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1.
Nat Commun ; 13(1): 2185, 2022 04 21.
Artigo em Inglês | MEDLINE | ID: mdl-35449169

RESUMO

Cardiac excitation-contraction coupling requires dyads, the nanoscopic microdomains formed adjacent to Z-lines by apposition of transverse tubules and junctional sarcoplasmic reticulum. Disruption of dyad architecture and function are common features of diseased cardiomyocytes. However, little is known about the mechanisms that modulate dyad organization during cardiac development, homeostasis, and disease. Here, we use proximity proteomics in intact, living hearts to identify proteins enriched near dyads. Among these proteins is CMYA5, an under-studied striated muscle protein that co-localizes with Z-lines, junctional sarcoplasmic reticulum proteins, and transverse tubules in mature cardiomyocytes. During cardiac development, CMYA5 positioning adjacent to Z-lines precedes junctional sarcoplasmic reticulum positioning or transverse tubule formation. CMYA5 ablation disrupts dyad architecture, dyad positioning at Z-lines, and junctional sarcoplasmic reticulum Ca2+ release, leading to cardiac dysfunction and inability to tolerate pressure overload. These data provide mechanistic insights into cardiomyopathy pathogenesis by demonstrating that CMYA5 anchors junctional sarcoplasmic reticulum to Z-lines, establishes dyad architecture, and regulates dyad Ca2+ release.


Assuntos
Acoplamento Excitação-Contração , Retículo Sarcoplasmático , Cálcio/metabolismo , Proteínas Musculares/metabolismo , Miócitos Cardíacos/metabolismo , Sarcolema/metabolismo , Retículo Sarcoplasmático/metabolismo
2.
Proc Natl Acad Sci U S A ; 119(7)2022 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-35135885

RESUMO

The medial entorhinal cortex (MEC) creates a map of local space, based on the firing patterns of grid, head-direction (HD), border, and object-vector (OV) cells. How these cell types are organized anatomically is debated. In-depth analysis of this question requires collection of precise anatomical and activity data across large populations of neurons during unrestrained behavior, which neither electrophysiological nor previous imaging methods fully afford. Here, we examined the topographic arrangement of spatially modulated neurons in the superficial layers of MEC and adjacent parasubiculum using miniaturized, portable two-photon microscopes, which allow mice to roam freely in open fields. Grid cells exhibited low levels of co-occurrence with OV cells and clustered anatomically, while border, HD, and OV cells tended to intermingle. These data suggest that grid cell networks might be largely distinct from those of border, HD, and OV cells and that grid cells exhibit strong coupling among themselves but weaker links to other cell types.


Assuntos
Mapeamento Encefálico/métodos , Córtex Entorrinal/anatomia & histologia , Córtex Entorrinal/fisiologia , Microscopia/instrumentação , Animais , Masculino , Camundongos , Miniaturização , Atividade Motora , Neurônios/fisiologia
3.
Neuron ; 110(3): 516-531.e6, 2022 02 02.
Artigo em Inglês | MEDLINE | ID: mdl-34793692

RESUMO

Social competition plays a pivotal role in determining individuals' social status. While the dorsomedial prefrontal cortex (dmPFC) is essential in regulating social competition, it remains unclear how information is processed within its local networks. Here, by applying optogenetic and chemogenetic manipulations in a dominance tube test, we reveal that, in accordance with pyramidal (PYR) neuron activation, excitation of the vasoactive intestinal polypeptide (VIP) or inhibition of the parvalbumin (PV) interneurons induces winning. The winning behavior is associated with sequential calcium activities initiated by VIP and followed by PYR and PV neurons. Using miniature two-photon microscopic (MTPM) and optrode recordings in awake mice, we show that VIP stimulation directly leads to a two-phased activity pattern of both PYR and PV neurons-rapid suppression followed by activation. The delayed activation of PV implies an embedded feedback tuning. This disinhibitory VIP-PV-PYR motif forms the core of a dmPFC microcircuit to control social competition.


Assuntos
Interneurônios , Parvalbuminas , Animais , Interneurônios/fisiologia , Camundongos , Parvalbuminas/metabolismo , Córtex Pré-Frontal/fisiologia , Células Piramidais/fisiologia , Peptídeo Intestinal Vasoativo/metabolismo
4.
Small ; 18(12): e2105989, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35088522

RESUMO

Biomedical imaging technology (like digital subtraction angiography (DSA)) based on contrast agents has been widely employed in the diagnosis of vascular-related diseases. While the DSA achieves the high-resolution observation of specified vessels and their downstream perfusion at the cost of invasive, radioactive operation and hepatorenal toxicity. To address those problems, this study develops arterial labeling ultrasound (US) subtraction angiography (ALUSA) based on a new perfluorobutane (PFB) nanodroplets with a lower vaporization threshold through spontaneous nucleation. The nanodroplets can be selectively vaporized to microbubbles, indicating a highly echogenic signal at B-mode images only using a diagnostic transducer. By labeling a single blood vessel for nanodroplets vaporization and tracking its downstream blood perfusion in segmental renal arteries at a frame rate of 500 Hz. The results demonstrate the color-coded super-resolution ALUSA image, exhibiting the downstream arcuate and interlobular arteries of each segmental renal artery with a resolution of 36 µm in a rabbit kidney. Furthermore, ALUSA could offer the vascular structures, blood flow velocity, and direction of their primary supply vessels in the mouse breast tumor. ALUSA fills the gap of noninvasive labeling angiography in US and opens a broad vista in the diagnosis and treatment of tumor and vascular-related diseases.


Assuntos
Acústica , Microbolhas , Angiografia Digital , Animais , Artérias , Camundongos , Coelhos , Ultrassonografia/métodos
5.
Front Genet ; 12: 710449, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34868196

RESUMO

Background: Chinese indigenous sheep can be classified into two types according to their tail morphology: fat-rumped and thin-tailed sheep, of which the typical breeds are Altay sheep and Tibetan sheep, respectively. Methods: To identify the differentially expressed proteins (DEPs) underlying the phenotypic differences between tail types, we used isobaric tags for relative and absolute quantification (iTRAQ) combined with multi-dimensional liquid chromatography tandem-mass spectrometry (LC-MS/MS) technology to detect candidate proteins. We then subjected these to a database search and identified the DEPs. Finally, bioinformatics technology was used to carry out Gene Ontology (GO) functional and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. Results: A total of 3,248 proteins were identified, of which 44 were up-regulated and 40 were down-regulated DEPs. Analyzing their GO function terms and KEGG pathways revealed that the functions of these DEPs are mainly binding, catalytic activity, structural molecule activity, molecular function regulator, and transporter activity. Among the genes encoding the DEPs, APOA2, GALK1, ADIPOQ, and NDUFS4 are associated with fat formation and metabolism. Conclusion: The APOA2, GALK1, ADIPOQ, and NDUFS4 genes may be involved in the deposition of fat in the tail of sheep. This study provides a scientific basis for the breeding of thin-tailed sheep.

6.
Biochem Soc Trans ; 49(6): 2581-2589, 2021 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-34854917

RESUMO

The store-operated calcium (Ca2+) entry (SOCE) is the Ca2+ entry mechanism used by cells to replenish depleted Ca2+ store. The dysregulation of SOCE has been reported in metastatic cancer. It is believed that SOCE promotes migration and invasion by remodeling the actin cytoskeleton and cell adhesion dynamics. There is recent evidence supporting that SOCE is critical for the spatial and the temporal coding of Ca2+ signals in the cell. In this review, we critically examined the spatiotemporal control of SOCE signaling and its implication in the specificity and robustness of signaling events downstream of SOCE, with a focus on the spatiotemporal SOCE signaling during cancer cell migration, invasion and metastasis. We further discuss the limitation of our current understanding of SOCE in cancer metastasis and potential approaches to overcome such limitation.


Assuntos
Cálcio/metabolismo , Metástase Neoplásica , Neoplasias/metabolismo , Sinalização do Cálcio , Humanos , Transporte de Íons , Neoplasias/patologia
7.
ACS Nano ; 15(10): 16913-16923, 2021 10 26.
Artigo em Inglês | MEDLINE | ID: mdl-34647449

RESUMO

The advent of localization-based super-resolution ultrasound (SRUS) imaging creates a vista for precision vasculature and hemodynamic measurements in brain science, cardiovascular diseases, and cancer. As blinking fluorophores are crucial to super-resolution optical imaging, blinking acoustic contrast agents enabling ultrasound localization microscopy have been highly sought, but only with limited success. Here we report on the discovery and characterization of a type of blinking acoustic nanodroplets (BANDs) ideal for SRUS. BANDs of 200-500 nm diameters comprise a perfluorocarbon-filled core and a shell of DSPC, Pluronic F68, and DSPE-PEG2000. When driven by clinically safe acoustic pulses (MI < 1.9) provided by a diagnostic ultrasound transducer, BANDs underwent reversible vaporization and reliquefaction, manifesting as "blinks", at rates of up to 5 kHz. By sparse activation of perfluorohexane-filled BANDs-C6 at high concentrations, only 100 frames of ultrasound imaging were sufficient to reconstruct super-resolution images of a no-flow tube through either cumulative localization or temporal radiality autocorrelation. Furthermore, the use of high-density BANDs-C6-4 (1 × 108/mL) with a 1:9 admixture of perfluorohexane and perfluorobutane supported the fast SRUS imaging of muscle vasculature in live animals, at 64 µm resolution requiring only 100 frames per layer. We anticipate that the BANDs developed here will greatly boost the application of SRUS in both basic science and clinical settings.


Assuntos
Piscadela , Meios de Contraste , Acústica , Animais , Imagem Óptica , Ultrassonografia
8.
Biol Open ; 10(5)2021 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-33942864

RESUMO

Chinese indigenous sheep can be classified into three types based on tail morphology: fat-tailed, fat-rumped, and thin-tailed sheep, of which the typical breeds are large-tailed Han sheep, Altay sheep, and Tibetan sheep, respectively. To unravel the molecular genetic basis underlying the phenotypic differences among Chinese indigenous sheep with these three different tail types, we used ovine high-density 600K single nucleotide polymorphism (SNP) arrays to detect genome-wide associations, and performed general linear model analysis to identify candidate genes, using genotyping technology to validate the candidate genes. Tail type is an important economic trait in sheep. However, the candidate genes associated with tail type are not known. The objective of this study was to identify SNP markers, genes, and chromosomal regions related to tail traits. We performed a genome-wide association study (GWAS) using data from 40 large-tailed Han sheep, 40 Altay sheep (cases) and 40 Tibetan sheep (controls). A total of 31 significant (P<0.05) SNPs associated with tail-type traits were detected. For significant SNPs' loci, we determined their physical location and performed a screening of candidate genes within each region. By combining information from previously reported and annotated biological functional genes, we identified SPAG17, Tbx15, VRTN, NPC2, BMP2 and PDGFD as the most promising candidate genes for tail-type traits. Based on the above identified candidate genes for tail-type traits, BMP2 and PDGFD genes were selected to investigate the relationship between SNPs within the tails in the Altay and Tibetan populations. rs119 T>C in exon1 of the BMP2 gene and one SNP in exon4 (rs69 C>A) of the PDGFD gene were detected. rs119 was of the TT genotype in Altay sheep, while it was of the CC genotype in Tibetan sheep. On rs69 of the PDGFD gene, Altay sheep presented with the CC genotype; however, Tibetan sheep presented with the AA genotype.


Assuntos
Adiposidade/genética , Estudo de Associação Genômica Ampla , Genoma , Carneiro Doméstico/genética , Ovinos/genética , Cauda , Animais , China , Biologia Computacional/métodos , Ontologia Genética , Marcadores Genéticos , Estudo de Associação Genômica Ampla/métodos , Genótipo , Humanos , Especificidade de Órgãos , Polimorfismo de Nucleotídeo Único , Ovinos/classificação , Carneiro Doméstico/classificação
9.
Nat Commun ; 12(1): 869, 2021 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-33558521

RESUMO

The beating heart possesses the intrinsic ability to adapt cardiac output to changes in mechanical load. The century-old Frank-Starling law and Anrep effect have documented that stretching the heart during diastolic filling increases its contractile force. However, the molecular mechanotransduction mechanism and its impact on cardiac health and disease remain elusive. Here we show that the mechanically activated Piezo1 channel converts mechanical stretch of cardiomyocytes into Ca2+ and reactive oxygen species (ROS) signaling, which critically determines the mechanical activity of the heart. Either cardiac-specific knockout or overexpression of Piezo1 in mice results in defective Ca2+ and ROS signaling and the development of cardiomyopathy, demonstrating a homeostatic role of Piezo1. Piezo1 is pathologically upregulated in both mouse and human diseased hearts via an autonomic response of cardiomyocytes. Thus, Piezo1 serves as a key cardiac mechanotransducer for initiating mechano-chemo transduction and consequently maintaining normal heart function, and might represent a novel therapeutic target for treating human heart diseases.


Assuntos
Canais Iônicos/metabolismo , Mecanotransdução Celular , Miocárdio/metabolismo , Animais , Arritmias Cardíacas/metabolismo , Arritmias Cardíacas/fisiopatologia , Cálcio/metabolismo , Sinalização do Cálcio , Cardiomiopatias/metabolismo , Cardiomiopatias/fisiopatologia , Deleção de Genes , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/fisiopatologia , Testes de Função Cardíaca , Homeostase , Camundongos Knockout , Miócitos Cardíacos/metabolismo , Especificidade de Órgãos , Pirazinas/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Tiadiazóis/metabolismo , Regulação para Cima
11.
Nat Methods ; 18(1): 46-49, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33408404

RESUMO

We have developed a miniature two-photon microscope equipped with an axial scanning mechanism and a long-working-distance miniature objective to enable multi-plane imaging over a volume of 420 × 420 × 180 µm3 at a lateral resolution of ~1 µm. Together with the detachable design that permits long-term recurring imaging, our miniature two-photon microscope can help decipher neuronal mechanisms in freely behaving animals.


Assuntos
Encéfalo/diagnóstico por imagem , Encéfalo/fisiologia , Microscopia de Fluorescência por Excitação Multifotônica/métodos , Miniaturização/métodos , Neuroimagem/métodos , Animais , Comportamento Animal , Encéfalo/citologia , Técnicas Citológicas , Locomoção , Masculino , Camundongos , Camundongos Endogâmicos C57BL
12.
Cell Res ; 31(6): 703-712, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33159153

RESUMO

Intracellular pH (pHi) homeostasis is crucial for cellular functions and signal transduction across all kingdoms of life. In particular, bacterial pHi homeostasis is important for physiology, ecology, and pathogenesis. Here we report an exquisite bacterial acid-resistance (AR) mechanism in which proton leak elicits a pre-emptive AR response. A single bacterial cell undergoes quantal electrochemical excitation, termed "BacFlash", which consists of membrane depolarization, transient pHi rise, and bursting production of reactive oxygen species. BacFlash ignition is dictated by acid stress in the form of proton leak across the plasma membrane and the rate of BacFlash occurrence is reversely correlated with the pHi buffering capacity. Through genome-wide screening, we further identify the ATP synthase Fo complex subunit a as the putative proton sensor for BacFlash biogenesis. Importantly, persistent BacFlash hyperactivity activates transcription of a panel of key AR genes and predisposes the cells to survive imminent extreme acid stress. These findings demonstrate a prototypical coupling between electrochemical excitation and nucleoid gene expression in prokaryotes.


Assuntos
Bactérias , Prótons , Membrana Celular , Expressão Gênica , Concentração de Íons de Hidrogênio
13.
Cell Discov ; 6: 74, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33133634

RESUMO

It remains challenging to construct a complete cell lineage map of the origin of vascular endothelial cells in any vertebrate embryo. Here, we report the application of in toto light-sheet fluorescence imaging of embryos to trace the origin of vascular endothelial cells (ECs) at single-cell resolution in zebrafish. We first adapted a previously reported method to embryo mounting and light-sheet imaging, created an alignment, fusion, and extraction all-in-one software (AFEIO) for processing big data, and performed quantitative analysis of cell lineage relationships using commercially available Imaris software. Our data revealed that vascular ECs originated from broad regions of the gastrula along the dorsal-ventral and anterior-posterior axes, of which the dorsal-anterior cells contributed to cerebral ECs, the dorsal-lateral cells to anterior trunk ECs, and the ventral-lateral cells to posterior trunk and tail ECs. Therefore, this work, to our knowledge, charts the first comprehensive map of the gastrula origin of vascular ECs in zebrafish, and has potential applications for studying the origin of any embryonic organs in zebrafish and other model organisms.

15.
Nat Methods ; 17(11): 1139-1146, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32989318

RESUMO

The ability to directly measure acetylcholine (ACh) release is an essential step toward understanding its physiological function. Here we optimized the GRABACh (GPCR-activation-based ACh) sensor to achieve substantially improved sensitivity in ACh detection, as well as reduced downstream coupling to intracellular pathways. The improved version of the ACh sensor retains the subsecond response kinetics, physiologically relevant affinity and precise molecular specificity for ACh of its predecessor. Using this sensor, we revealed compartmental ACh signals in the olfactory center of transgenic flies in response to external stimuli including odor and body shock. Using fiber photometry recording and two-photon imaging, our ACh sensor also enabled sensitive detection of single-trial ACh dynamics in multiple brain regions in mice performing a variety of behaviors.


Assuntos
Acetilcolina/metabolismo , Técnicas Biossensoriais/métodos , Encéfalo/metabolismo , Animais , Animais Geneticamente Modificados , Comportamento Animal/fisiologia , Colinérgicos/farmacologia , Drosophila/genética , Drosophila/metabolismo , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Células HEK293 , Humanos , Camundongos , Corpos Pedunculados/metabolismo , Neurônios/metabolismo , Córtex Olfatório/metabolismo , Receptor Muscarínico M3/genética , Receptor Muscarínico M3/metabolismo , Córtex Somatossensorial/metabolismo
16.
Neurosci Bull ; 36(10): 1182-1190, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32797396

RESUMO

An ultimate goal of neuroscience is to decipher the principles underlying neuronal information processing at the molecular, cellular, circuit, and system levels. The advent of miniature fluorescence microscopy has furthered the quest by visualizing brain activities and structural dynamics in animals engaged in self-determined behaviors. In this brief review, we summarize recent advances in miniature fluorescence microscopy for neuroscience, focusing mostly on two mainstream solutions - miniature single-photon microscopy, and miniature two-photon microscopy. We discuss their technical advantages and limitations as well as unmet challenges for future improvement. Examples of preliminary applications are also presented to reflect on a new trend of brain imaging in experimental paradigms involving body movements, long and complex protocols, and even disease progression and aging.


Assuntos
Encéfalo/diagnóstico por imagem , Microscopia de Fluorescência , Neuroimagem , Animais , Neurônios
17.
Nat Cell Biol ; 22(3): 332-340, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32123336

RESUMO

Mapping of the holistic cell behaviours sculpting the four-chambered mammalian heart has been a goal or previous studies, but so far only success in transparent invertebrates and lower vertebrates with two-chambered hearts has been achieved. Using a live-imaging system comprising a customized vertical light-sheet microscope equipped with a mouse embryo culture module, a heartbeat-gated imaging strategy and a digital image processing framework, we realized volumetric imaging of developing mouse hearts at single-cell resolution and with uninterrupted cell lineages for up to 1.5 d. Four-dimensional landscapes of Nppa+ cardiomyocyte cell behaviours revealed a blueprint for ventricle chamber formation by which biased outward migration of the outermost cardiomyocytes is coupled with cell intercalation and horizontal division. The inner-muscle architecture of trabeculae was developed through dual mechanisms: early fate segregation and transmural cell arrangement involving both oriented cell division and directional migration. Thus, live-imaging reconstruction of uninterrupted cell lineages affords a transformative means for deciphering mammalian organogenesis.


Assuntos
Ventrículos do Coração/citologia , Ventrículos do Coração/embriologia , Processamento de Imagem Assistida por Computador/métodos , Miócitos Cardíacos/citologia , Animais , Divisão Celular , Linhagem da Célula , Movimento Celular , Embrião de Mamíferos/citologia , Desenvolvimento Embrionário , Coração/embriologia , Camundongos , Microscopia , Morfogênese , Miocárdio/citologia , Análise de Célula Única , Técnicas de Cultura de Tecidos
18.
Cell Death Dis ; 11(3): 181, 2020 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-32165613

RESUMO

Fatty acids are the most major substrate source for adult cardiac energy generation. Prohibitin 2 (PHB2), a highly conserved protein located in mitochondrial inner membrane, plays key roles in cellular energy metabolic homeostasis. However, its functions in regulating cardiac fatty acid metabolism have remained largely unknown. Our study demonstrates that cardiac-specific knockout of Phb2 leads to accumulation of lipid droplets and causes heart failure. Mechanistically, ablation of PHB2 impairs cardiac fatty acid oxidation (FAO) through downregulating carnitine palmitoyltransferase1b (CPT1b), a rate-limiting enzyme of cardiac mitochondrial FAO. Moreover, overexpression of CPT1b alleviates impaired FAO in PHB2-deficient cardiomyocytes. Thus, our study provides direct evidence for the link between PHB2 and cardiac fatty acid metabolism. Our study points out that PHB2 is a potential FAO regulator in cardiac mitochondrial inner membrane, as well as the connection between PHB2 and CPT1b and their relationships to cardiac pathology especially to cardiac fatty acid metabolic disorder.


Assuntos
Ácidos Graxos/metabolismo , Insuficiência Cardíaca/metabolismo , Proteínas Repressoras/deficiência , Animais , Humanos , Camundongos , Oxirredução
19.
Nat Commun ; 10(1): 5277, 2019 11 21.
Artigo em Inglês | MEDLINE | ID: mdl-31754099

RESUMO

Mitochondrial calcium ([Ca2+]mito) dynamics plays vital roles in regulating fundamental cellular and organellar functions including bioenergetics. However, neuronal [Ca2+]mito dynamics in vivo and its regulation by brain activity are largely unknown. By performing two-photon Ca2+ imaging in the primary motor (M1) and visual cortexes (V1) of awake behaving mice, we find that discrete [Ca2+]mito transients occur synchronously over somatic and dendritic mitochondrial network, and couple with cytosolic calcium ([Ca2+]cyto) transients in a probabilistic, rather than deterministic manner. The amplitude, duration, and frequency of [Ca2+]cyto transients constitute important determinants of the coupling, and the coupling fidelity is greatly increased during treadmill running (in M1 neurons) and visual stimulation (in V1 neurons). Moreover, Ca2+/calmodulin kinase II is mechanistically involved in modulating the dynamic coupling process. Thus, activity-dependent dynamic [Ca2+]mito-to-[Ca2+]cyto coupling affords an important mechanism whereby [Ca2+]mito decodes brain activity for the regulation of mitochondrial bioenergetics to meet fluctuating neuronal energy demands as well as for neuronal information processing.


Assuntos
Encéfalo/metabolismo , Sinalização do Cálcio , Cálcio/metabolismo , Citosol/metabolismo , Mitocôndrias/metabolismo , Neurônios/metabolismo , Córtex Visual/metabolismo , Animais , Encéfalo/citologia , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Camundongos Endogâmicos C57BL , Microscopia Eletrônica de Varredura , Microscopia de Fluorescência por Excitação Multifotônica , Mitocôndrias/ultraestrutura , Córtex Motor/citologia , Córtex Motor/metabolismo , Córtex Visual/citologia
20.
FASEB J ; 33(12): 13310-13322, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31530015

RESUMO

Mitochondria are fundamental organelles for cellular and systemic metabolism, and their dysfunction has been implicated in the development of diverse metabolic diseases. Boosted mitochondrial metabolism might be able to protect against metabolic stress and prevent metabolic disorders. Here we show that NADH:ubiquinone oxidoreductase (NDU)-FAB1, also known as mitochondrial acyl carrier protein, acts as a novel enhancer of mitochondrial metabolism and protects against obesity and insulin resistance. Mechanistically, NDUFAB1 coordinately enhances lipoylation and activation of pyruvate dehydrogenase mediated by the mitochondrial fatty acid synthesis pathway and increases the assembly of respiratory complexes and supercomplexes. Skeletal muscle-specific ablation of NDUFAB1 causes systemic disruption of glucose homeostasis and defective insulin signaling, leading to growth arrest and early death within 5 postnatal days. In contrast, NDUFAB1 overexpression effectively protects mice against obesity and insulin resistance when the animals are challenged with a high-fat diet. Our findings indicate that NDUFAB1 could be a novel mitochondrial target to prevent obesity and insulin resistance by enhancing mitochondrial metabolism.-Zhang, R., Hou, T., Cheng, H., Wang, X. NDUFAB1 protects against obesity and insulin resistance by enhancing mitochondrial metabolism.


Assuntos
Complexo I de Transporte de Elétrons/fisiologia , Resistência à Insulina , Insulina/metabolismo , Mitocôndrias/metabolismo , Músculo Esquelético/patologia , Obesidade/prevenção & controle , Substâncias Protetoras/farmacologia , Animais , Dieta Hiperlipídica/efeitos adversos , Metabolismo Energético , Glucose/metabolismo , Homeostase , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Mitocôndrias/patologia , Músculo Esquelético/metabolismo , Obesidade/etiologia , Obesidade/metabolismo , Obesidade/patologia , Transdução de Sinais
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