bims-mimbat 2024-09-29 papers

bims-mimbat

Biomed News

on Mitochondrial metabolism in brown adipose tissue

Issue of 2024–09–29
fourteen papers selected by
José Carlos de Lima-Júnior, Washington University

A transmitochondrial sodium gradient controls membrane potential in mammalian mitochondria.
Brown Fat Fuels the Fire in Fever.
Differential mitochondrial adaptation and FNDC5 production in brown and white adipose tissue in response to cold and obesity.
Assessment of amino acid charge states based on cryo-electron microscopy and molecular dynamics simulations of respiratory complex I.
Setting the curve: the biophysical properties of lipids in mitochondrial form and function.
Anaesthetics disrupt complex I-linked respiration and reverse the ATP synthase.
Predicting standardized uptake value of brown adipose tissue from CT scans using convolutional neural networks.
The mitochondrial physiology of torpor in ruby-throated hummingbirds, Archilochus colubris.
CPEB2-activated Prdm16 translation promotes brown adipocyte function and prevents obesity.
Mitochondrial membrane potential and oxidative stress interact to regulate Oma1-dependent processing of Opa1 and mitochondrial dynamics.
HDAC5 controls a hypothalamic STAT5b-TH axis, the sympathetic activation of ATP-consuming futile cycles and adult-onset obesity in male mice.
Glutathione peroxidase 3 is essential for countering senescence in adipose remodelling by maintaining mitochondrial homeostasis.
From Muscle-Based Nonshivering Thermogenesis to Malignant Hyperthermia in Mammals.
Bone Morphogenetic Protein 9 Protects Against Myocardial Infarction by Improving Lymphatic Drainage Function and Triggering DECR1-Mediated Mitochondrial Bioenergetics.

Cell. 2024 Sep 17. pii: S0092-8674(24)00974-7. [Epub ahead of print]

A transmitochondrial sodium gradient controls membrane potential in mammalian mitochondria.

Pablo Hernansanz-Agustín, Carmen Morales-Vidal, Enrique Calvo, Paolo Natale, Yolanda Martí-Mateos, Sara Natalia Jaroszewicz, José Luis Cabrera-Alarcón, Rebeca Acín-Pérez, Iván López-Montero, Jesús Vázquez, José Antonio Enríquez.

  Eukaryotic cell function and survival rely on the use of a mitochondrial H+ electrochemical gradient (Δp), which is composed of an inner mitochondrial membrane (IMM) potential (ΔΨmt) and a pH gradient (ΔpH). So far, ΔΨmt has been assumed to be composed exclusively of H+. Here, using a rainbow of mitochondrial and nuclear genetic models, we have discovered that a Na+ gradient equates with the H+ gradient and controls half of ΔΨmt in coupled-respiring mammalian mitochondria. This parallelism is controlled by the activity of the long-sought Na+-specific Na+/H+ exchanger (mNHE), which we have identified as the P-module of complex I (CI). Deregulation of this mNHE function, without affecting the canonical enzymatic activity or the assembly of CI, occurs in Leber's hereditary optic neuropathy (LHON), which has profound consequences in ΔΨmt and mitochondrial Ca2+ homeostasis and explains the previously unknown molecular pathogenesis of this neurodegenerative disease.

Keywords:  LHON; Na(+) gradient; complex I; mitochondrial Na(+)/H(+) antiporter; ΔΨmt

DOI:  https://doi.org/10.1016/j.cell.2024.08.045
J Lipid Res. 2024 Sep 25. pii: S0022-2275(24)00163-9. [Epub ahead of print] 100658

Brown Fat Fuels the Fire in Fever.

Samantha J Krysa, Jonathan R Brestoff.

Fever is a host-pathogen defense mechanism in which the immune system drives a physiologic increase in core body temperature. For over 50 years, it has been known that brown adipose tissue (BAT) temperature is increased during the febrile response. However, recent studies suggested that the primary thermogenic protein Uncoupling protein 1 (UCP1) in brown adipocytes does not contribute to fever induction in mice, casting doubt about the functional contribution of BAT to fever. In a new set of studies, Li et al (2024) provide compelling evidence that fatty acid oxidation is markedly increased in BAT in a Salmonella infection model of fever and strongly suggest that metabolic adaptation in BAT may play a critical role in the febrile response. This article re-opens the debate about how thermogenic and metabolic programs in BAT contribute to fever and raises new questions about whether BAT contributes to host defense against pathogens.

DOI: https://doi.org/10.1016/j.jlr.2024.100658
Obesity (Silver Spring). 2024 Sep 26.

Differential mitochondrial adaptation and FNDC5 production in brown and white adipose tissue in response to cold and obesity.

Gabriela Neira, Ana Wenting Hernández-Pardos, Sara Becerril, Beatriz Ramírez, Víctor Valentí, Rafael Moncada, Victoria Catalán, Javier Gómez-Ambrosi, María A Burrell, Camilo Silva, Javier Escalada, Gema Frühbeck, Amaia Rodríguez.

OBJECTIVE: Fibronectin type III domain-containing protein 5 (FNDC5) modulates adipocyte metabolism by increasing white and brown adipose tissue (WAT and BAT) browning and activity, respectively. We investigated whether FNDC5 can regulate visceral WAT and BAT adaptive thermogenesis by improving mitochondrial homeostasis in response to cold and obesity.
METHODS: Adipose tissue expression of FNDC5 and factors involved in mitochondrial homeostasis were determined in patients with normal weight and obesity (n = 159) and in rats with diet-induced obesity after 1 week of cold exposure (n = 61). The effect of different FNDC5 concentrations on mitochondrial biogenesis, dynamics, and mitophagy was evaluated in vitro in human adipocytes.
RESULTS: In human visceral adipocytes, FNDC5/irisin triggered mitochondrial biogenesis (TFAM) and fusion (MFN1, MFN2, and OPA1) while inhibiting peripheral fission (DNM1L and FIS1) and mitophagy (PINK1 and PRKN). Circulating and visceral WAT expression of FNDC5 was decreased in patients and experimental animals with obesity, whereas its receptor, integrin αV, was upregulated. Obesity increased mitochondrial fusion while decreasing mitophagy in visceral WAT from patients and rats. By contrast, in rat BAT, an upregulation of Fndc5 and genes involved in mitochondrial biogenesis and fission was observed. Cold exposure promoted mitochondrial biogenesis and healthy peripheral fission while repressing Fndc5 expression and mitophagy in BAT from rats.
CONCLUSIONS: Depot differences in FNDC5 production and mitochondrial adaptations in response to obesity and cold might indicate a self-regulatory mechanism to control thermogenesis in response to energy needs.

DOI: https://doi.org/10.1002/oby.24132
Biochim Biophys Acta Bioenerg. 2024 Sep 24. pii: S0005-2728(24)00482-1. [Epub ahead of print] 149512

Assessment of amino acid charge states based on cryo-electron microscopy and molecular dynamics simulations of respiratory complex I.

Jonathan Lasham, Amina Djurabekova, Georgios Kolypetris, Volker Zickermann, Janet Vonck, Vivek Sharma.

  The charge states of titratable amino acid residues play a key role in the function of membrane-bound bioenergetic proteins. However, determination of these charge states both through experimental and computational approaches is extremely challenging. Cryo-EM density maps can provide insights on the charge states of titratable amino acid residues. By performing classical atomistic molecular dynamics simulations on the high resolution cryo-EM structures of respiratory complex I from Yarrowia lipolytica, we analyze the conformational and charge states of a key acidic residue in its ND1 subunit, aspartic acid D203, which is also a mitochondrial disease mutation locus. We suggest that in the native state of respiratory complex I, D203 is negatively charged and maintains a stable hydrogen bond to a conserved arginine residue. Alternatively, upon conformational change in the turnover state of the enzyme, its sidechain attains a charge-neutral status. We discuss the implications of this analysis on the molecular mechanism of respiratory complex I.

Keywords:  Charge transfer; Conformational dynamics; Coupling mechanism; Electrostatics; Proton pump; Protonation states

DOI:  https://doi.org/10.1016/j.bbabio.2024.149512
J Lipid Res. 2024 Sep 18. pii: S0022-2275(24)00148-2. [Epub ahead of print] 100643

Setting the curve: the biophysical properties of lipids in mitochondrial form and function.

Kailash Venkatraman, Christopher T Lee, Itay Budin.

  Mitochondrial membranes are defined by their diverse functions, complex geometries, and unique lipidomes. In the inner mitochondrial membrane (IMM), highly-curved membrane folds known as cristae house the electron transport chain and are the primary sites of cellular energy production. The outer mitochondrial membrane (OMM) is flat by contrast, but is critical for the initiation and mediation of processes key to mitochondrial physiology: mitophagy, inter-organelle contacts, fission and fusion dynamics and metabolite transport. While the lipid composition of both the IMM and OMM have been characterized across a variety of cell types, a mechanistic understanding for how individual lipid classes contribute to mitochondrial structure and function remains nebulous. In this review, we address the biophysical properties of mitochondrial lipids and their related functional roles. We highlight the intrinsic curvature of the bulk mitochondrial phospholipid pool, with an emphasis on the nuances surrounding the mitochondrially-synthesized cardiolipin. We also outline emerging questions about other lipid classes, ether lipids and sterols, with potential roles in mitochondrial physiology. We propose that further investigation is warranted to elucidate the specific properties of these lipids and their influence on mitochondrial architecture and function.

Keywords:  Cardiolipin; Curvature; Mitochondria; Phospholipids; Plasmalogens; Sterols

DOI:  https://doi.org/10.1016/j.jlr.2024.100643
Biochim Biophys Acta Bioenerg. 2024 Sep 24. pii: S0005-2728(24)00481-X. [Epub ahead of print] 149511

Anaesthetics disrupt complex I-linked respiration and reverse the ATP synthase.

Enrique Rodriguez, Bella Peng, Nick Lane.

  The mechanism of volatile general anaesthetics has long been a mystery. Anaesthetics have no structural motifs in common, beyond lipid solubility, yet all exert a similar effect. The fact that the inert gas xenon is an anaesthetic suggests their common mechanism might relate to physical rather than chemical properties. Electron transfer through chiral proteins can induce spin polarization. Recent work suggests that anaesthetics dissipate spin polarization during electron transfer to oxygen, slowing respiration. Here we show that the volatile anaesthetics isoflurane and sevoflurane specifically disrupt complex I-linked respiration in the thoraces of Drosophila melanogaster, with less effect on maximal respiration. Suppression of complex I-linked respiration was greatest with isoflurane. Using high-resolution tissue fluorespirometry, we show that these anaesthetics simultaneously increase mitochondrial membrane potential, implying reversal of the ATP synthase. Inhibition of ATP synthase with oligomycin prevented respiration and increased membrane potential back to the maximal (LEAK state) potential. Magnesium-green fluorescence predicted a collapse in ATP availability following a single anaesthetic dose, consistent with ATP hydrolysis through reversal of the ATP synthase. Raised membrane potential corresponded to a rise in ROS flux, especially with isoflurane. Anaesthetic doses causing respiratory suppression were in the same range as those that induce anaesthesia, although we could not establish tissue concentrations. Our findings show that anaesthetics suppress complex I-linked respiration with concerted downstream effects. But we cannot explain why only mutations in complex I, and not elsewhere in the electron-transfer system, confer hypersensitivity to anaesthetics.

Keywords:  Anaesthetic; Complex I; Isoflurane; Mitochondria; Respiration; Sevoflurane

DOI:  https://doi.org/10.1016/j.bbabio.2024.149511
Nat Commun. 2024 Sep 27. 15(1): 8402

Predicting standardized uptake value of brown adipose tissue from CT scans using convolutional neural networks.

Ertunc Erdil, Anton S Becker, Moritz Schwyzer, Borja Martinez-Tellez, Jonatan R Ruiz, Thomas Sartoretti, H Alberto Vargas, A Irene Burger, Alin Chirindel, Damian Wild, Nicola Zamboni, Bart Deplancke, Vincent Gardeux, Claudia Irene Maushart, Matthias Johannes Betz, Christian Wolfrum, Ender Konukoglu.

The standard method for identifying active Brown Adipose Tissue (BAT) is [18F]-Fluorodeoxyglucose ([18F]-FDG) PET/CT imaging, which is costly and exposes patients to radiation, making it impractical for population studies. These issues can be addressed with computational methods that predict [18F]-FDG uptake by BAT from CT; earlier population studies pave the way for developing such methods by showing some correlation between the Hounsfield Unit (HU) of BAT in CT and the corresponding [18F]-FDG uptake in PET. In this study, we propose training convolutional neural networks (CNNs) to predict [18F]-FDG uptake by BAT from unenhanced CT scans in the restricted regions that are likely to contain BAT. Using the Attention U-Net architecture, we perform experiments on datasets from four different cohorts, the largest study to date. We segment BAT regions using predicted [18F]-FDG uptake values, achieving 23% to 40% better accuracy than conventional CT thresholding. Additionally, BAT volumes computed from the segmentations distinguish the subjects with and without active BAT with an AUC of 0.8, compared to 0.6 for CT thresholding. These findings suggest CNNs can facilitate large-scale imaging studies more efficiently and cost-effectively using only CT.

DOI: https://doi.org/10.1038/s41467-024-52622-w
J Exp Biol. 2024 Sep 25. pii: jeb.248027. [Epub ahead of print]

The mitochondrial physiology of torpor in ruby-throated hummingbirds, Archilochus colubris.

Amalie J Hutchinson, James F Staples, Christopher G Gugleilmo.

  Hummingbirds save energy by facultatively entering torpor, but the physiological mechanisms underlying this metabolic suppression are largely unknown. We compared whole-animal and pectoralis mitochondrial metabolism between torpid and normothermic ruby-throated hummingbirds (Archilochus colubris). When fasting, hummingbirds were exposed to 10℃ ambient temperature at night, they entered torpor; average body temperature decreased by nearly 25℃ (From ∼37 to ∼13℃), and whole-animal metabolic rate (VO2) decreased by 95% compared to normothermia, a much greater metabolic suppression compared with mammalian daily heterotherms. We then measured pectoralis mitochondrial oxidative phosphorylation (OXPHOS) fueled by either carbohydrate or fatty acid substrates at both 39℃ and 10℃ in torpid and normothermic hummingbirds. Aside from a 20% decrease in electron transport system complex I-supported respiration with pyruvate, the capacity for OXPHOS at a common in vivo temperature did not differ in isolated mitochondria between torpor and normothermia. Similarly, the activities of pectoralis pyruvate dehydrogenase and 3-hydroxyacyl-CoA dehydrogenase did not differ between the states. Unlike heterothermic mammals, hummingbirds do not suppress muscle mitochondrial metabolism in torpor by active, temperature-independent mechanisms. Other mechanisms that may underly this impressive whole-animal metabolic suppression include decreasing ATP demand or relying on rapid passive cooling facilitated by the very small body size of A. colubris.

Keywords:  Avian; Daily torpor; Heterothermy; Thermoregulation

DOI:  https://doi.org/10.1242/jeb.248027
Mol Metab. 2024 Sep 19. pii: S2212-8778(24)00165-0. [Epub ahead of print]89 102034

CPEB2-activated Prdm16 translation promotes brown adipocyte function and prevents obesity.

Wen-Hsin Lu, Hui-Feng Chen, Pei-Chih King, Chi Peng, Yi-Shuian Huang.

   OBJECTIVE: Brown adipose tissue (BAT) plays an important role in mammalian thermogenesis through the expression of uncoupling protein 1 (UCP1). Our previous study identified cytoplasmic polyadenylation element binding protein 2 (CPEB2) as a key regulator that activates the translation of Ucp1 with a long 3'-untranslated region (Ucp1L) in response to adrenergic signaling. Mice lacking CPEB2 or Ucp1L exhibited reduced UCP1 expression and impaired thermogenesis; however, only CPEB2-null mice displayed obesogenic phenotypes. Hence, this study aims to investigate how CPEB2-controlled translation impacts body weight.
METHODS: Body weight measurements were conducted on mice with global knockout (KO) of CPEB2, UCP1 or Ucp1L, as well as those with conditional knockout of CPEB2 in neurons or adipose tissues. RNA sequencing coupled with bioinformatics analysis was used to identify dysregulated gene expression in CPEB2-deficient BAT. The role of CPEB2 in regulating PRD1-BF1-RIZ1 homologous-domain containing 16 (PRDM16) expression was subsequently confirmed by RT-qPCR, Western blotting, polysomal profiling and luciferase reporter assays. Adeno-associated viruses (AAV) expressing CPEB2 or PRDM16 were delivered into BAT to assess their efficacy in mitigating weight gain in CPEB2-KO mice.
RESULTS: We validated that defective BAT function contributed to the increased weight gain in CPEB2-KO mice. Transcriptomic profiling revealed upregulated expression of genes associated with muscle development in CPEB2-KO BAT. Given that both brown adipocytes and myocytes stem from myogenic factor 5-expressing precursors, with their cell-fate differentiation regulated by PRDM16, we identified that Prdm16 was translationally upregulated by CPEB2. Ectopic expression of PRDM16 in CPEB2-deprived BAT restored gene expression profiles and decreased weight gain in CPEB2-KO mice.
CONCLUSIONS: In addition to Ucp1L, activation of Prdm16 translation by CPEB2 is critical for sustaining brown adipocyte function. These findings unveil a new layer of post-transcriptional regulation governed by CPEB2, fine-tuning thermogenic and metabolic activities of brown adipocytes to control body weight.

Keywords:  Brown adipose tissue; CPEB2; Obesity; PRDM16; Thermogenesis; Translational control

DOI:  https://doi.org/10.1016/j.molmet.2024.102034
FASEB J. 2024 Sep 30. 38(18): e70066

Mitochondrial membrane potential and oxidative stress interact to regulate Oma1-dependent processing of Opa1 and mitochondrial dynamics.

Garrett M Fogo, Sarita Raghunayakula, Katlynn J Emaus, Francisco J Torres Torres, Joseph M Wider, Thomas H Sanderson.

  Mitochondrial form and function are regulated by the opposing forces of mitochondrial dynamics: fission and fusion. Mitochondrial dynamics are highly active and consequential during neuronal ischemia/reperfusion (I/R) injury. Mitochondrial fusion is executed at the mitochondrial inner membrane by Opa1. The balance of long (L-Opa1) and proteolytically cleaved short (S-Opa1) isoforms is critical for efficient fusion. Oma1 is the predominant stress-responsive protease for Opa1 processing. In neuronal cell models, we assessed Oma1 and Opa1 regulation during mitochondrial stress. In an immortalized mouse hippocampal neuron line (HT22), Oma1 was sensitive to mitochondrial membrane potential depolarization (rotenone, FCCP) and hyperpolarization (oligomycin). Further, oxidative stress was sufficient to increase Oma1 activity and necessary for depolarization-induced proteolysis. We generated Oma1 knockout (KO) HT22 cells that displayed normal mitochondrial morphology and fusion capabilities. FCCP-induced mitochondrial fragmentation was exacerbated in Oma1 KO cells. However, Oma1 KO cells were better equipped to perform restorative fusion after fragmentation, presumably due to preserved L-Opa1. We extended our investigations to a combinatorial stress of neuronal oxygen-glucose deprivation and reoxygenation (OGD/R), where we found that Opa1 processing and Oma1 activation were initiated during OGD in an ROS-dependent manner. These findings highlight a novel dependence of Oma1 on oxidative stress in response to depolarization. Further, we demonstrate contrasting fission/fusion roles for Oma1 in the acute response and recovery stages of mitochondrial stress. Collectively, our results add intersectionality and nuance to the previously proposed models of Oma1 activity.

Keywords:  membrane fusion; membrane potential; mitochondria; mitochondrial dynamics; proteostasis; reactive oxygen species

DOI:  https://doi.org/10.1096/fj.202400313R
Mol Metab. 2024 Sep 19. pii: S2212-8778(24)00164-9. [Epub ahead of print] 102033

HDAC5 controls a hypothalamic STAT5b-TH axis, the sympathetic activation of ATP-consuming futile cycles and adult-onset obesity in male mice.

Raian E Contreras, Tim Gruber, Ismael González-García, Sonja C Schriever, Meri De Angelis, Noemi Mallet, Miriam Bernecker, Beata Legutko, Dhiraj Kabra, Mathias Schmidt, Matthias H Tschöp, Ruth Gutierrez-Aguilar, Jane Mellor, Cristina Garcia-Caceres, Paul T Pfluger.

  With age, metabolic perturbations accumulate to elevate our obesity burden. While age-onset obesity is mostly driven by a sedentary lifestyle and high calorie intake, genetic and epigenetic factors also play a role. Among these, members of the large histone deacetylase (HDAC) family are of particular importance as key metabolic determinants for healthy ageing, or metabolic dysfunction. Here, we aimed to interrogate the role of class 2 family member HDAC5 in controlling systemic metabolism and age-related obesity under non-obesogenic conditions. Starting at 6 months of age, we observed adult-onset obesity in chow-fed male global HDAC5-KO mice, that was accompanied by marked reductions in adrenergic-stimulated ATP-consuming futile cycles, including BAT activity and UCP1 levels, WAT-lipolysis, skeletal muscle, WAT and liver futile creatine and calcium cycles, and ultimately energy expenditure. Female mice did not differ between genotypes. The lower peripheral sympathetic nervous system (SNS) activity in mature male KO mice was linked to higher dopaminergic neuronal activity within the dorsomedial arcuate nucleus (dmARC) and elevated hypothalamic dopamine levels. Mechanistically, we reveal that hypothalamic HDAC5 acts as co-repressor of STAT5b over the control of Tyrosine hydroxylase (TH) gene transactivation, which ultimately orchestrates the activity of dmARH dopaminergic neurons and energy metabolism in male mice under non-obesogenic conditions.

Keywords:  Adult-onset obesity; Brown fat thermogenesis; Dopamine; Histone deacetylase 5; Hypothalamus

DOI:  https://doi.org/10.1016/j.molmet.2024.102033
Redox Biol. 2024 Sep 19. pii: S2213-2317(24)00343-4. [Epub ahead of print]77 103365

Glutathione peroxidase 3 is essential for countering senescence in adipose remodelling by maintaining mitochondrial homeostasis.

Yijie Song, Mengjie Zhu, Md Ariful Islam, Wenyi Gu, Kavsar Alim, Chien-Shan Cheng, Jingxian Chen, Yu Xu, Hongxi Xu.

  Adipose tissue senescence is a precursor to organismal aging and understanding adipose remodelling contributes to discovering novel anti-aging targets. Glutathione peroxidase 3 (GPx3), a critical endogenous antioxidant enzyme, is diminished in the subcutaneous adipose tissue (sWAT) with white adipose expansion. Based on the active role of the antioxidant system in counteracting aging, we investigated the involvement of GPx3 in adipose senescence. We determined that knockdown of GPx3 in adipose tissue by adeno-associated viruses impaired mitochondrial function in mice, increased susceptibility to obesity, and exacerbated adipose tissue senescence. Impairment of GPx3 may cause mitochondrial dysfunction through inner mitochondrial membrane disruption. Adipose reshaping management (cold stimulation and intermittent diet) counteracted the aging of tissues, with an increase in GPx3 expression. Overall metabolic improvement induced by cold stimulation was partially attenuated when GPx3 was depleted. GPx3 may be involved in adipose browning by interacting with UCP1, and GPx3 may be a limiting factor for intracellular reactive oxygen species (ROS) accumulation during stem cell browning. Collectively, these findings emphasise the importance of restoring the imbalanced redox state in adipose tissue to counteract aging and that GPx3 may be a potential target for maintaining mitochondrial homeostasis and longevity.

Keywords:  Adipose tissue; Anti-Senescence; Glutathione peroxidase 3; Mitochondrial

DOI:  https://doi.org/10.1016/j.redox.2024.103365
Annu Rev Physiol. 2025 Sep 20.

From Muscle-Based Nonshivering Thermogenesis to Malignant Hyperthermia in Mammals.

Bradley S Launikonis, Robyn M Murphy.

For physiological processes in the vital organs of eutherian mammals to function, it is important to maintain constant core body temperature at ∼37°C. Mammals generate heat internally by thermogenesis. The focus of this review is on heat generated in resting skeletal muscles, using the same cellular components that muscles use to regulate cytoplasmic calcium concentrations [Ca2+] and contraction. Key to this process, known as muscle-based nonshivering thermogenesis (MB-NST), are tiny Ca2+ movements and associated ATP turnover coordinated by the plasma membrane, sarcoplasmic reticulum (SR), and the mitochondria. MB-NST has made mammals with gain-of-function SR ryanodine receptor (RyR) variants vulnerable to excessive heat generation that can be potentially lethal, known as malignant hyperthermia. Studies of RyR variants using recently developed techniques have advanced our understanding of MB-NST.

DOI: https://doi.org/10.1146/annurev-physiol-022724-105205
Circulation. 2024 Sep 24.

Bone Morphogenetic Protein 9 Protects Against Myocardial Infarction by Improving Lymphatic Drainage Function and Triggering DECR1-Mediated Mitochondrial Bioenergetics.

Zikun Duan, Zhouqing Huang, Wei Lei, Ke Zhang, Wei Xie, Hua Jin, Maolan Wu, Ningrui Wang, Xiaokun Li, Aimin Xu, Hao Zhou, Fan Wu, Yulin Li, Zhuofeng Lin.

   BACKGROUND: BMP9 (bone morphogenetic protein 9) is a member of the TGF-β (transforming growth factor β) family of cytokines with pleiotropic effects on glucose metabolism, fibrosis, and lymphatic development. However, the role of BMP9 in myocardial infarction (MI) remains elusive.
METHODS: The expressional profiles of BMP9 in cardiac tissues and plasma samples of subjects with MI were determined by immunoassay or immunoblot. The role of BMP9 in MI was determined by evaluating the impact of BMP9 deficiency and replenishment with adeno-associated virus-mediated BMP9 expression or recombinant human BMP9 protein in mice.
RESULTS: We show that circulating BMP9 and its cardiac levels are markedly increased in humans and mice with MI and are negatively associated with cardiac function. It is important to note that BMP9 deficiency exacerbates left ventricular dysfunction, increases infarct size, and augments cardiac fibrosis in mice with MI. In contrast, replenishment of BMP9 significantly attenuates these adverse effects. We further demonstrate that BMP9 improves lymphatic drainage function, thereby leading to a decrease of cardiac edema. In addition, BMP9 increases the expression of mitochondrial DECR1 (2,4-dienoyl-CoA reductase 1), a rate-limiting enzyme involved in β-oxidation, which, in turn, promotes cardiac mitochondrial bioenergetics and mitigates MI-induced cardiomyocyte injury. Moreover, DECR1 deficiency exacerbates MI-induced cardiac damage in mice, whereas this adverse effect is restored by the treatment of adeno-associated virus-mediated DECR1. Consistently, DECR1 deletion abrogates the beneficial effect of BMP9 against MI-induced cardiomyopathy and cardiac damage in mice.
CONCLUSIONS: These results suggest that BMP9 protects against MI by fine-tuning the multiorgan cross-talk among the liver, lymph, and the heart.

Keywords:  BMP9; DECR1; lymphatic drainage dysfunction; mitochondrial bioenergetics; myocardial infarction

DOI:  https://doi.org/10.1161/CIRCULATIONAHA.123.065935