bims-mimbat 2024-04-07 papers

bims-mimbat

Biomed News

on Mitochondrial metabolism in brown adipose tissue

Issue of 2024‒04‒07
eight papers selected by
José Carlos de Lima-Júnior, Washington University

Structural mechanisms of mitochondrial uncoupling protein 1 regulation in thermogenesis.
Long-range electron proton coupling in respiratory complex I - insights from molecular simulations of the quinone chamber and antiporter-like subunits.
Involution of brown adipose tissue through a Syntaxin 4 dependent pyroptosis pathway.
Glycogen synthesis is required for adaptive thermogenesis in beige adipose tissue and affects diet-induced obesity.
The 2-oxoglutarate/malate carrier extends the family of mitochondrial carriers capable of fatty acid and 2,4-dinitrophenol-activated proton transport.
Futile cycles: Emerging utility from apparent futility.
A spatiotemporal proteomic map of human adipogenesis.
Glucose controls lipolysis through Golgi PtdIns4P-mediated regulation of ATGL.

Trends Biochem Sci. 2024 Apr 01. pii: S0968-0004(24)00071-9. [Epub ahead of print]

Structural mechanisms of mitochondrial uncoupling protein 1 regulation in thermogenesis.

Scott A Jones, Jonathan J Ruprecht, Paul G Crichton, Edmund R S Kunji.

  In mitochondria, the oxidation of nutrients is coupled to ATP synthesis by the generation of a protonmotive force across the mitochondrial inner membrane. In mammalian brown adipose tissue (BAT), uncoupling protein 1 (UCP1, SLC25A7), a member of the SLC25 mitochondrial carrier family, dissipates the protonmotive force by facilitating the return of protons to the mitochondrial matrix. This process short-circuits the mitochondrion, generating heat for non-shivering thermogenesis. Recent cryo-electron microscopy (cryo-EM) structures of human UCP1 have provided new molecular insights into the inhibition and activation of thermogenesis. Here, we discuss these structures, describing how purine nucleotides lock UCP1 in a proton-impermeable conformation and rationalizing potential conformational changes of this carrier in response to fatty acid activators that enable proton leak for thermogenesis.

Keywords:  SLC25 mitochondrial carrier family; UCP1; bioenergetics; brown adipose tissue; non-shivering thermogenesis; thermogenin

DOI:  https://doi.org/10.1016/j.tibs.2024.03.005
Biochem J. 2024 Apr 10. 481(7): 499-514

Long-range electron proton coupling in respiratory complex I - insights from molecular simulations of the quinone chamber and antiporter-like subunits.

Amina Djurabekova, Jonathan Lasham, Oleksii Zdorevskyi, Volker Zickermann, Vivek Sharma.

  Respiratory complex I is a redox-driven proton pump. Several high-resolution structures of complex I have been determined providing important information about the putative proton transfer paths and conformational transitions that may occur during catalysis. However, how redox energy is coupled to the pumping of protons remains unclear. In this article, we review biochemical, structural and molecular simulation data on complex I and discuss several coupling models, including the key unresolved mechanistic questions. Focusing both on the quinone-reductase domain as well as the proton-pumping membrane-bound domain of complex I, we discuss a molecular mechanism of proton pumping that satisfies most experimental and theoretical constraints. We suggest that protonation reactions play an important role not only in catalysis, but also in the physiologically-relevant active/deactive transition of complex I.

Keywords:  MD simulations; energy conversion; mitochondrial respiration; protein dynamics; proton pump

DOI:  https://doi.org/10.1042/BCJ20240009
Nat Commun. 2024 Apr 02. 15(1): 2856

Involution of brown adipose tissue through a Syntaxin 4 dependent pyroptosis pathway.

Xiaofan Yu, Gabrielle Benitez, Peter Tszki Wei, Sofia V Krylova, Ziyi Song, Li Liu, Meifan Zhang, Alus M Xiaoli, Henna Wei, Fenfen Chen, Simone Sidoli, Fajun Yang, Kosaku Shinoda, Jeffrey E Pessin, Daorong Feng.

Aging, chronic high-fat diet feeding, or housing at thermoneutrality induces brown adipose tissue (BAT) involution, a process characterized by reduction of BAT mass and function with increased lipid droplet size. Single nuclei RNA sequencing of aged mice identifies a specific brown adipocyte population of Ucp1-low cells that are pyroptotic and display a reduction in the longevity gene syntaxin 4 (Stx4a). Similar to aged brown adipocytes, Ucp1-STX4KO mice display loss of brown adipose tissue mass and thermogenic dysfunction concomitant with increased pyroptosis. Restoration of STX4 expression or suppression of pyroptosis activation protects against the decline in both mass and thermogenic activity in the aged and Ucp1-STX4KO mice. Mechanistically, STX4 deficiency reduces oxidative phosphorylation, glucose uptake, and glycolysis leading to reduced ATP levels, a known triggering signal for pyroptosis. Together, these data demonstrate an understanding of rapid brown adipocyte involution and that physiologic aging and thermogenic dysfunction result from pyroptotic signaling activation.

DOI: https://doi.org/10.1038/s41467-024-46944-y
Am J Physiol Endocrinol Metab. 2024 Apr 03.

Glycogen synthesis is required for adaptive thermogenesis in beige adipose tissue and affects diet-induced obesity.

Shixuan Zhuo, Meijuan Bai, Zinan Wang, Lingling Chen, Zixuan Li, Jinzhu Chen, Xiaoyi Ye, Cheng Guo, Yan Chen.

  Glycogen is a form of energy storage for glucose in different tissues such as liver and skeletal muscle. It remains incompletely understood how glycogen impacts on adipose tissue functionality. Cold exposure elevated the expression of Gys1 which encodes glycogen synthase 1 in brown adipose tissue (BAT) and inguinal white adipose tissue (iWAT). The in vivo function of Gys1 was analyzed using a mouse model in which Gys1 was deleted specifically in adipose tissues. Under normal chow conditions, Gys1 deletion caused little changes to body weight and glucose metabolism. Deletion of Gys1 abrogated upregulation of UCP1 and other thermogenesis-related genes in iWAT upon prolonged cold exposure or treatment with b3-adrenergic receptor agonist CL-316,243. Stimulation of UCP1 by CL-316,243 in adipose-derived stromal cells (SVFs) was also reduced by Gys1 deletion. Both the basal glycogen content and CL-316,243-stimulated glycogen accumulation in adipose tissues were reduced by Gys1 deletion. High-fat diet-induced obesity and insulin resistance were aggravated in Gys1-deleted mice. The loss of body weight upon CL-316,243 treatment was also abrogated by the loss of Gys1. In conclusion, our results underscore the pivotal role of glycogen synthesis in adaptive thermogenesis in beige adipose tissue and its impact on diet-induced obesity in mice.

Keywords:  adipose tissue; glycogen; obesity; thermogenesis

DOI:  https://doi.org/10.1152/ajpendo.00074.2024
Acta Physiol (Oxf). 2024 Apr 05. e14143

The 2-oxoglutarate/malate carrier extends the family of mitochondrial carriers capable of fatty acid and 2,4-dinitrophenol-activated proton transport.

Kristina Žuna, Tatyana Tyschuk, Taraneh Beikbaghban, Felix Sternberg, Jürgen Kreiter, Elena E Pohl.

  AIMS: Metabolic reprogramming in cancer cells has been linked to mitochondrial dysfunction. The mitochondrial 2-oxoglutarate/malate carrier (OGC) has been suggested as a potential target for preventing cancer progression. Although OGC is involved in the malate/aspartate shuttle, its exact role in cancer metabolism remains unclear. We aimed to investigate whether OGC may contribute to the alteration of mitochondrial inner membrane potential by transporting protons.METHODS: The expression of OGC in mouse tissues and cancer cells was investigated by PCR and Western blot analysis. The proton transport function of recombinant murine OGC was evaluated by measuring the membrane conductance (Gm) of planar lipid bilayers. OGC-mediated substrate transport was measured in proteoliposomes using 14C-malate.
RESULTS: OGC increases proton Gm only in the presence of natural (long-chain fatty acids, FA) or chemical (2,4-dinitrophenol) protonophores. The increase in OGC activity directly correlates with the increase in the number of unsaturated bonds of the FA. OGC substrates and inhibitors compete with FA for the same protein binding site. Arginine 90 was identified as a critical amino acid for the binding of FA, ATP, 2-oxoglutarate, and malate, which is a first step towards understanding the OGC-mediated proton transport mechanism.
CONCLUSION: OGC extends the family of mitochondrial transporters with dual function: (i) metabolite transport and (ii) proton transport facilitated in the presence of protonophores. Elucidating the contribution of OGC to uncoupling may be essential for the design of targeted drugs for the treatment of cancer and other metabolic diseases.

Keywords:  SLC25A11; long‐chain fatty acids; mitochondrial transport; planar bilayer membranes; proton transport; total membrane conductance

DOI:  https://doi.org/10.1111/apha.14143
Cell Metab. 2024 Mar 27. pii: S1550-4131(24)00087-1. [Epub ahead of print]

Futile cycles: Emerging utility from apparent futility.

Anand Kumar Sharma, Radhika Khandelwal, Christian Wolfrum.

  Futile cycles are biological phenomena where two opposing biochemical reactions run simultaneously, resulting in a net energy loss without appreciable productivity. Such a state was presumed to be a biological aberration and thus deemed an energy-wasting "futile" cycle. However, multiple pieces of evidence suggest that biological utilities emerge from futile cycles. A few established functions of futile cycles are to control metabolic sensitivity, modulate energy homeostasis, and drive adaptive thermogenesis. Yet, the physiological regulation, implication, and pathological relevance of most futile cycles remain poorly studied. In this review, we highlight the abundance and versatility of futile cycles and propose a classification scheme. We further discuss the energetic implications of various futile cycles and their impact on basal metabolic rate, their bona fide and tentative pathophysiological implications, and putative drug interactions.

Keywords:  BMR; energy expenditure; futile calcium cycling; futile creatine cycle; futile cycle; futile lipid cycle; obesity; uncoupler

DOI:  https://doi.org/10.1016/j.cmet.2024.03.008
Nat Metab. 2024 Apr 02.

A spatiotemporal proteomic map of human adipogenesis.

Felix Klingelhuber, Scott Frendo-Cumbo, Muhmmad Omar-Hmeadi, Lucas Massier, Pamela Kakimoto, Austin J Taylor, Morgane Couchet, Sara Ribicic, Martin Wabitsch, Ana C Messias, Arcangela Iuso, Timo D Müller, Mikael Rydén, Niklas Mejhert, Natalie Krahmer.

White adipocytes function as major energy reservoirs in humans by storing substantial amounts of triglycerides, and their dysfunction is associated with metabolic disorders; however, the mechanisms underlying cellular specialization during adipogenesis remain unknown. Here, we generate a spatiotemporal proteomic atlas of human adipogenesis, which elucidates cellular remodelling as well as the spatial reorganization of metabolic pathways to optimize cells for lipid accumulation and highlights the coordinated regulation of protein localization and abundance during adipocyte formation. We identify compartment-specific regulation of protein levels and localization changes of metabolic enzymes to reprogramme branched-chain amino acids and one-carbon metabolism to provide building blocks and reduction equivalents. Additionally, we identify C19orf12 as a differentiation-induced adipocyte lipid droplet protein that interacts with the translocase of the outer membrane complex of lipid droplet-associated mitochondria and regulates adipocyte lipid storage by determining the capacity of mitochondria to metabolize fatty acids. Overall, our study provides a comprehensive resource for understanding human adipogenesis and for future discoveries in the field.

DOI: https://doi.org/10.1038/s42255-024-01025-8
Nat Cell Biol. 2024 Apr 01.

Glucose controls lipolysis through Golgi PtdIns4P-mediated regulation of ATGL.

Lianggong Ding, Florian Huwyler, Fen Long, Wu Yang, Jonas Binz, Kendra Wernlé, Matthias Pfister, Manuel Klug, Miroslav Balaz, Barbara Ukropcova, Jozef Ukropec, Chunyan Wu, Tongtong Wang, Min Gao, Pierre-Alain Clavien, Philipp Dutkowski, Mark W Tibbitt, Christian Wolfrum.

Metabolic crosstalk of the major nutrients glucose, amino acids and fatty acids (FAs) ensures systemic metabolic homeostasis. The coordination between the supply of glucose and FAs to meet various physiological demands is especially important as improper nutrient levels lead to metabolic disorders, such as diabetes and metabolic dysfunction-associated steatohepatitis (MASH). In response to the oscillations in blood glucose levels, lipolysis is thought to be mainly regulated hormonally to control FA liberation from lipid droplets by insulin, catecholamine and glucagon. However, whether general cell-intrinsic mechanisms exist to directly modulate lipolysis via glucose sensing remains largely unknown. Here we report the identification of such an intrinsic mechanism, which involves Golgi PtdIns4P-mediated regulation of adipose triglyceride lipase (ATGL)-driven lipolysis via intracellular glucose sensing. Mechanistically, depletion of intracellular glucose results in lower Golgi PtdIns4P levels, and thus reduced assembly of the E3 ligase complex CUL7FBXW8 in the Golgi apparatus. Decreased levels of the E3 ligase complex lead to reduced polyubiquitylation of ATGL in the Golgi and enhancement of ATGL-driven lipolysis. This cell-intrinsic mechanism regulates both the pool of intracellular FAs and their extracellular release to meet physiological demands during fasting and glucose deprivation. Moreover, genetic and pharmacological manipulation of the Golgi PtdIns4P-CUL7FBXW8-ATGL axis in mouse models of simple hepatic steatosis and MASH, as well as during ex vivo perfusion of a human steatotic liver graft leads to the amelioration of steatosis, suggesting that this pathway might be a promising target for metabolic dysfunction-associated steatotic liver disease and possibly MASH.

DOI: https://doi.org/10.1038/s41556-024-01386-y