bims-mimbat 2024-01-21 papers

bims-mimbat

Biomed News

on Mitochondrial metabolism in brown adipose tissue

Issue of 2024–01–21
twelve papers selected by
José Carlos de Lima-Júnior, Washington University

ATF4 expression in thermogenic adipocytes is required for cold-induced thermogenesis in mice via FGF21-independent mechanisms.
Genetically encoded tool for manipulation of ΔΨm identifies the latter as the driver of integrative stress response induced by ATP Synthase dysfunction.
SCD1 sustains brown fat sympathetic innervation and thermogenesis during the long-term cold exposure.
Very-low-density lipoprotein triglyceride and free fatty acid plasma kinetics in women with high or low brown adipose tissue volume and overweight/obesity.
Partial loss of MCU mitigates pathology in vivo across a diverse range of neurodegenerative disease models.
Remodelling the inguinal adipose sensory system to switch on the furnace: Electroacupuncture stimulation induces brown adipose thermogenesis.
In situ architecture of Opa1-dependent mitochondrial cristae remodeling.
The mitochondrial ATP-dependent potassium channel (mitoKATP) controls skeletal muscle structure and function.
Identification of SLC25A46 interaction interfaces with mitochondrial membrane fusogens Mfn2 and Opa1.
An ETFDH-driven metabolon supports OXPHOS efficiency in skeletal muscle by regulating coenzyme Q homeostasis.
A membrane-associated phosphoswitch in Rad controls adrenergic regulation of cardiac calcium channels.
TRPM8-dependent shaking in mammals and birds.

Sci Rep. 2024 01 18. 14(1): 1563

ATF4 expression in thermogenic adipocytes is required for cold-induced thermogenesis in mice via FGF21-independent mechanisms.

Sarah H Bjorkman, Alex Marti, Jayashree Jena, Luis Miguel García-Peña, Eric T Weatherford, Kevin Kato, Jivan Koneru, Jason Chen, Ayushi Sood, Matthew J Potthoff, Christopher M Adams, E Dale Abel, Renata O Pereira.

In brown adipose tissue (BAT), short-term cold exposure induces the activating transcription factor 4 (ATF4), and its downstream target fibroblast growth factor 21 (FGF21). Induction of ATF4 in BAT in response to mitochondrial stress is required for thermoregulation, partially by increasing FGF21 expression. In the present study, we tested the hypothesis that Atf4 and Fgf21 induction in BAT are both required for BAT thermogenesis under physiological stress by generating mice selectively lacking either Atf4 (ATF4 BKO) or Fgf21 (FGF21 BKO) in UCP1-expressing adipocytes. After 3 days of cold exposure, core body temperature was significantly reduced in ad-libitum-fed ATF4 BKO mice, which correlated with Fgf21 downregulation in brown and beige adipocytes, and impaired browning of white adipose tissue. Conversely, despite having reduced browning, FGF21 BKO mice had preserved core body temperature after cold exposure. Mechanistically, ATF4, but not FGF21, regulates amino acid import and metabolism in response to cold, likely contributing to BAT thermogenic capacity under ad libitum-fed conditions. Importantly, under fasting conditions, both ATF4 and FGF21 were required for thermogenesis in cold-exposed mice. Thus, ATF4 regulates BAT thermogenesis under fed conditions likely in a FGF21-independent manner, in part via increased amino acid uptake and metabolism.

DOI: https://doi.org/10.1038/s41598-024-52004-8
bioRxiv. 2023 Dec 27. pii: 2023.12.27.573435. [Epub ahead of print]

Genetically encoded tool for manipulation of ΔΨm identifies the latter as the driver of integrative stress response induced by ATP Synthase dysfunction.

Mangyu Choe, Denis V Titov.

Mitochondrial membrane potential (ΔΨm) is one of the key parameters controlling cellular bioenergetics. Investigation of the role of ΔΨm in live cells is complicated by a lack of tools for its direct manipulation without off-target effects. Here, we adopted the uncoupling protein UCP1 from brown adipocytes as a genetically encoded tool for direct manipulation of ΔΨm. We validated the ability of exogenously expressed UCP1 to induce uncoupled respiration and lower ΔΨm in mammalian cells. UCP1 expression lowered ΔΨm to the same extent as chemical uncouplers but did not inhibit cell proliferation, suggesting that it manipulates ΔΨm without the off-target effects of chemical uncouplers. Using UCP1, we revealed that elevated ΔΨm is the driver of the Integrated Stress Response induced by ATP synthase inhibition in mammalian cells.

DOI: https://doi.org/10.1101/2023.12.27.573435
Biochem Biophys Res Commun. 2024 Jan 08. pii: S0006-291X(24)00028-7. [Epub ahead of print]696 149493

SCD1 sustains brown fat sympathetic innervation and thermogenesis during the long-term cold exposure.

Zongcai Liu, Sijin Zhu, Zhiwei Zhao, Shan Tang, Jingyu Tan, Chong Xue, Qijia Tang, Fengshuo Liu, Xiao Li, Jingyuan Chen, Huanyu Lu, Wenjing Luo.

  Brown fat adipose tissue (BAT) is a therapeutic potential target to improve obesity, diabetes and cold acclimation in mammals. During the long-term cold exposure, the hyperplastic sympathetic network is crucial for BAT the maintain the highly thermogenic status. It has been proved that the sympathetic nervous drives the thermogenic activity of BAT via the release of norepinephrine. However, it is still unclear that how the thermogenic BAT affects the remodeling of the hyperplastic sympathetic network, especially during the long-term cold exposure. Here, we showed that following long-term cold exposure, SCD1-mediated monounsaturated fatty acid biosynthesis pathway was enriched, and the ratios of monounsaturated/saturated fatty acids were significantly up-regulated in BAT. And SCD1-deficiency in BAT decreased the capacity of cold acclimation, and suppressed long-term cold mediated BAT thermogenic activation. Furthermore, by using thermoneutral exposure and sympathetic nerve excision models, we disclosed that SCD1-deficiency in BAT affected the thermogenic activity, depended on sympathetic nerve. In mechanism, SCD1-deficiency resulted in the unbalanced ratio of palmitic acid (PA)/palmitoleic acid (PO), with obviously higher level of PA and lower level of PO. And PO supplement efficiently reversed the inhibitory role of SCD1-deficiency on BAT thermogenesis and the hyperplastic sympathetic network. Thus, our data provided insight into the role of SCD1-mediated monounsaturated fatty acids metabolism to the interaction between thermogenic activity BAT and hyperplastic sympathetic networks, and illustrated the critical role of monounsaturated fatty acids biosynthetic pathway in cold acclimation during the long-term cold exposure.

Keywords:  Brown adipose; Cold exposure; SCD1; Sympathetic innervation; Thermogenesis

DOI:  https://doi.org/10.1016/j.bbrc.2024.149493
Cell Rep Med. 2024 Jan 16. pii: S2666-3791(23)00599-2. [Epub ahead of print]5(1): 101370

Very-low-density lipoprotein triglyceride and free fatty acid plasma kinetics in women with high or low brown adipose tissue volume and overweight/obesity.

Maria Chondronikola, Jun Yoshino, Raja Ramaswamy, Joseph Daniel Giardina, Richard Laforest, Richard L Wahl, Bruce W Patterson, Bettina Mittendorfer, Samuel Klein.

  Although a high amount of brown adipose tissue (BAT) is associated with low plasma triglyceride concentration, the mechanism responsible for this relationship in people is not clear. Here, we evaluate the interrelationships among BAT, very-low-density lipoprotein triglyceride (VLDL-TG), and free fatty acid (FFA) plasma kinetics during thermoneutrality in women with overweight/obesity who had a low (<20 mL) or high (≥20 mL) volume of cold-activated BAT (assessed by using positron emission tomography in conjunction with 2-deoxy-2-[18F]-fluoro-glucose). We find that plasma TG and FFA concentrations are lower and VLDL-TG and FFA plasma clearance rates are faster in women with high BAT than low BAT volume, whereas VLDL-TG and FFA appearance rates in plasma are not different between the two groups. These findings demonstrate that women with high BAT volume have lower plasma TG and FFA concentrations than women with low BAT volumes because of increased VLDL-TG and FFA clearance rates. This study was registered at ClinicalTrials.gov (NCT02786251).

Keywords:  brown fat; free fatty acids; kinetics; lipids; metabolism; obesity; triglycerides; women

DOI:  https://doi.org/10.1016/j.xcrm.2023.101370
Cell Rep. 2024 Jan 17. pii: S2211-1247(24)00009-3. [Epub ahead of print]43(2): 113681

Partial loss of MCU mitigates pathology in vivo across a diverse range of neurodegenerative disease models.

Madeleine J Twyning, Roberta Tufi, Thomas P Gleeson, Kinga M Kolodziej, Susanna Campesan, Ana Terriente-Felix, Lewis Collins, Federica De Lazzari, Flaviano Giorgini, Alexander J Whitworth.

  Mitochondrial calcium (Ca2+) uptake augments metabolic processes and buffers cytosolic Ca2+ levels; however, excessive mitochondrial Ca2+ can cause cell death. Disrupted mitochondrial function and Ca2+ homeostasis are linked to numerous neurodegenerative diseases (NDs), but the impact of mitochondrial Ca2+ disruption is not well understood. Here, we show that Drosophila models of multiple NDs (Parkinson's, Huntington's, Alzheimer's, and frontotemporal dementia) reveal a consistent increase in neuronal mitochondrial Ca2+ levels, as well as reduced mitochondrial Ca2+ buffering capacity, associated with increased mitochondria-endoplasmic reticulum contact sites (MERCs). Importantly, loss of the mitochondrial Ca2+ uptake channel MCU or overexpression of the efflux channel NCLX robustly suppresses key pathological phenotypes across these ND models. Thus, mitochondrial Ca2+ imbalance is a common feature of diverse NDs in vivo and is an important contributor to the disease pathogenesis. The broad beneficial effects from partial loss of MCU across these models presents a common, druggable target for therapeutic intervention.

Keywords:  Alzheimer's disease; CP: Neuroscience; Drosophila; Huntington's disease; MCU; NCLX; Parkinson's disease; calcium overload; frontotemporal dementia; mitochondrial calcium; neurodegeneration

DOI:  https://doi.org/10.1016/j.celrep.2024.113681
Diabetes Obes Metab. 2024 Jan 16.

Remodelling the inguinal adipose sensory system to switch on the furnace: Electroacupuncture stimulation induces brown adipose thermogenesis.

Mengjiang Lu, Ziwei Yu, Xingyu Yang, Li An, Xinyue Jing, Tiancheng Xu, Mengqian Yuan, Bin Xu, Zhi Yu.

  Brown and white adipose tissue mediate thermogenesis through the thermogenetic centre of the brain, but safe methods for activating thermogensis and knowledge of the associated molecular mechanisms are lacking. We investigated body surface electroacupuncture stimulation (ES) at ST25 (targeted at the abdomen) induction of brown adipose thermogenesis and the neural mechanism of this process. Inguinal white adipose tissue (iWAT) and interscapular brown adipose tissue (iBAT) were collected and the thermogenic protein expression levels were measured to evaluate iBAT thermogenesis capacity. The thermogenic centre activating region and sympathetic outflow were evaluated based on neural electrical activity and c-fos expression levels. iWAT sensory axon plasticity was analysed with whole-mount adipose tissue imaging. ES activated the sympathetic nerves in iBAT and the c-fos-positive cells induced sympathetic outflow activation to the iBAT from the medial preoptic area (MPA), the dorsomedial hypothalamus (DM) and the raphe pallidus nucleus (RPA). iWAT denervation mice exhibited decreased c-fos-positive cells in the DM and RPA, and lower recombinant uncoupling orotein 1 peroxisome proliferator-activated receptor, β3-adrenergic receptor, and tyrosine hydroxylase expression. Remodelling the iWAT sensory axons recovered the signal from the MPA to the RPA and induced iBAT thermogenesis. The sympathetic denervation attenuated sensory nerve density. ES induced sympathetic outflow from the thermogenetic centres to iBAT, which mediated thermogenesis. iWAT sensory axon remodelling induced the MPA-DM-RPA-iBAT thermogenesis pathway.

Keywords:  adipose thermogenesis; electroacupuncture; inguinal white adipose tissue; interscapular brown adipose tissue; sensory system

DOI:  https://doi.org/10.1111/dom.15444
EMBO J. 2024 Jan 15.

In situ architecture of Opa1-dependent mitochondrial cristae remodeling.

Michelle Y Fry, Paula P Navarro, Pusparanee Hakim, Virly Y Ananda, Xingping Qin, Juan C Landoni, Sneha Rath, Zintis Inde, Camila Makhlouta Lugo, Bridget E Luce, Yifan Ge, Julie L McDonald, Ilzat Ali, Leillani L Ha, Benjamin P Kleinstiver, David C Chan, Kristopher A Sarosiek, Luke H Chao.

  Cristae membrane state plays a central role in regulating mitochondrial function and cellular metabolism. The protein Optic atrophy 1 (Opa1) is an important crista remodeler that exists as two forms in the mitochondrion, a membrane-anchored long form (l-Opa1) and a processed short form (s-Opa1). The mechanisms for how Opa1 influences cristae shape have remained unclear due to lack of native three-dimensional views of cristae. We perform in situ cryo-electron tomography of cryo-focused ion beam milled mouse embryonic fibroblasts with defined Opa1 states to understand how each form of Opa1 influences cristae architecture. In our tomograms, we observe a variety of cristae shapes with distinct trends dependent on s-Opa1:l-Opa1 balance. Increased l-Opa1 levels promote cristae stacking and elongated mitochondria, while increased s-Opa1 levels correlated with irregular cristae packing and round mitochondria shape. Functional assays indicate a role for l-Opa1 in wild-type apoptotic and calcium handling responses, and show a compromised respiratory function under Opa1 imbalance. In summary, we provide three-dimensional visualization of cristae architecture to reveal relationships between mitochondrial ultrastructure and cellular function dependent on Opa1-mediated membrane remodeling.

Keywords:  Cristae Remodeling; Cryo-Electron Tomography; Cryo-Focused Ion Beam Milling; Mitochondrial Biology

DOI:  https://doi.org/10.1038/s44318-024-00027-2
Cell Death Dis. 2024 Jan 17. 15(1): 58

The mitochondrial ATP-dependent potassium channel (mitoKATP) controls skeletal muscle structure and function.

Giulia Di Marco, Gaia Gherardi, Agnese De Mario, Ilaria Piazza, Martina Baraldo, Andrea Mattarei, Bert Blaauw, Rosario Rizzuto, Diego De Stefani, Cristina Mammucari.

MitoKATP is a channel of the inner mitochondrial membrane that controls mitochondrial K+ influx according to ATP availability. Recently, the genes encoding the pore-forming (MITOK) and the regulatory ATP-sensitive (MITOSUR) subunits of mitoKATP were identified, allowing the genetic manipulation of the channel. Here, we analyzed the role of mitoKATP in determining skeletal muscle structure and activity. Mitok-/- muscles were characterized by mitochondrial cristae remodeling and defective oxidative metabolism, with consequent impairment of exercise performance and altered response to damaging muscle contractions. On the other hand, constitutive mitochondrial K+ influx by MITOK overexpression in the skeletal muscle triggered overt mitochondrial dysfunction and energy default, increased protein polyubiquitination, aberrant autophagy flux, and induction of a stress response program. MITOK overexpressing muscles were therefore severely atrophic. Thus, the proper modulation of mitoKATP activity is required for the maintenance of skeletal muscle homeostasis and function.

DOI: https://doi.org/10.1038/s41419-024-06426-x
bioRxiv. 2023 Dec 29. pii: 2023.12.29.573615. [Epub ahead of print]

Identification of SLC25A46 interaction interfaces with mitochondrial membrane fusogens Mfn2 and Opa1.

Sivakumar Boopathy, Camila Makhlouta Lugo, Bridget E Luce, Julie L McDonald, Pusparanee Hakim, Jackeline Ponce, Beatrix Ueberheide, Luke H Chao.

Mitochondrial fusion requires the sequential merger of four bilayers to two. The outer-membrane solute carrier protein SLC25A46 interacts with both the outer and inner-membrane dynamin family GTPases Mfn1/2 and Opa1. While SLC25A46 levels are known affect mitochondrial morphology, how SLC25A46 interacts with Mfn1/2 and Opa1 to regulate membrane fusion is not understood. In this study, we use crosslinking mass-spectrometry and AlphaFold 2 modeling to identify interfaces mediating a SLC25A46-Opa1-Mfn1/2 complex. We reveal that the bundle signaling element of Opa1 interacts with SLC25A46, and the helical repeat 1 region of Mfn2 interacts with the SLC25A46 N-terminus. We validate these newly identified interaction interfaces and show that they play a role in mitochondrial network maintenance.

DOI: https://doi.org/10.1101/2023.12.29.573615
Nat Metab. 2024 Jan 19.

An ETFDH-driven metabolon supports OXPHOS efficiency in skeletal muscle by regulating coenzyme Q homeostasis.

Juan Cruz Herrero Martín, Beñat Salegi Ansa, Gerardo Álvarez-Rivera, Sonia Domínguez-Zorita, Pilar Rodríguez-Pombo, Belén Pérez, Enrique Calvo, Alberto Paradela, David G Miguez, Alejandro Cifuentes, José M Cuezva, Laura Formentini.

Coenzyme Q (Q) is a key lipid electron transporter, but several aspects of its biosynthesis and redox homeostasis remain undefined. Various flavoproteins reduce ubiquinone (oxidized form of Q) to ubiquinol (QH2); however, in eukaryotes, only oxidative phosphorylation (OXPHOS) complex III (CIII) oxidizes QH2 to Q. The mechanism of action of CIII is still debated. Herein, we show that the Q reductase electron-transfer flavoprotein dehydrogenase (ETFDH) is essential for CIII activity in skeletal muscle. We identify a complex (comprising ETFDH, CIII and the Q-biosynthesis regulator COQ2) that directs electrons from lipid substrates to the respiratory chain, thereby reducing electron leaks and reactive oxygen species production. This metabolon maintains total Q levels, minimizes QH2-reductive stress and improves OXPHOS efficiency. Muscle-specific Etfdh-/- mice develop myopathy due to CIII dysfunction, indicating that ETFDH is a required OXPHOS component and a potential therapeutic target for mitochondrial redox medicine.

DOI: https://doi.org/10.1038/s42255-023-00956-y
J Clin Invest. 2024 Jan 16. pii: e176943. [Epub ahead of print]

A membrane-associated phosphoswitch in Rad controls adrenergic regulation of cardiac calcium channels.

Arianne Papa, Pedro J Del Rivero Morfin, Bi-Xing Chen, Lin Yang, Alex N Katchman, Sergey I Zakharov, Guoxia Liu, Michael S Bohnen, Vivian Zheng, Moshe Katz, Suraj Subramaniam, Joel A Hirsch, Sharon Weiss, Nathan Dascal, Arthur Karlin, Geoffrey S Pitt, Henry M Colecraft, Manu Ben Johny, Steven O Marx.

  The ability to fight or flee from a threat relies upon an acute adrenergic surge that augments cardiac output, which is dependent upon increased cardiac contractility and heart rate. This cardiac response depends on β-adrenergic-initiated reversal of the small RGK G-protein Rad-mediated inhibition of voltage-gated calcium channels (CaV) acting through the Cavβ subunit. Here, we investigate how Rad couples phosphorylation to augmented Ca2+ influx and increased cardiac contraction. We show that reversal requires phosphorylation of Ser272 and Ser300 within Rad's polybasic, hydrophobic C-terminal domain (CTD). Phosphorylation of Ser25 and Ser38 in Rad's N-terminal domain (NTD) alone is ineffective. Phosphorylation of Ser272 and Ser300 or the addition of four Asp to the CTD reduces Rad's association with the negatively charged, cytoplasmic plasmalemmal surface and with CaVβ, even in the absence of CaVα, measured here by FRET. Addition of a post-translationally prenylated CAAX motif to Rad's C-terminus, which constitutively tethers Rad to the membrane, prevents the physiological and biochemical effects of both phosphorylation and Asp-substitution. Thus, dissociation of Rad from the sarcolemma, and consequently from CaVβ, is sufficient for sympathetic up-regulation of Ca2+ currents.

Keywords:  Calcium channels; Cardiology; Cardiovascular disease; Excitation contraction coupling

DOI:  https://doi.org/10.1172/JCI176943
bioRxiv. 2024 Jan 16. pii: 2023.12.27.573364. [Epub ahead of print]

TRPM8-dependent shaking in mammals and birds.

Tudor Selescu, Ramona-Andreea Bivoleanu, Mirela Iodi Carstens, Alexandra Manolache, Violeta-Maria Caragea, Debora-Elena Hutanu, Rathej Meerupally, Edward T Wei, Earl Carstens, Katharina Zimmermann, Alexandru Babes.

Removing water from wet fur or feathers is important for thermoregulation in warm-blooded animals. The "wet dog shake" (WDS) behavior has been largely characterized in mammals but to a much lesser extent in birds. Although it is known that TRPM8 is the main molecular transducer of low temperature in mammals, it is not clear if wetness-induced shaking in furred and feathered animals is dependent on TRPM8. Here, we show that a novel TRPM8 agonist induces WDS in rodents and, importantly, in birds, similar to the shaking behavior evoked by water-spraying. Furthermore, the WDS onset depends on TRPM8, as we show in water-sprayed mice. Overall, our results provide multiple evidence for a TRPM8 dependence of WDS behaviors in all tested species. These suggest that a convergent evolution selected similar shaking behaviors to expel water from fur and feathers, with TRPM8 being involved in wetness sensing in both mammals and birds.

DOI: https://doi.org/10.1101/2023.12.27.573364