previously unknown endocrine mechanism that has important implications for our understanding of leptin resistance.

DOI: https://doi.org/10.1101/2023.09.12.557454
Nat Cell Biol. 2023 Sep 28.

Regulators of mitonuclear balance link mitochondrial metabolism to mtDNA expression.

Nicholas J Kramer, Gyan Prakash, R Stefan Isaac, Karine Choquet, Iliana Soto, Boryana Petrova, Hope E Merens, Naama Kanarek, L Stirling Churchman.

Mitochondrial oxidative phosphorylation (OXPHOS) complexes are assembled from proteins encoded by both nuclear and mitochondrial DNA. These dual-origin enzymes pose a complex gene regulatory challenge for cells requiring coordinated gene expression across organelles. To identify genes involved in dual-origin protein complex synthesis, we performed fluorescence-activated cell-sorting-based genome-wide screens analysing mutant cells with unbalanced levels of mitochondrial- and nuclear-encoded subunits of Complex IV. We identified genes involved in OXPHOS biogenesis, including two uncharacterized genes: PREPL and NME6. We found that PREPL specifically impacts Complex IV biogenesis by acting at the intersection of mitochondrial lipid metabolism and protein synthesis, whereas NME6, an uncharacterized nucleoside diphosphate kinase, controls OXPHOS biogenesis through multiple mechanisms reliant on its NDPK domain. Firstly, NME6 forms a complex with RCC1L, which together perform nucleoside diphosphate kinase activity to maintain local mitochondrial pyrimidine triphosphate levels essential for mitochondrial RNA abundance. Secondly, NME6 modulates the activity of mitoribosome regulatory complexes, altering mitoribosome assembly and mitochondrial RNA pseudouridylation. Taken together, we propose that NME6 acts as a link between compartmentalized mitochondrial metabolites and mitochondrial gene expression.

DOI: https://doi.org/10.1038/s41556-023-01244-3
J Am Chem Soc. 2023 Sep 26.

Enantioselective Total Syntheses of Cassane Furanoditerpenoids and Their Stimulation of Cellular Respiration in Brown Adipocytes.

Hendrik H Bulthaupt, Fabian Glatz, Sven M Papidocha, Chunyan Wu, Shawn Teh, Susanne Wolfrum, Lucia Balážová, Christian Wolfrum, Erick M Carreira.

We report the first and enantioselective total syntheses of (+)-1-deacetylcaesalmin C, (+)-δ-caesalpin, (+)-norcaesalpinin MC, and (+)-norcaesalpinin P. Salient features of the synthetic strategy are an exo-selective intramolecular Diels-Alder reaction of a furanoquinone monoketal and subsequent chemoselective reduction of the resulting pentacyclic furfuryl ketal, furnishing a keystone intermediate. The latter enables access to the collection of natural products through implementation of stereoselective oxidations. Having accessed the cassane furanoditerpenoids, we unveil previously unknown bioactivity: (+)-1-deacetylcaesalmin C stimulates respiration in brown adipocytes, which has been suggested to play a central role in treatment of obesity.

DOI: https://doi.org/10.1021/jacs.3c07597
Mol Cell Endocrinol. 2023 Sep 22. pii: S0303-7207(23)00225-3. [Epub ahead of print]578 112074

Chloroquine attenuates diet-induced obesity and glucose intolerance through a mechanism that might involve FGF-21, but not UCP-1-mediated thermogenesis and inhibition of adipocyte autophagy.

Milene Ortiz-Silva, Bianca F Leonardi, Érique Castro, Álbert S Peixoto, Gustavo R Gilio, Tiago E Oliveira, Caroline A Tomazelli, Maynara L Andrade, Mayara F Moreno, Thiago Belchior, Juliana Magdalon, Thayna S Vieira, Carlos M Donado-Pestana, William T Festuccia.

  Chloroquine diphosphate (CQ), a weak base used to inhibit autophagic flux and treat malaria and rheumatoid diseases, has been shown, through unknown mechanisms, to improve glucose and lipid homeostasis in patients and rodents. We investigate herein the molecular mechanisms underlying these CQ beneficial metabolic actions in diet-induced obese mice. For this, C57BL6/J mice fed with either a chow or a high-fat diet (HFD) and uncoupling protein 1 (UCP-1) KO and adipocyte Atg7-deficient mice fed with a HFD were treated or not with CQ (60 mg/kg of body weight/day) during 8 weeks and evaluated for body weight, adiposity, glucose homeostasis and brown and white adipose tissues (BAT and WAT) UCP-1 content. CQ reduced body weight gain and adipose tissue and liver masses in mice fed with a HFD, without altering food intake, oxygen consumption, respiratory exchange ratio, spontaneous motor activity and feces caloric content. CQ attenuated the insulin intolerance, hyperglycemia, hyperinsulinemia, hypertriglyceridemia and hypercholesterolemia induced by HFD intake, such effects that were associated with increases in serum and liver fibroblast growth factor 21 (FGF-21) and BAT and WAT UCP-1 content. Interestingly, CQ beneficial metabolic actions of reducing body weight and adiposity and improving glucose homeostasis were preserved in HFD-fed UCP-1 KO and adipocyte Atg7 deficient mice. CQ reduces body weight gain and adiposity and improves glucose homeostasis in diet-induced obese mice through mechanisms that might involve FGF-21, but not UCP1-mediated nonshivering thermogenesis or inhibition of adipocyte autophagy.

Keywords:  Autophagy; Chloroquine; Energy balance; FGF-21; Glucose homeostasis; UCP-1

DOI:  https://doi.org/10.1016/j.mce.2023.112074
Nature. 2023 Sep 27.

Inhibition of fatty acid oxidation enables heart regeneration in adult mice.

Xiang Li, Fan Wu, Stefan Günther, Mario Looso, Carsten Kuenne, Ting Zhang, Marion Wiesnet, Stephan Klatt, Sven Zukunft, Ingrid Fleming, Gernot Poschet, Astrid Wietelmann, Ann Atzberger, Michael Potente, Xuejun Yuan, Thomas Braun.

Postnatal maturation of cardiomyocytes is characterized by a metabolic switch from glycolysis to fatty acid oxidation, chromatin reconfiguration and exit from the cell cycle, instating a barrier for adult heart regeneration1,2. Here, to explore whether metabolic reprogramming can overcome this barrier and enable heart regeneration, we abrogate fatty acid oxidation in cardiomyocytes by inactivation of Cpt1b. We find that disablement of fatty acid oxidation in cardiomyocytes improves resistance to hypoxia and stimulates cardiomyocyte proliferation, allowing heart regeneration after ischaemia-reperfusion injury. Metabolic studies reveal profound changes in energy metabolism and accumulation of α-ketoglutarate in Cpt1b-mutant cardiomyocytes, leading to activation of the α-ketoglutarate-dependent lysine demethylase KDM5 (ref. 3). Activated KDM5 demethylates broad H3K4me3 domains in genes that drive cardiomyocyte maturation, lowering their transcription levels and shifting cardiomyocytes into a less mature state, thereby promoting proliferation. We conclude that metabolic maturation shapes the epigenetic landscape of cardiomyocytes, creating a roadblock for further cell divisions. Reversal of this process allows repair of damaged hearts.

DOI: https://doi.org/10.1038/s41586-023-06585-5