bims-mimbat Biomed News
on Mitochondrial metabolism in brown adipose tissue
Issue of 2023–10–29
seven papers selected by
José Carlos de Lima-Júnior, Washington University
  1. Lipocalin 2 regulates mitochondrial phospholipidome remodeling, dynamics, and function in brown adipose tissue in male mice.
  2. Mitochondrial complex I ROS production and redox signaling in hypoxia.
  3. Maternal thyroid hormone receptor β activation in mice sparks brown fat thermogenesis in the offspring.
  4. Brown adipose tissue evaluation using water and triglyceride as indices by diffuse reflectance spectroscopy.
  5. Mitochondrial matrix RTN4IP1/OPA10 is an oxidoreductase for coenzyme Q synthesis.
  6. Lactate biosensors for spectrally and spatially multiplexed fluorescence imaging.
  7. Lactate activates the mitochondrial electron transport chain independently of its metabolism.
  1. Nat Commun. 2023 Oct 23. 14(1): 6729
    Lipocalin 2 regulates mitochondrial phospholipidome remodeling, dynamics, and function in brown adipose tissue in male mice.
    Hongming Su, Hong Guo, Xiaoxue Qiu, Te-Yueh Lin, Chao Qin, Gail Celio, Peter Yong, Mark Senders, Xianlin Han, David A Bernlohr, Xiaoli Chen.
      Mitochondrial function is vital for energy metabolism in thermogenic adipocytes. Impaired mitochondrial bioenergetics in brown adipocytes are linked to disrupted thermogenesis and energy balance in obesity and aging. Phospholipid cardiolipin (CL) and phosphatidic acid (PA) jointly regulate mitochondrial membrane architecture and dynamics, with mitochondria-associated endoplasmic reticulum membranes (MAMs) serving as the platform for phospholipid biosynthesis and metabolism. However, little is known about the regulators of MAM phospholipid metabolism and their connection to mitochondrial function. We discover that LCN2 is a PA binding protein recruited to the MAM during inflammation and metabolic stimulation. Lcn2 deficiency disrupts mitochondrial fusion-fission balance and alters the acyl-chain composition of mitochondrial phospholipids in brown adipose tissue (BAT) of male mice. Lcn2 KO male mice exhibit an increase in the levels of CLs containing long-chain polyunsaturated fatty acids (LC-PUFA), a decrease in CLs containing monounsaturated fatty acids, resulting in mitochondrial dysfunction. This dysfunction triggers compensatory activation of peroxisomal function and the biosynthesis of LC-PUFA-containing plasmalogens in BAT. Additionally, Lcn2 deficiency alters PA production, correlating with changes in PA-regulated phospholipid-metabolizing enzymes and the mTOR signaling pathway. In conclusion, LCN2 plays a critical role in the acyl-chain remodeling of phospholipids and mitochondrial bioenergetics by regulating PA production and its function in activating signaling pathways.
    DOI:  https://doi.org/10.1038/s41467-023-42473-2
  2. Redox Biol. 2023 Oct 16. pii: S2213-2317(23)00327-0. [Epub ahead of print]67 102926
    Mitochondrial complex I ROS production and redox signaling in hypoxia.
    Chidozie N Okoye, Shon A Koren, Andrew P Wojtovich.
      Mitochondria are a main source of cellular energy. Oxidative phosphorylation (OXPHOS) is the major process of aerobic respiration. Enzyme complexes of the electron transport chain (ETC) pump protons to generate a protonmotive force (Δp) that drives OXPHOS. Complex I is an electron entry point into the ETC. Complex I oxidizes nicotinamide adenine dinucleotide (NADH) and transfers electrons to ubiquinone in a reaction coupled with proton pumping. Complex I also produces reactive oxygen species (ROS) under various conditions. The enzymatic activities of complex I can be regulated by metabolic conditions and serves as a regulatory node of the ETC. Complex I ROS plays diverse roles in cell metabolism ranging from physiologic to pathologic conditions. Progress in our understanding indicates that ROS release from complex I serves important signaling functions. Increasing evidence suggests that complex I ROS is important in signaling a mismatch in energy production and demand. In this article, we review the role of ROS from complex I in sensing acute hypoxia.
    Keywords:  Acute hypoxia; Mitochondrial complex I; Oxygen sensing; ROS signaling
    DOI:  https://doi.org/10.1016/j.redox.2023.102926
  3. Nat Commun. 2023 Oct 24. 14(1): 6742
    Maternal thyroid hormone receptor β activation in mice sparks brown fat thermogenesis in the offspring.
    Rebecca Oelkrug, Lisbeth Harder, Mehdi Pedaran, Anne Hoffmann, Beke Kolms, Julica Inderhees, Sogol Gachkar, Julia Resch, Kornelia Johann, Olaf Jöhren, Kerstin Krause, Jens Mittag.
      It is well established that maternal thyroid hormones play an important role for the developing fetus; however, the consequences of maternal hyperthyroidism for the offspring remain poorly understood. Here we show in mice that maternal 3,3',5-triiodothyronine (T3) treatment during pregnancy leads to improved glucose tolerance in the adult male offspring and hyperactivity of brown adipose tissue (BAT) thermogenesis in both sexes starting early after birth. The activated BAT provides advantages upon cold exposure, reducing the strain on other thermogenic organs like muscle. This maternal BAT programming requires intact maternal thyroid hormone receptor β (TRβ) signaling, as offspring of mothers lacking this receptor display the opposite phenotype. On the molecular level, we identify distinct T3 induced alterations in maternal serum metabolites, including choline, a key metabolite for healthy pregnancy. Taken together, our results connect maternal TRβ activation to the fetal programming of a thermoregulatory phenotype in the offspring.
    DOI:  https://doi.org/10.1038/s41467-023-42425-w
  4. J Biophotonics. 2023 Oct 27. e202300183
    Brown adipose tissue evaluation using water and triglyceride as indices by diffuse reflectance spectroscopy.
    Tomomi Iida, Yukio Ueda, Hideo Tsukada, Dai Fukumoto, Takafumi Hamaoka.
      Brown adipose tissue (BAT) is related to lipid and glucose metabolism, and BAT evaluation is expected to contribute to disease prevention and treatment. We aimed to establish a BAT evaluation method using simple and non-invasive diffuse reflectance spectroscopy (DRS). We acquired diffuse reflectance spectra of BAT using DRS from rats with cold stimulation and analyzed the second-derivative spectra. To predict the amount of triglyceride in BAT from the second-derivative spectra, partial least-squares regression analysis was performed, and we examined whether BAT weight can be predicted from the amount of triglyceride by single regression analysis. By focusing on changes in the amount of triglyceride in BAT with cold stimulation, it was suggested that this amount could be predicted spectroscopically, and the predicted amount of triglyceride could be used to estimate the BAT weight with cold stimulation. If these results can be translated into humans, they may contribute to preventing metabolic disorders. This article is protected by copyright. All rights reserved.
    Keywords:  brown adipose tissue; diffuse reflectance spectroscopy; partial least-squares regression analysis; triglyceride; water
    DOI:  https://doi.org/10.1002/jbio.202300183
  5. Nat Chem Biol. 2023 Oct 26.
    Mitochondrial matrix RTN4IP1/OPA10 is an oxidoreductase for coenzyme Q synthesis.
    Isaac Park, Kwang-Eun Kim, Jeesoo Kim, Ae-Kyeong Kim, Subin Bae, Minkyo Jung, Jinhyuk Choi, Pratyush Kumar Mishra, Taek-Min Kim, Chulhwan Kwak, Myeong-Gyun Kang, Chang-Mo Yoo, Ji Young Mun, Kwang-Hyeon Liu, Kyu-Sun Lee, Jong-Seo Kim, Jae Myoung Suh, Hyun-Woo Rhee.
      Targeting proximity-labeling enzymes to specific cellular locations is a viable strategy for profiling subcellular proteomes. Here, we generated transgenic mice (MAX-Tg) expressing a mitochondrial matrix-targeted ascorbate peroxidase. Comparative analysis of matrix proteomes from the muscle tissues showed differential enrichment of mitochondrial proteins. We found that reticulon 4-interacting protein 1 (RTN4IP1), also known as optic atrophy-10, is enriched in the mitochondrial matrix of muscle tissues and is an NADPH oxidoreductase. Interactome analysis and in vitro enzymatic assays revealed an essential role for RTN4IP1 in coenzyme Q (CoQ) biosynthesis by regulating the O-methylation activity of COQ3. Rtn4ip1-knockout myoblasts had markedly decreased CoQ9 levels and impaired cellular respiration. Furthermore, muscle-specific knockdown of dRtn4ip1 in flies resulted in impaired muscle function, which was reversed by dietary supplementation with soluble CoQ. Collectively, these results demonstrate that RTN4IP1 is a mitochondrial NAD(P)H oxidoreductase essential for supporting mitochondrial respiration activity in the muscle tissue.
    DOI:  https://doi.org/10.1038/s41589-023-01452-w
  6. Nat Commun. 2023 Oct 27. 14(1): 6598
    Lactate biosensors for spectrally and spatially multiplexed fluorescence imaging.
    Yusuke Nasu, Abhi Aggarwal, Giang N T Le, Camilla Trang Vo, Yuki Kambe, Xinxing Wang, Felix R M Beinlich, Ashley Bomin Lee, Tina R Ram, Fangying Wang, Kelsea A Gorzo, Yuki Kamijo, Marc Boisvert, Suguru Nishinami, Genki Kawamura, Takeaki Ozawa, Hirofumi Toda, Grant R Gordon, Shaoyu Ge, Hajime Hirase, Maiken Nedergaard, Marie-Eve Paquet, Mikhail Drobizhev, Kaspar Podgorski, Robert E Campbell.
      L-Lactate is increasingly appreciated as a key metabolite and signaling molecule in mammals. However, investigations of the inter- and intra-cellular dynamics of L-lactate are currently hampered by the limited selection and performance of L-lactate-specific genetically encoded biosensors. Here we now report a spectrally and functionally orthogonal pair of high-performance genetically encoded biosensors: a green fluorescent extracellular L-lactate biosensor, designated eLACCO2.1, and a red fluorescent intracellular L-lactate biosensor, designated R-iLACCO1. eLACCO2.1 exhibits excellent membrane localization and robust fluorescence response. To the best of our knowledge, R-iLACCO1 and its affinity variants exhibit larger fluorescence responses than any previously reported intracellular L-lactate biosensor. We demonstrate spectrally and spatially multiplexed imaging of L-lactate dynamics by coexpression of eLACCO2.1 and R-iLACCO1 in cultured cells, and in vivo imaging of extracellular and intracellular L-lactate dynamics in mice.
    DOI:  https://doi.org/10.1038/s41467-023-42230-5
  7. Mol Cell. 2023 Oct 20. pii: S1097-2765(23)00800-6. [Epub ahead of print]
    Lactate activates the mitochondrial electron transport chain independently of its metabolism.
    Xin Cai, Charles P Ng, Olivia Jones, Tak Shun Fung, Keun Woo Ryu, Dayi Li, Craig B Thompson.
      Lactate has long been considered a cellular waste product. However, we found that as extracellular lactate accumulates, it also enters the mitochondrial matrix and stimulates mitochondrial electron transport chain (ETC) activity. The resulting increase in mitochondrial ATP synthesis suppresses glycolysis and increases the utilization of pyruvate and/or alternative respiratory substrates. The ability of lactate to increase oxidative phosphorylation does not depend on its metabolism. Both L- and D-lactate are effective at enhancing ETC activity and suppressing glycolysis. Furthermore, the selective induction of mitochondrial oxidative phosphorylation by unmetabolized D-lactate reversibly suppressed aerobic glycolysis in both cancer cell lines and proliferating primary cells in an ATP-dependent manner and enabled cell growth on respiratory-dependent bioenergetic substrates. In primary T cells, D-lactate enhanced cell proliferation and effector function. Together, these findings demonstrate that lactate is a critical regulator of the ability of mitochondrial oxidative phosphorylation to suppress glucose fermentation.
    Keywords:  TCA cycle; electron transport chain; glycolysis; lactate; mitochondria; oxidative phosphorylation
    DOI:  https://doi.org/10.1016/j.molcel.2023.09.034
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