bims-mimbat 2024-03-24 papers

bims-mimbat

Biomed News

on Mitochondrial metabolism in brown adipose tissue

Issue of 2024–03–24
eleven papers selected by
José Carlos de Lima-Júnior, Washington University

The effects of the β1 -adrenergic receptor antagonist bisoprolol administration on mirabegron-stimulated human brown adipose tissue thermogenesis.
Highland deer mice support increased thermogenesis in response to chronic cold hypoxia by shifting uptake of circulating fatty acids from muscles to brown adipose tissue.
The phospholipids cardiolipin and phosphatidylethanolamine differentially regulate MDC biogenesis.
ERMA (TMEM94) is a P-type ATPase transporter for Mg2+ uptake in the endoplasmic reticulum.
A kinetic dichotomy between mitochondrial and nuclear gene expression processes.
Mutational scanning pinpoints distinct binding sites of key ATGL regulators in lipolysis.
MCU-independent Ca2+ uptake mediates mitochondrial Ca2+ overload and necrotic cell death in a mouse model of Duchenne muscular dystrophy.
Trigonelline is an NAD+ precursor that improves muscle function during ageing and is reduced in human sarcopenia.
Lac-Phe mediates the effects of metformin on food intake and body weight.
Muscle-UCP3 in the regulation of energy metabolism.
Integrating the response to stressed mitochondria.

Acta Physiol (Oxf). 2024 Mar 19. e14127

The effects of the β1 -adrenergic receptor antagonist bisoprolol administration on mirabegron-stimulated human brown adipose tissue thermogenesis.

Lauralyne Dumont, Alexandre Caron, Gabriel Richard, Etienne Croteau, Mélanie Fortin, Frédérique Frisch, Serge Phoenix, Stéphanie Dubreuil, Brigitte Guérin, Éric E Turcotte, André C Carpentier, Denis P Blondin.

   AIM: Pharmacological stimulation of human brown adipose tissue (BAT) has been hindered by ineffective activation or undesirable off-target effects. Oral administration of the maximal allowable dose of mirabegron (200 mg), a β3 -adrenergic receptor (β3 -AR) agonist, has been effective in stimulating BAT thermogenesis and whole-body energy expenditure. However, this has been accompanied by undesirable cardiovascular effects. Therefore, we hypothesized that combining mirabegron with a β1 -AR antagonist could suppress these unwanted effects and increase the stimulation of the β3 -AR and β2 -AR in BAT.
METHODS: We performed a randomized crossover trial (NCT04823442) in 8 lean men. Mirabegron (200 mg) was administered orally with or without the β1 -AR antagonist bisoprolol (10 mg). Dynamic [11 C]-acetate and 2-deoxy-2-[18 F]fluoro-d-glucose PET/CT scans were performed sequentially after oral administration of mirabegron ± bisoprolol.
RESULTS: Compared to room temperature, mirabegron alone increased BAT oxidative metabolism (0.84 ± 0.46 vs. 1.79 ± 0.91 min-1 , p = 0.0433), but not when combined with bisoprolol. The metabolic rate of glucose in BAT, measured using [18 F]FDG PET, was significantly higher with mirabegron than mirabegron with bisoprolol (24 ± 10 vs. 16 ± 8 nmol/g/min, p = 0.0284). Bisoprolol inhibited the mirabegron-induced increase in systolic blood pressure and heart rate.
CONCLUSION: The administration of bisoprolol decreases the adverse cardiovascular effects of mirabegron. However, the provided dose also blunted the mirabegron-stimulated increase in BAT lipolysis, thermogenesis, and glucose uptake. The attenuation in BAT blood flow induced by the large dose of bisoprolol may have limited BAT thermogenesis.

Keywords:  adipose tissue; adrenergic receptor; brown adipose tissue; energy metabolism; positron emission tomography; stable isotope; thermogenesis

DOI:  https://doi.org/10.1111/apha.14127
J Exp Biol. 2024 Mar 20. pii: jeb.247340. [Epub ahead of print]

Highland deer mice support increased thermogenesis in response to chronic cold hypoxia by shifting uptake of circulating fatty acids from muscles to brown adipose tissue.

Sulayman A Lyons, Grant B McClelland.

  During maximal cold challenge (cold-induced V˙O2max) in hypoxia, highland deer mice (Peromyscus maniculatus) show higher rates of circulatory fatty acid delivery compared with lowland deer mice. Fatty acid delivery also increases with acclimation to cold hypoxia (CH) and likely plays a major role in supporting the high rates of thermogenesis observed in highland deer mice. However, it is unknown which tissues take up these fatty acids and their relative contribution to thermogenesis. The goal of this study was to determine the uptake of circulating fatty acids into 24 different tissues during hypoxic cold-induced V˙O2max, by using [1-14C]2-bromopalmitic acid. To uncover evolved and environment-induced changes in fatty acid uptake, we compared lab born and raised highland and lowland deer mice, acclimated to either thermoneutral (TN; 30°C, 21 kPa O2) or CH (5°C, 12 kPa O2) conditions. During hypoxic cold-induced V˙O2max, CH acclimated highlanders decreased muscle fatty acid uptake and increased uptake into brown adipose tissue (BAT) relative to TN highlanders, a response was absent in lowlanders. CH acclimation was also associated with increased activities of enzymes citrate synthase and β-hydroxyacyl-CoA dehydrogenase in the BAT of highlanders, and higher FAT/CD36 abundance in both populations. This is the first study to show that cold-induced fatty acid uptake is distributed across a wide range of tissues. Highland deer mice show plasticity in this fatty acid distribution in response to CH, and combined with higher rates of tissue delivery, contributes to their survival in the cold high alpine.

Keywords:   Peromyscus maniculatus ; Heat production; Non-esterified fatty acids; Phenotypic plasticity; Skeletal muscle; [1-14C]2-bromopalmitic acid

DOI:  https://doi.org/10.1242/jeb.247340
J Cell Biol. 2024 May 06. pii: e202302069. [Epub ahead of print]223(5):

The phospholipids cardiolipin and phosphatidylethanolamine differentially regulate MDC biogenesis.

Tianyao Xiao, Alyssa M English, Zachary N Wilson, J Alan Maschek, James E Cox, Adam L Hughes.

Cells utilize multiple mechanisms to maintain mitochondrial homeostasis. We recently characterized a pathway that remodels mitochondria in response to metabolic alterations and protein overload stress. This remodeling occurs via the formation of large membranous structures from the mitochondrial outer membrane called mitochondrial-derived compartments (MDCs), which are eventually released from mitochondria and degraded. Here, we conducted a microscopy-based screen in budding yeast to identify factors that regulate MDC formation. We found that two phospholipids, cardiolipin (CL) and phosphatidylethanolamine (PE), differentially regulate MDC biogenesis. CL depletion impairs MDC biogenesis, whereas blocking mitochondrial PE production leads to constitutive MDC formation. Additionally, in response to metabolic MDC activators, cellular and mitochondrial PE declines, and overexpressing mitochondrial PE synthesis enzymes suppress MDC biogenesis. Altogether, our data indicate a requirement for CL in MDC biogenesis and suggest that PE depletion may stimulate MDC formation downstream of MDC-inducing metabolic stress.

DOI: https://doi.org/10.1083/jcb.202302069
Mol Cell. 2024 Mar 13. pii: S1097-2765(24)00177-1. [Epub ahead of print]

ERMA (TMEM94) is a P-type ATPase transporter for Mg2+ uptake in the endoplasmic reticulum.

Neelanjan Vishnu, Manigandan Venkatesan, Travis R Madaris, Mridula K Venkateswaran, Kristen Stanley, Karthik Ramachandran, Adhishree Chidambaram, Abitha K Madesh, Wenli Yang, Jyotsna Nair, Melanie Narkunan, Tharani Muthukumar, Varsha Karanam, Leroy C Joseph, Amy Le, Ayodeji Osidele, M Imran Aslam, John P Morrow, May C Malicdan, Peter B Stathopulos, Muniswamy Madesh.

  Intracellular Mg2+ (iMg2+) is bound with phosphometabolites, nucleic acids, and proteins in eukaryotes. Little is known about the intracellular compartmentalization and molecular details of Mg2+ transport into/from cellular organelles such as the endoplasmic reticulum (ER). We found that the ER is a major iMg2+ compartment refilled by a largely uncharacterized ER-localized protein, TMEM94. Conventional and AlphaFold2 predictions suggest that ERMA (TMEM94) is a multi-pass transmembrane protein with large cytosolic headpiece actuator, nucleotide, and phosphorylation domains, analogous to P-type ATPases. However, ERMA uniquely combines a P-type ATPase domain and a GMN motif for ERMg2+ uptake. Experiments reveal that a tyrosine residue is crucial for Mg2+ binding and activity in a mechanism conserved in both prokaryotic (mgtB and mgtA) and eukaryotic Mg2+ ATPases. Cardiac dysfunction by haploinsufficiency, abnormal Ca2+ cycling in mouse Erma+/- cardiomyocytes, and ERMA mRNA silencing in human iPSC-cardiomyocytes collectively define ERMA as an essential component of ERMg2+ uptake in eukaryotes.

Keywords:  AlphaFold2; ERMA; GMN motif; P-type ATPase; RNAi screen; TMEM94; calcium; endoplasmic reticulum; hepatocytes; human cardiomyocytes; lactate; magnesium; mitochondria; mutations; refill; uptake

DOI:  https://doi.org/10.1016/j.molcel.2024.02.033
Mol Cell. 2024 Mar 14. pii: S1097-2765(24)00170-9. [Epub ahead of print]

A kinetic dichotomy between mitochondrial and nuclear gene expression processes.

Erik McShane, Mary Couvillion, Robert Ietswaart, Gyan Prakash, Brendan M Smalec, Iliana Soto, Autum R Baxter-Koenigs, Karine Choquet, L Stirling Churchman.

  Oxidative phosphorylation (OXPHOS) complexes, encoded by both mitochondrial and nuclear DNA, are essential producers of cellular ATP, but how nuclear and mitochondrial gene expression steps are coordinated to achieve balanced OXPHOS subunit biogenesis remains unresolved. Here, we present a parallel quantitative analysis of the human nuclear and mitochondrial messenger RNA (mt-mRNA) life cycles, including transcript production, processing, ribosome association, and degradation. The kinetic rates of nearly every stage of gene expression differed starkly across compartments. Compared with nuclear mRNAs, mt-mRNAs were produced 1,100-fold more, degraded 7-fold faster, and accumulated to 160-fold higher levels. Quantitative modeling and depletion of mitochondrial factors LRPPRC and FASTKD5 identified critical points of mitochondrial regulatory control, revealing that the mitonuclear expression disparities intrinsically arise from the highly polycistronic nature of human mitochondrial pre-mRNA. We propose that resolving these differences requires a 100-fold slower mitochondrial translation rate, illuminating the mitoribosome as a nexus of mitonuclear co-regulation.

Keywords:  LRPPRC; Leighs disease; RNA life cycle; gene regulation; genetic conflict; metabolic regulation; mitochondrial gene expression; mitochondrial translation; mitonuclear balance; organellular biogenesis; oxidative phosphorylation

DOI:  https://doi.org/10.1016/j.molcel.2024.02.028
Nat Commun. 2024 Mar 21. 15(1): 2516

Mutational scanning pinpoints distinct binding sites of key ATGL regulators in lipolysis.

Johanna M Kohlmayr, Gernot F Grabner, Anna Nusser, Anna Höll, Verina Manojlović, Bettina Halwachs, Sarah Masser, Evelyne Jany-Luig, Hanna Engelke, Robert Zimmermann, Ulrich Stelzl.

ATGL is a key enzyme in intracellular lipolysis and plays an important role in metabolic and cardiovascular diseases. ATGL is tightly regulated by a known set of protein-protein interaction partners with activating or inhibiting functions in the control of lipolysis. Here, we use deep mutational protein interaction perturbation scanning and generate comprehensive profiles of single amino acid variants that affect the interactions of ATGL with its regulatory partners: CGI-58, G0S2, PLIN1, PLIN5 and CIDEC. Twenty-three ATGL amino acid variants yield a specific interaction perturbation pattern when validated in co-immunoprecipitation experiments in mammalian cells. We identify and characterize eleven highly selective ATGL switch mutations which affect the interaction of one of the five partners without affecting the others. Switch mutations thus provide distinct interaction determinants for ATGL's key regulatory proteins at an amino acid resolution. When we test triglyceride hydrolase activity in vitro and lipolysis in cells, the activity patterns of the ATGL switch variants trace to their protein interaction profile. In the context of structural data, the integration of variant binding and activity profiles provides insights into the regulation of lipolysis and the impact of mutations in human disease.

DOI: https://doi.org/10.1038/s41467-024-46937-x
Sci Rep. 2024 Mar 21. 14(1): 6751

MCU-independent Ca2+ uptake mediates mitochondrial Ca2+ overload and necrotic cell death in a mouse model of Duchenne muscular dystrophy.

Michael J Bround, Eaman Abay, Jiuzhou Huo, Julian R Havens, Allen J York, Donald M Bers, Jeffery D Molkentin.

Mitochondrial Ca2+ overload can mediate mitochondria-dependent cell death, a major contributor to several human diseases. Indeed, Duchenne muscular dystrophy (MD) is driven by dysfunctional Ca2+ influx across the sarcolemma that causes mitochondrial Ca2+ overload, organelle rupture, and muscle necrosis. The mitochondrial Ca2+ uniporter (MCU) complex is the primary characterized mechanism for acute mitochondrial Ca2+ uptake. One strategy for preventing mitochondrial Ca2+ overload is deletion of the Mcu gene, the pore forming subunit of the MCU-complex. Conversely, enhanced MCU-complex Ca2+ uptake is achieved by deleting the inhibitory Mcub gene. Here we show that myofiber-specific Mcu deletion was not protective in a mouse model of Duchenne MD. Specifically, Mcu gene deletion did not reduce muscle histopathology, did not improve muscle function, and did not prevent mitochondrial Ca2+ overload. Moreover, myofiber specific Mcub gene deletion did not augment Duchenne MD muscle pathology. Interestingly, we observed MCU-independent Ca2+ uptake in dystrophic mitochondria that was sufficient to drive mitochondrial permeability transition pore (MPTP) activation and skeletal muscle necrosis, and this same type of activity was observed in heart, liver, and brain mitochondria. These results demonstrate that mitochondria possess an uncharacterized MCU-independent Ca2+ uptake mechanism that is sufficient to drive MPTP-dependent necrosis in MD in vivo.

DOI: https://doi.org/10.1038/s41598-024-57340-3
Nat Metab. 2024 Mar 19.

Trigonelline is an NAD+ precursor that improves muscle function during ageing and is reduced in human sarcopenia.

Mathieu Membrez, Eugenia Migliavacca, Stefan Christen, Keisuke Yaku, Jennifer Trieu, Alaina K Lee, Francesco Morandini, Maria Pilar Giner, Jade Stiner, Mikhail V Makarov, Emma S Garratt, Maria F Vasiloglou, Lucie Chanvillard, Emilie Dalbram, Amy M Ehrlich, José Luis Sanchez-Garcia, Carles Canto, Leonidas G Karagounis, Jonas T Treebak, Marie E Migaud, Ramin Heshmat, Farideh Razi, Neerja Karnani, Afshin Ostovar, Farshad Farzadfar, Stacey K H Tay, Matthew J Sanders, Karen A Lillycrop, Keith M Godfrey, Takashi Nakagawa, Sofia Moco, René Koopman, Gordon S Lynch, Vincenzo Sorrentino, Jerome N Feige.

Mitochondrial dysfunction and low nicotinamide adenine dinucleotide (NAD+) levels are hallmarks of skeletal muscle ageing and sarcopenia1-3, but it is unclear whether these defects result from local changes or can be mediated by systemic or dietary cues. Here we report a functional link between circulating levels of the natural alkaloid trigonelline, which is structurally related to nicotinic acid4, NAD+ levels and muscle health in multiple species. In humans, serum trigonelline levels are reduced with sarcopenia and correlate positively with muscle strength and mitochondrial oxidative phosphorylation in skeletal muscle. Using naturally occurring and isotopically labelled trigonelline, we demonstrate that trigonelline incorporates into the NAD+ pool and increases NAD+ levels in Caenorhabditis elegans, mice and primary myotubes from healthy individuals and individuals with sarcopenia. Mechanistically, trigonelline does not activate GPR109A but is metabolized via the nicotinate phosphoribosyltransferase/Preiss-Handler pathway5,6 across models. In C. elegans, trigonelline improves mitochondrial respiration and biogenesis, reduces age-related muscle wasting and increases lifespan and mobility through an NAD+-dependent mechanism requiring sirtuin. Dietary trigonelline supplementation in male mice enhances muscle strength and prevents fatigue during ageing. Collectively, we identify nutritional supplementation of trigonelline as an NAD+-boosting strategy with therapeutic potential for age-associated muscle decline.

DOI: https://doi.org/10.1038/s42255-024-00997-x
Nat Metab. 2024 Mar 18.

Lac-Phe mediates the effects of metformin on food intake and body weight.

Shuke Xiao, Veronica L Li, Xuchao Lyu, Xudong Chen, Wei Wei, Fahim Abbasi, Joshua W Knowles, Alan Sheng-Hwa Tung, Shuliang Deng, Gaurav Tiwari, Xu Shi, Shuning Zheng, Laurie Farrell, Zsu-Zsu Chen, Kent D Taylor, Xiuqing Guo, Mark O Goodarzi, Alexis C Wood, Yii-Der Ida Chen, Leslie A Lange, Stephen S Rich, Jerome I Rotter, Clary B Clish, Usman A Tahir, Robert E Gerszten, Mark D Benson, Jonathan Z Long.

Metformin is a widely prescribed anti-diabetic medicine that also reduces body weight. There is ongoing debate about the mechanisms that mediate metformin's effects on energy balance. Here, we show that metformin is a powerful pharmacological inducer of the anorexigenic metabolite N-lactoyl-phenylalanine (Lac-Phe) in cells, in mice and two independent human cohorts. Metformin drives Lac-Phe biosynthesis through the inhibition of complex I, increased glycolytic flux and intracellular lactate mass action. Intestinal epithelial CNDP2+ cells, not macrophages, are the principal in vivo source of basal and metformin-inducible Lac-Phe. Genetic ablation of Lac-Phe biosynthesis in male mice renders animals resistant to the effects of metformin on food intake and body weight. Lastly, mediation analyses support a role for Lac-Phe as a downstream effector of metformin's effects on body mass index in participants of a large population-based observational cohort, the Multi-Ethnic Study of Atherosclerosis. Together, these data establish Lac-Phe as a critical mediator of the body weight-lowering effects of metformin.

DOI: https://doi.org/10.1038/s42255-024-00999-9
Mitochondrion. 2024 Mar 16. pii: S1567-7249(24)00030-8. [Epub ahead of print] 101872

Muscle-UCP3 in the regulation of energy metabolism.

Lucio Della Guardia, Livio Luzi, Roberto Codella.

  Uncoupling protein-3 (UCP3) is a mitochondria-regulatory protein with potential energy- homeostatic functions. This study explores the role of UCP3 in the regulation of muscle- and energy metabolism. UCP3 is critical for tuning substrate utilization, favoring lipid oxidation, particularly in conditions of high-fat availability. While UCP3 is non-essential for lipid oxidation during energy excess, it proves vital during fasting, indicating an energy-homeostatic trait. Preliminary evidence indicates UCP3' promotion of glucose uptake and oxidation, at least in conditions of high glucose/low fat availability. However, the dynamics of how fats and glucose differentially influence UCP3 remain undefined. UCP3 exhibits inducible proton transport and uncoupling activity, operating in a dual manner: a resting state with no/low activity and an activated state in the presence of activators. Uncoupling may enhance thermogenesis in specific conditions and in the presence of activators such as fatty acids, thyroid hormones, and catecholamines. This energy-dissipative activity adapts to varying energy availability, balancing energy dissipation with fatty acid oxidation to optimize whole-body energy homeostasis: fasting triggers UCP3 upregulation, enhancing lipid utilization while suppressing uncoupling. Additionally, UCP3 upregulation induces glucose and lipid disposal from the bloodstream and decreases tri-/diglyceride storage in muscle. This process improves mitochondrial functionality and insulin signaling, leading to enhanced systemic gluco-metabolic balance and protection from metabolic conditions. Reviewed evidence suggests that UCP3 plays a crucial role in adapting the system to changing energy conditions. However, the precise role of UCP3 in regulating metabolism requires further elucidation.

Keywords:  Energy expenditure; Lipid oxidation; Metabolic diseases; Mitochondria; Thermogenesis; Uncoupling proteins

DOI:  https://doi.org/10.1016/j.mito.2024.101872
Mol Cell. 2024 Mar 21. pii: S1097-2765(24)00168-0. [Epub ahead of print]84(6): 995-997

Integrating the response to stressed mitochondria.

Elliot Dine, Richard J Youle.

Chakrabarty et al.1 demonstrate that phospho-EIF2α (pEIF2α), the translation initiation factor that mediates the integrated stress response (ISR), is necessary and sufficient for the autophagic degradation of mitochondria following the addition of mitochondrial stressors.

DOI: https://doi.org/10.1016/j.molcel.2024.02.026