bims-mimbat 2023-11-26 papers

bims-mimbat

Biomed News

on Mitochondrial metabolism in brown adipose tissue

Issue of 2023‒11‒26
twelve papers selected by
José Carlos de Lima-Júnior, Washington University

Mutation at the entrance of the quinone cavity severely disrupts quinone binding in respiratory complex I.
Mirabegron displays anticancer effects by globally browning adipose tissues.
Membrane potential accelerates sugar uptake by stabilizing the outward facing conformation of the Na/glucose symporter vSGLT.
Hyperleptinemia contributes to antipsychotic drug-associated obesity and metabolic disorders.
Inferring mitochondrial and cytosolic metabolism by coupling isotope tracing and deconvolution.
Modulation of hepatic transcription factor EB activity during cold exposure uncovers direct regulation of bis(monoacylglycero)phosphate lipids by Pla2g15.
Mitochondrial hyperfusion induces metabolic remodeling in lung endothelial cells by modifying the activities of electron transport chain complexes I and III.
Birds are better at regulating heat loss through their legs than their bills: implications for body shape evolution in response to climate.
Great tits (Parus major) in a west European temperate forest show little seasonal variation in metabolic energy requirements.
Mitochondrial phosphoproteomes are functionally specialized across tissues.
Brown adipose tissue transplantation improves skin fibrosis in localized scleroderma.
Anomalous peroxidase activity of cytochrome c is the primary pathogenic target in Barth syndrome.

Sci Rep. 2023 Nov 21. 13(1): 20413

Mutation at the entrance of the quinone cavity severely disrupts quinone binding in respiratory complex I.

Jason Tae Yi, Panyue Wang, Alexei A Stuchebrukhov.

In all resolved structures of complex I, there exists a tunnel-like Q-chamber for ubiquinone binding and reduction. The entrance to the Q-chamber in ND1 subunit forms a narrow bottleneck, which is rather tight and requires thermal conformational changes for ubiquinone to get in and out of the binding chamber. The substitution of alanine with threonine at the bottleneck (AlaThr MUT), associated with 3460/ND1 mtDNA mutation in human complex I, is implicated in Leber's Hereditary Optic Neuropathy (LHON). Here, we show the AlaThr MUT further narrows the Q-chamber entrance cross-section area by almost 30%, increasing the activation free energy barrier of quinone passage by approximately 5 kJ mol-1. This severely disrupts quinone binding and reduction as quinone passage through the bottleneck is slowed down almost tenfold. Our estimate of the increase in free energy barrier is entirely due to the bottleneck narrowing, leading to a reduction of the transition state entropy between WT and MUT, and thus more difficult quinone passage. Additionally, we investigate details of possible water exchange between the Q-chamber and membrane. We find water exchange is dynamic in WT but may be severely slowed in MUT. We propose that LHON symptoms caused by 3460/ND1 mtDNA mutation are due to slowed quinone binding. This leads to an increased production of reactive oxidative species due to upstream electron backup at the FMN site of complex I, thus resulting in a mt bioenergetic defect.

DOI: https://doi.org/10.1038/s41598-023-47314-2
Nat Commun. 2023 Nov 22. 14(1): 7610

Mirabegron displays anticancer effects by globally browning adipose tissues.

Xiaoting Sun, Wenhai Sui, Zepeng Mu, Sisi Xie, Jinxiu Deng, Sen Li, Takahiro Seki, Jieyu Wu, Xu Jing, Xingkang He, Yangang Wang, Xiaokun Li, Yunlong Yang, Ping Huang, Minghua Ge, Yihai Cao.

Metabolic reprogramming in malignant cells is a hallmark of cancer that relies on augmented glycolytic metabolism to support their growth, invasion, and metastasis. However, the impact of global adipose metabolism on tumor growth and the drug development by targeting adipose metabolism remain largely unexplored. Here we show that a therapeutic paradigm of drugs is effective for treating various cancer types by browning adipose tissues. Mirabegron, a clinically available drug for overactive bladders, displays potent anticancer effects in various animal cancer models, including untreatable cancers such as pancreatic ductal adenocarcinoma and hepatocellular carcinoma, via the browning of adipose tissues. Genetic deletion of the uncoupling protein 1, a key thermogenic protein in adipose tissues, ablates the anticancer effect. Similarly, the removal of brown adipose tissue, which is responsible for non-shivering thermogenesis, attenuates the anticancer activity of mirabegron. These findings demonstrate that mirabegron represents a paradigm of anticancer drugs with a distinct mechanism for the effective treatment of multiple cancers.

DOI: https://doi.org/10.1038/s41467-023-43350-8
Nat Commun. 2023 11 18. 14(1): 7511

Membrane potential accelerates sugar uptake by stabilizing the outward facing conformation of the Na/glucose symporter vSGLT.

Farha Khan, Matthias Elgeti, Samuel Grandfield, Aviv Paz, Fiona B Naughton, Frank V Marcoline, Thorsten Althoff, Natalia Ermolova, Ernest M Wright, Wayne L Hubbell, Michael Grabe, Jeff Abramson.

Sodium-dependent glucose transporters (SGLTs) couple a downhill Na+ ion gradient to actively transport sugars. Here, we investigate the impact of the membrane potential on vSGLT structure and function using sugar uptake assays, double electron-electron resonance (DEER), electrostatic calculations, and kinetic modeling. Negative membrane potentials, as present in all cell types, shift the conformational equilibrium of vSGLT towards an outward-facing conformation, leading to increased sugar transport rates. Electrostatic calculations identify gating charge residues responsible for this conformational shift that when mutated reduce galactose transport and eliminate the response of vSGLT to potential. Based on these findings, we propose a comprehensive framework for sugar transport via vSGLT, where the cellular membrane potential facilitates resetting of the transporter after cargo release. This framework holds significance not only for SGLTs but also for other transporters and channels.

DOI: https://doi.org/10.1038/s41467-023-43119-z
Sci Transl Med. 2023 Nov 22. 15(723): eade8460

Hyperleptinemia contributes to antipsychotic drug-associated obesity and metabolic disorders.

Shangang Zhao, Qian Lin, Wei Xiong, Li Li, Leon Straub, Dinghong Zhang, Rizaldy Zapata, Qingzhang Zhu, Xue-Nan Sun, Zhuzhen Zhang, Jan-Bernd Funcke, Chao Li, Shiuhwei Chen, Yi Zhu, Nisi Jiang, Guannan Li, Ziying Xu, Steven C Wyler, May-Yun Wang, Juli Bai, Xianlin Han, Christine M Kusminski, Ningyan Zhang, Zhiqiang An, Joel K Elmquist, Olivia Osborn, Chen Liu, Philipp E Scherer.

Despite their high degree of effectiveness in the management of psychiatric conditions, exposure to antipsychotic drugs, including olanzapine and risperidone, is frequently associated with substantial weight gain and the development of diabetes. Even before weight gain, a rapid rise in circulating leptin concentrations can be observed in most patients taking antipsychotic drugs. To date, the contribution of this hyperleptinemia to weight gain and metabolic deterioration has not been defined. Here, with an established mouse model that recapitulates antipsychotic drug-induced obesity and insulin resistance, we not only confirm that hyperleptinemia occurs before weight gain but also demonstrate that hyperleptinemia contributes directly to the development of obesity and associated metabolic disorders. By suppressing the rise in leptin through the use of a monoclonal leptin-neutralizing antibody, we effectively prevented weight gain, restored glucose tolerance, and preserved adipose tissue and liver function in antipsychotic drug-treated mice. Mechanistically, suppressing excess leptin resolved local tissue and systemic inflammation typically associated with antipsychotic drug treatment. We conclude that hyperleptinemia is a key contributor to antipsychotic drug-associated weight gain and metabolic deterioration. Leptin suppression may be an effective approach to reducing the undesirable side effects of antipsychotic drugs.

DOI: https://doi.org/10.1126/scitranslmed.ade8460
Nat Commun. 2023 11 18. 14(1): 7525

Inferring mitochondrial and cytosolic metabolism by coupling isotope tracing and deconvolution.

Alon Stern, Mariam Fokra, Boris Sarvin, Ahmad Abed Alrahem, Won Dong Lee, Elina Aizenshtein, Nikita Sarvin, Tomer Shlomi.

The inability to inspect metabolic activities within distinct subcellular compartments has been a major barrier to our understanding of eukaryotic cell metabolism. Previous work addressed this challenge by analyzing metabolism in isolated organelles, which grossly bias metabolic activity. Here, we describe a method for inferring physiological metabolic fluxes and metabolite concentrations in mitochondria and cytosol based on isotope tracing experiments performed with intact cells. This is made possible by computational deconvolution of metabolite isotopic labeling patterns and concentrations into cytosolic and mitochondrial counterparts, coupled with metabolic and thermodynamic modelling. Our approach lowers the uncertainty regarding compartmentalized fluxes and concentrations by one and three orders of magnitude compared to existing modelling approaches, respectively. We derive a quantitative view of mitochondrial and cytosolic metabolic activities in central carbon metabolism across cultured cell lines without performing cell fractionation, finding major variability in compartmentalized malate-aspartate shuttle fluxes. We expect our approach for inferring metabolism at a subcellular resolution to be instrumental for a variety of studies of metabolic dysfunction in human disease and for bioengineering.

DOI: https://doi.org/10.1038/s41467-023-42824-z
bioRxiv. 2023 Nov 10. pii: 2023.11.03.565498. [Epub ahead of print]

Modulation of hepatic transcription factor EB activity during cold exposure uncovers direct regulation of bis(monoacylglycero)phosphate lipids by Pla2g15.

Raghav Jain, Gisela Geoghegan, Jessica Davidson, Daniel J Nesbitt, Akira Abe, Xiaojuan Chao, Isabella James, Amy Cavanagh, Sylwia Michorowska, Rakesh Verma, Kathryn Scheuler, Vania Hinkovska-Galcheva, Evgenia Shishkova, Wen-Xing Ding, Joshua J Coon, James A Shayman, Judith A Simcox.

Cold exposure is an environmental stress that elicits a rapid metabolic shift in endotherms and is required for survival. The liver provides metabolic flexibility through its ability to rewire lipid metabolism to respond to an increased demand in energy for thermogenesis. We leveraged cold exposure to identify novel lipids contributing to energy homeostasis and found that lysosomal bis(monoacylglycero)phosphate (BMP) lipids were significantly increased in the liver during acute cold exposure. BMP lipid changes occurred independently of lysosomal abundance but were dependent on the lysosomal transcriptional regulator transcription factor EB (TFEB). Knockdown of TFEB in hepatocytes decreased BMP lipid levels. Through molecular biology and biochemical assays, we found that TFEB regulates lipid catabolism during cold exposure and that TFEB knockdown mice were cold intolerant. To identify how TFEB regulates BMP lipid levels, we used a combinatorial approach to identify TFEB target Pla2g15 , a lysosomal phospholipase, as capable of degrading BMP lipids in in vitro liposome assays. Knockdown of Pla2g15 in hepatocytes led to a decrease in BMP lipid species. Together, our studies uncover a required role of TFEB in mediating lipid liver remodeling during cold exposure and identified Pla2g15 as an enzyme that regulates BMP lipid catabolism.

DOI: https://doi.org/10.1101/2023.11.03.565498
Free Radic Biol Med. 2023 Nov 16. pii: S0891-5849(23)01101-2. [Epub ahead of print]

Mitochondrial hyperfusion induces metabolic remodeling in lung endothelial cells by modifying the activities of electron transport chain complexes I and III.

Manivannan Yegambaram, Xutong Sun, Qing Lu, Yan Jin, Wojciech Ornatowski, Jamie Soto, Saurabh Aggarwal, Ting Wang, Kim Tieu, Haiwei Gu, Jeffrey R Fineman, Stephen M Black.

  OBJECTIVE: Pulmonary hypertension (PH) is a progressive disease with vascular remodeling as a critical structural alteration. We have previously shown that metabolic reprogramming is an early initiating mechanism in animal models of PH. This metabolic dysregulation has been linked to remodeling the mitochondrial network to favor fission. However, whether the mitochondrial fission/fusion balance underlies the metabolic reprogramming found early in PH development is unknown.METHODS: Utilizing a rat early model of PH, in conjunction with cultured pulmonary endothelial cells (PECs), we utilized metabolic flux assays, Seahorse Bioassays, measurements of electron transport chain (ETC) complex activity, fluorescent microscopy, and molecular approaches to investigate the link between the disruption of mitochondrial dynamics and the early metabolic changes that occur in PH.
RESULTS: We observed increased fusion mediators, including Mfn1, Mfn2, and Opa1, and unchanged fission mediators, including Drp1 and Fis1, in a two-week monocrotaline-induced PH animal model (early-stage PH). We were able to establish a connection between increases in fusion mediator Mfn1 and metabolic reprogramming. Using an adenoviral expression system to enhance Mfn1 levels in pulmonary endothelial cells and utilizing 13C-glucose labeled substrate, we found increased production of 13C lactate and decreased TCA cycle metabolites, revealing a Warburg phenotype. The use of a 13C5-glutamine substrate showed evidence that hyperfusion also induces oxidative carboxylation. The increase in glycolysis was linked to increased hypoxia-inducible factor 1α (HIF-1α) protein levels secondary to the disruption of cellular bioenergetics and higher levels of mitochondrial reactive oxygen species (mt-ROS). The elevation in mt-ROS correlated with attenuated ETC complexes I and III activities. Utilizing a mitochondrial-targeted antioxidant to suppress mt-ROS, limited HIF-1α protein levels, which reduced cellular glycolysis and reestablished mitochondrial membrane potential.
CONCLUSIONS: Our data connects mitochondrial fusion-mediated mt-ROS to the Warburg phenotype in early-stage PH development.

Keywords:  Glycolysis; Metabolomics; Mitochondrial function; Mitofusin; Pulmonary hypertension

DOI:  https://doi.org/10.1016/j.freeradbiomed.2023.11.008
Biol Lett. 2023 Nov;19(11): 20230373

Birds are better at regulating heat loss through their legs than their bills: implications for body shape evolution in response to climate.

Alexandra McQueen, Ryan Barnaby, Matthew R E Symonds, Glenn J Tattersall.

  Endotherms use their appendages-such as legs, tails, ears and bills-for thermoregulation by controlling blood flow to near-surface blood vessels, conserving heat when it is cold, and dissipating heat in hot conditions. Larger appendages allow greater heat dissipation, and appendage sizes vary latitudinally according to Allen's rule. However, little is known about the relative importance of different appendages for thermoregulation. We investigate physiological control of heat loss via bird bills and legs using infrared thermography of wild birds. Our results demonstrate that birds are less able to regulate heat loss via their bills than their legs. In cold conditions, birds lower their leg surface temperature to below that of their plumage surface, retaining heat at their core. In warm conditions, birds increase their leg surface temperature to above that of their plumage surface, expelling heat. By contrast, bill surface temperature remains approximately 2°C warmer than the plumage surface, indicating consistent heat loss under almost all conditions. Poorer physiological control of heat loss via bird bills likely entails stronger selection for shorter bills in cold climates. This could explain why bird bills show stronger latitudinal size clines than bird legs, with implications for predicting shape-shifting responses to climate change.

Keywords:  Allen's rule; beak; heat exchange; infrared thermography; shape-shifting; thermoregulation

DOI:  https://doi.org/10.1098/rsbl.2023.0373
J Therm Biol. 2023 Nov 13. pii: S0306-4565(23)00289-9. [Epub ahead of print]118 103748

Great tits (Parus major) in a west European temperate forest show little seasonal variation in metabolic energy requirements.

Cesare Pacioni, Marina Sentís, Catherine Hambly, John R Speakman, Anvar Kerimov, Andrey Bushuev, Luc Lens, Diederik Strubbe.

  Understanding how birds annually allocate energy to cope with changing environmental conditions and physiological states is a crucial question in avian ecology. There are several hypotheses to explain species' energy allocation. One prominent hypothesis suggests higher energy expenditure in winter due to increased thermoregulatory costs. The "reallocation" hypothesis suggests no net difference in seasonal energy requirements, while the "increased demand" hypothesis predicts higher energy requirements during the breeding season. Birds are expected to adjust their mass and/or metabolic intensity in ways that are consistent with their energy requirements. Here, we look for metabolic signatures of seasonal variation in energy requirements of a resident passerine of a temperate-zone (great tit, Parus major). To do so, we measured whole-body and mass-independent basal (BMR), summit (Msum), and field (FMR) metabolic rates during late winter and during breeding in Belgian great tits. During the breeding season, birds had on average 10% higher whole-body BMR and FMR compared to winter, while their Msum decreased by 7% from winter to breeding. Mass-independent metabolic rates showed a 10% increase in BMR and a 7% decrease in Msum from winter to breeding. Whole-body BMR was correlated with Msum, but this relationship did not hold for mass-independent metabolic rates. The modest seasonal change we observed suggests that great tits in our temperature study area maintain a largely stable energy budget throughout the year, which appears mostly consistent with the reallocation hypothesis.

Keywords:  Energy expenditure; Great tit; Metabolic rates

DOI:  https://doi.org/10.1016/j.jtherbio.2023.103748
Life Sci Alliance. 2024 Feb;pii: e202302147. [Epub ahead of print]7(2):

Mitochondrial phosphoproteomes are functionally specialized across tissues.

Fynn M Hansen, Laura S Kremer, Ozge Karayel, Isabell Bludau, Nils-Göran Larsson, Inge Kühl, Matthias Mann.

Mitochondria are essential organelles whose dysfunction causes human pathologies that often manifest in a tissue-specific manner. Accordingly, mitochondrial fitness depends on versatile proteomes specialized to meet diverse tissue-specific requirements. Increasing evidence suggests that phosphorylation may play an important role in regulating tissue-specific mitochondrial functions and pathophysiology. Building on recent advances in mass spectrometry (MS)-based proteomics, we here quantitatively profile mitochondrial tissue proteomes along with their matching phosphoproteomes. We isolated mitochondria from mouse heart, skeletal muscle, brown adipose tissue, kidney, liver, brain, and spleen by differential centrifugation followed by separation on Percoll gradients and performed high-resolution MS analysis of the proteomes and phosphoproteomes. This in-depth map substantially quantifies known and predicted mitochondrial proteins and provides a resource of core and tissue-specific mitochondrial proteins (mitophos.de). Predicting kinase substrate associations for different mitochondrial compartments indicates tissue-specific regulation at the phosphoproteome level. Illustrating the functional value of our resource, we reproduce mitochondrial phosphorylation events on dynamin-related protein 1 responsible for its mitochondrial recruitment and fission initiation and describe phosphorylation clusters on MIGA2 linked to mitochondrial fusion.

DOI: https://doi.org/10.26508/lsa.202302147
FASEB J. 2023 Dec;37(12): e23315

Brown adipose tissue transplantation improves skin fibrosis in localized scleroderma.

Qian Zhang, Zhuokai Liang, Yingjie Zhang, Juzi Liu, Yunjun Liao, Feng Lu, Jianhua Gao, Junrong Cai.

  Adipose tissue transplantation shows great therapeutic potential in reversing localized scleroderma-associated skin fibrosis. Brown adipose tissue (BAT) can specifically secrete various cytokines against fibrosis, but its therapeutic potential in improving skin fibrosis has not yet been demonstrated. In this study, we have demonstrated the superior therapeutic efficacy of BAT transplantation for sclerotic skin by transplanting two distinct types of adipose tissue. In comparison to the white adipose tissue (WAT) group, mice treated with BAT transplantation exhibited a significant reduction in dermal thickness. BAT transplantation effectively reverses skin sclerosis through mechanisms involving inflammation reduction, promotion of angiogenesis, inhibition of myofibroblast accumulation, and collagen deposition. This therapeutic effect can be attributed to its unique paracrine effects. Furthermore, transcriptome sequencing (RNA-Seq) revealed upregulation of pathways associated with lipogenesis and fatty acid metabolism in BAT while downregulating pathways are related to transforming growth factor β(TGF-β), epithelial-mesenchymal transition (EMT), and inflammatory response. These findings suggest that BAT transplantation holds great promise as a novel approach for localized scleroderma treatment.

Keywords:  brown adipose tissue; fat tranplantation; sclerpderma; skin fibrosis

DOI:  https://doi.org/10.1096/fj.202301575RR
Nat Metab. 2023 Nov 23.

Anomalous peroxidase activity of cytochrome c is the primary pathogenic target in Barth syndrome.

Valerian E Kagan, Yulia Y Tyurina, Karolina Mikulska-Ruminska, Deena Damschroder, Eduardo Vieira Neto, Alessia Lasorsa, Alexander A Kapralov, Vladimir A Tyurin, Andrew A Amoscato, Svetlana N Samovich, Austin B Souryavong, Haider H Dar, Abu Ramim, Zhuqing Liang, Pablo Lazcano, Jiajia Ji, Michael W Schmidtke, Kirill Kiselyov, Aybike Korkmaz, Georgy K Vladimirov, Margarita A Artyukhova, Pushpa Rampratap, Laura K Cole, Ammanamanchi Niyatie, Emma-Kate Baker, Jim Peterson, Grant M Hatch, Jeffrey Atkinson, Jerry Vockley, Bernhard Kühn, Robert Wessells, Patrick C A van der Wel, Ivet Bahar, Hülya Bayir, Miriam L Greenberg.

Barth syndrome (BTHS) is a life-threatening genetic disorder with unknown pathogenicity caused by mutations in TAFAZZIN (TAZ) that affect remodeling of mitochondrial cardiolipin (CL). TAZ deficiency leads to accumulation of mono-lyso-CL (MLCL), which forms a peroxidase complex with cytochrome c (cyt c) capable of oxidizing polyunsaturated fatty acid-containing lipids. We hypothesized that accumulation of MLCL facilitates formation of anomalous MLCL-cyt c peroxidase complexes and peroxidation of polyunsaturated fatty acid phospholipids as the primary BTHS pathogenic mechanism. Using genetic, biochemical/biophysical, redox lipidomic and computational approaches, we reveal mechanisms of peroxidase-competent MLCL-cyt c complexation and increased phospholipid peroxidation in different TAZ-deficient cells and animal models and in pre-transplant biopsies from hearts of patients with BTHS. A specific mitochondria-targeted anti-peroxidase agent inhibited MLCL-cyt c peroxidase activity, prevented phospholipid peroxidation, improved mitochondrial respiration of TAZ-deficient C2C12 myoblasts and restored exercise endurance in a BTHS Drosophila model. Targeting MLCL-cyt c peroxidase offers therapeutic approaches to BTHS treatment.

DOI: https://doi.org/10.1038/s42255-023-00926-4