bims-mimbat 2023-09-24 papers

bims-mimbat

Biomed News

on Mitochondrial metabolism in brown adipose tissue

Issue of 2023–09–24
six papers selected by
José Carlos de Lima-Júnior, Washington University

When the cold gets under your skin: Evidence for brown adipose tissue activity in Samoan adults.
High levels of uric acid inhibit BAT thermogenic capacity through regulation of AMPK.
Single-nucleus RNA-sequencing reveals NRF1/NFE2L1 as a key factor determining the thermogenesis and cellular heterogeneity and dynamics of brown adipose tissues in mice.
Coenzyme Q10 trapping in mitochondrial complex I underlies Leber's hereditary optic neuropathy.
Scalable Generation of Pre-Vascularized and Functional Human Beige Adipose Organoids.
Manipulating mitochondrial electron flow enhances tumor immunogenicity.

Am J Biol Anthropol. 2023 Sep 23.

When the cold gets under your skin: Evidence for brown adipose tissue activity in Samoan adults.

Alexandra Niclou, Lupesina Vesi, Maria Arorae, New Caledonia Naseri, Kima Faasalele Savusa, Take Naseri, James P DeLany, Stephen T McGarvey, Anna C Rivara, Cara Ocobock.

   OBJECTIVES: Brown adipose tissue (BAT) is a heat-producing organ aiding nonshivering thermogenesis (NST) during cold stress. Due to its potential cold-adaptive role BAT has been predominantly studied in cold and temperate climate populations, but not among warm-climate adults. This work explores if BAT activity can be inferred in Samoans.
MATERIALS AND METHODS: We inferred BAT activity by comparing metabolic rate and surface heat dissipation using indirect calorimetry and thermal imaging between room temperature and cold exposure among Samoans (N = 61, females: n = 38) from 'Upolu Island, Samoa. BAT activity was inferred using ANOVA linear regression models with the variables measured at cold exposure as outcomes. T-tests were used to compare changes in surface temperature between room temperature and cold exposure.
RESULTS: Metabolic rate significantly increased after cooling. In both the supraclavicular area, a known BAT location, and the sternum, a non-BAT location, temperatures decreased significantly upon cold exposure. Differences in supraclavicular temperatures between room temperature and cold were significantly smaller than differences in sternum temperatures between exposures. These results suggest that BAT thermogenesis occurred in known BAT-locations and thus contributed to NST during cooling.
CONCLUSIONS: This study adds to our understanding of BAT activity across different populations and climates. Further study may illuminate whether the cold-adaptive properties of BAT may have played a role in the successful expansion of populations across the globe, including warm-climate groups.

Keywords:  Polynesia; brown adipose tissue; metabolic rate; thermoregulation

DOI:  https://doi.org/10.1002/ajpa.24848
Am J Physiol Endocrinol Metab. 2023 Sep 21.

High levels of uric acid inhibit BAT thermogenic capacity through regulation of AMPK.

Meijuan Dong, Kun An, Li Mao.

  Hyperuricemia (HUA) is strongly associated with the increasing prevalence of obesity, but the underlying mechanism remains elusive. Dysfunction of brown adipose tissue (BAT) could lead to obesity. However, studies on the role of HUA on BAT are lacking. Our retrospective clinical analysis showed that serum uric acid (UA) is significantly associated with BAT in humans. To investigate the role of UA in regulating BAT function, we used UA to treat primary brown adipocytes (BAC) in vitro and established HUA mice. In vitro results showed that HUA suppressed thermogenic gene expression and oxygen consumption rate. Accordingly, HUA mice exhibited lower energy expenditure and body temperature, with larger lipid droplets and lower thermogenic gene expression. These results demonstrate that HUA inhibits BAT thermogenic capacity in vitro and in vivo. To further elucidate the mechanism of UA on adipocytes, mRNA-sequencing analysis was performed and screened for "AMP-activated protein kinase (AMPK) signaling pathway" and "mitochondrial biogenesis". Further tests in vivo and vitro showed that the phosphorylation of AMPK was suppressed by HUA. Activation of AMPK alleviated the inhibition of AMPK phosphorylation by HUA and increased mitochondrial biogenesis, subsequently restoring the impaired BAT thermogenic capacity in vitro and vivo. Thus, we confirmed that HUA suppresses mitochondrial biogenesis by regulating AMPK, thereby inhibiting BAT thermogenic capacity. Taken together, our study identifies UA as a novel regulator of BAT thermogenic capacity, providing a new strategy to combat obesity.

Keywords:  AMPK; Brown fat; Thermogenesis; Uric acid; mitochondria

DOI:  https://doi.org/10.1152/ajpendo.00092.2023
Redox Biol. 2023 Sep 11. pii: S2213-2317(23)00280-X. [Epub ahead of print]67 102879

Single-nucleus RNA-sequencing reveals NRF1/NFE2L1 as a key factor determining the thermogenesis and cellular heterogeneity and dynamics of brown adipose tissues in mice.

Wei Shen, Suping Ren, Yongyong Hou, Zhuo Zuo, Shengnan Liu, Zhiyuan Liu, Jingqi Fu, Huihui Wang, Bei Yang, Rui Zhao, Yanyan Chen, Masayuki Yamamoto, Yuanyuan Xu, Qiang Zhang, Jingbo Pi.

  Brown adipose tissue (BAT) is a major site of non-shivering thermogenesis in mammals and plays an important role in energy homeostasis. Nuclear factor-erythroid 2-related factor 1 (NFE2L1, also known as Nrf1), a master regulator of cellular metabolic homeostasis and numerous stress responses, has been found to function as a critical driver in BAT thermogenic adaption to cold or obesity by providing proteometabolic quality control. Our recent studies using adipocyte-specific Nfe2l1 knockout [Nfe2l1(f)-KO] mice demonstrated that NFE2L1-dependent transcription of lipolytic genes is crucial for white adipose tissue (WAT) homeostasis and plasticity. In the present study, we found that Nfe2l1(f)-KO mice develop an age-dependent whitening and shrinking of BAT, with signatures of down-regulation of proteasome, impaired mitochondrial function, reduced thermogenesis, pro-inflammation, and elevated regulatory cell death (RCD). Mechanistic studies revealed that deficiency of Nfe2l1 in brown adipocytes (BAC) primarily results in down-regulation of lipolytic genes, which decelerates lipolysis, making BAC unable to fuel thermogenesis. These changes lead to BAC hypertrophy, inflammation-associated RCD, and consequently cold intolerance. Single-nucleus RNA-sequencing of BAT reveals that deficiency of Nfe2l1 induces significant transcriptomic changes leading to aberrant expression of a variety of genes involved in lipid metabolism, proteasome, mitochondrial stress, inflammatory responses, and inflammation-related RCD in distinct subpopulations of BAC. Taken together, our study demonstrated that NFE2L1 serves as a vital transcriptional regulator that controls the lipid metabolic homeostasis in BAC, which in turn determines the metabolic dynamics, cellular heterogeneity and subsequently cell fates in BAT.

Keywords:  BAT whitening; Lipolysis; NFE2L1; brown adipocyte; snRNA-seq

DOI:  https://doi.org/10.1016/j.redox.2023.102879
Proc Natl Acad Sci U S A. 2023 Sep 26. 120(39): e2304884120

Coenzyme Q10 trapping in mitochondrial complex I underlies Leber's hereditary optic neuropathy.

Jack T Fuller, Steven Barnes, Lorenzo A Sadun, Pujan Ajmera, Anastassia N Alexandrova, Alfredo A Sadun.

  How does a single amino acid mutation occurring in the blinding disease, Leber's hereditary optic neuropathy (LHON), impair electron shuttling in mitochondria? We investigated changes induced by the m.3460 G>A mutation in mitochondrial protein ND1 using the tools of Molecular Dynamics and Free Energy Perturbation simulations, with the goal of determining the mechanism by which this mutation affects mitochondrial function. A recent analysis suggested that the mutation's replacement of alanine A52 with a threonine perturbs the stability of a region where binding of the electron shuttling protein, Coenzyme Q10, occurs. We found two functionally opposing changes involving the role of Coenzyme Q10. The first showed that quantum electron transfer from the terminal Fe/S complex, N2, to the Coenzyme Q10 headgroup, docked in its binding pocket, is enhanced. However, this positive adjustment is overshadowed by our finding that the mobility of Coenzyme Q10 in its oxidized and reduced states, entering and exiting its binding pocket, is disrupted by the mutation in a manner that leads to conditions promoting the generation of reactive oxygen species. An increase in reactive oxygen species caused by the LHON mutation has been proposed to be responsible for this optic neuropathy.

Keywords:  Coenzyme Q10; blinding genetic disease; mitochondria; molecular dynamics simulation; quantum electron tunneling

DOI:  https://doi.org/10.1073/pnas.2304884120
Adv Sci (Weinh). 2023 Sep 20. e2301499

Scalable Generation of Pre-Vascularized and Functional Human Beige Adipose Organoids.

Mélanie Escudero, Laurence Vaysse, Gozde Eke, Marion Peyrou, Francesc Villarroya, Sophie Bonnel, Yannick Jeanson, Louisa Boyer, Christophe Vieu, Benoit Chaput, Xi Yao, Frédéric Deschaseaux, Mélissa Parny, Isabelle Raymond-Letron, Christian Dani, Audrey Carrière, Laurent Malaquin, Louis Casteilla.

  Obesity and type 2 diabetes are becoming a global sociobiomedical burden. Beige adipocytes are emerging as key inducible actors and putative relevant therapeutic targets for improving metabolic health. However, in vitro models of human beige adipose tissue are currently lacking and hinder research into this cell type and biotherapy development. Unlike traditional bottom-up engineering approaches that aim to generate building blocks, here a scalable system is proposed to generate pre-vascularized and functional human beige adipose tissue organoids using the human stromal vascular fraction of white adipose tissue as a source of adipose and endothelial progenitors. This engineered method uses a defined biomechanical and chemical environment using tumor growth factor β (TGFβ) pathway inhibition and specific gelatin methacryloyl (GelMA) embedding parameters to promote the self-organization of spheroids in GelMA hydrogel, facilitating beige adipogenesis and vascularization. The resulting vascularized organoids display key features of native beige adipose tissue including inducible Uncoupling Protein-1 (UCP1) expression, increased uncoupled mitochondrial respiration, and batokines secretion. The controlled assembly of spheroids allows to translate organoid morphogenesis to a macroscopic scale, generating vascularized centimeter-scale beige adipose micro-tissues. This approach represents a significant advancement in developing in vitro human beige adipose tissue models and facilitates broad applications ranging from basic research to biotherapies.

Keywords:  adipose-derived stroma/stem cells (ASC); beige and brown adipocytes; guided-assembly; hydrogels; microtissues; organoid morphogenesis; stromal vascular fraction

DOI:  https://doi.org/10.1002/advs.202301499
Science. 2023 Sep 22. 381(6664): 1316-1323

Manipulating mitochondrial electron flow enhances tumor immunogenicity.

Kailash Chandra Mangalhara, Siva Karthik Varanasi, Melissa A Johnson, Mannix J Burns, Gladys R Rojas, Pau B Esparza Moltó, Alva G Sainz, Nimesha Tadepalle, Keene L Abbott, Gaurav Mendiratta, Dan Chen, Yagmur Farsakoglu, Tenzin Kunchok, Filipe Araujo Hoffmann, Bianca Parisi, Mercedes Rincon, Matthew G Vander Heiden, Marcus Bosenberg, Diana C Hargreaves, Susan M Kaech, Gerald S Shadel.

Although tumor growth requires the mitochondrial electron transport chain (ETC), the relative contribution of complex I (CI) and complex II (CII), the gatekeepers for initiating electron flow, remains unclear. In this work, we report that the loss of CII, but not that of CI, reduces melanoma tumor growth by increasing antigen presentation and T cell-mediated killing. This is driven by succinate-mediated transcriptional and epigenetic activation of major histocompatibility complex-antigen processing and presentation (MHC-APP) genes independent of interferon signaling. Furthermore, knockout of methylation-controlled J protein (MCJ), to promote electron entry preferentially through CI, provides proof of concept of ETC rewiring to achieve antitumor responses without side effects associated with an overall reduction in mitochondrial respiration in noncancer cells. Our results may hold therapeutic potential for tumors that have reduced MHC-APP expression, a common mechanism of cancer immunoevasion.

DOI: https://doi.org/10.1126/science.abq1053