José López‐Barneo

Hospital Universitario Virgen del Rocío

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Patricia Ortega‐Sáenz

Hospital Universitario Virgen del Rocío

Ricardo Pardal

Universidad de Sevilla

Lin Gao

Hospital Universitario Virgen del Rocío

Alberto Pascual

Instituto de Biomedicina de Sevilla

Juán Ureña

Universidad de Sevilla

Juan José Toledo‐Aral

Instituto de Biomedicina de Sevilla

Antonio Castellano

Universidad de Sevilla

Patricia González‐Rodríguez

Hospital Universitario Virgen del Rocío

Javier Villadiego

Hospital Universitario Virgen del Rocío

José I. Piruat

Universidad de Sevilla

Cooperative Institutions

Universidad de Sevilla

168

Hospital Universitario Virgen del Rocío

149

Instituto de Biomedicina de Sevilla

126

Centro de Investigación Biomédica en Red

Biomedical Research Networking Center on Neurodegenerative Diseases

Consejo Superior de Investigaciones Científicas

Instituto de Salud Carlos III

Universitat de Barcelona

Northwestern University

Inserm

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Gene expression analyses reveal metabolic specifications in acute O₂‐sensing chemoreceptor cells

The Journal of Physiology (2017)

Lin Gao Victoria Bonilla Paula García‐Flores Ignacio Arias‐Mayenco Patricia Ortega‐Sáenz

Key points Glomus cells in the carotid body (CB) and chromaffin cells in the adrenal medulla (AM) are essential for reflex cardiorespiratory adaptation to hypoxia. However, the mechanisms whereby these cells detect changes in O 2 tension are poorly understood. The metabolic properties of acute O 2 ‐sensing cells have been investigated by comparing the transcriptomes of CB and AM cells, which are O 2 ‐sensitive, with superior cervical ganglion neurons, which are practically O 2 ‐insensitive. In O 2 ‐sensitive cells, we found a characteristic prolyl hydroxylase 3 down‐regulation and hypoxia inducible factor 2α up‐regulation, as well as overexpression of genes coding for three atypical mitochondrial electron transport subunits and pyruvate carboxylase, an enzyme that replenishes tricarboxylic acid cycle intermediates. In agreement with this observation, the inhibition of succinate dehydrogenase impairs CB acute O 2 sensing. The responsiveness of peripheral chemoreceptor cells to acute hypoxia depends on a ‘signature metabolic profile’. Abstract Acute O 2 sensing is a fundamental property of cells in the peripheral chemoreceptors, e.g. glomus cells in the carotid body (CB) and chromaffin cells in the adrenal medulla (AM), and is necessary for adaptation to hypoxia. These cells contain O 2 ‐sensitive ion channels, which mediate membrane depolarization and transmitter release upon exposure to hypoxia. However, the mechanisms underlying the detection of changes in O 2 tension by cells are still poorly understood. Recently, we suggested that CB glomus cells have specific metabolic features that favour the accumulation of reduced quinone and the production of mitochondrial NADH and reactive oxygen species during hypoxia. These signals alter membrane ion channel activity. To investigate the metabolic profile characteristic of acute O 2 ‐sensing cells, we used adult mice to compare the transcriptomes of three cell types derived from common sympathoadrenal progenitors, but exhibiting variable responsiveness to acute hypoxia: CB and AM cells, which are O 2 ‐sensitive (glomus cells > chromaffin cells), and superior cervical ganglion neurons, which are practically O 2 ‐insensitive. In the O 2 ‐sensitive cells, we found a characteristic mRNA expression pattern of prolyl hydroxylase 3/hypoxia inducible factor 2α and up‐regulation of several genes, in particular three atypical mitochondrial electron transport subunits and some ion channels. In addition, we found that pyruvate carboxylase, an enzyme fundamental to tricarboxylic acid cycle anaplerosis, is overexpressed in CB glomus cells. We also observed that the inhibition of succinate dehydrogenase impairs CB acute O 2 sensing. Our data suggest that responsiveness to acute hypoxia depends on a ‘signature metabolic profile’ in chemoreceptor cells.

Glomus cell

Peripheral chemoreceptors

Hypoxia

Chromaffin cell

10.1113/jp274684

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Citations (57)

Neurotrophic Properties, Chemosensory Responses and Neurogenic Niche of the Human Carotid Body

Advances in experimental medicine and biology (2015)

Patricia Ortega‐Sáenz Javier Villadiego Ricardo Pardal Juan José Toledo‐Aral José López‐Barneo

10.1007/978-3-319-18440-1_16

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Citations (6)

Obituaries – Christopher Peers

Physiology News (2018)

José López‐Barneo

10.36866/pn.112.51

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Citations (0)

Mitochondrial integrated stress response controls lung epithelial cell fate

Nature (2023)

SeungHye Han Minho Lee Youngjin Shin Regina Giovanni Ram Prosad Chakrabarty

Abstract Alveolar epithelial type 1 (AT1) cells are necessary to transfer oxygen and carbon dioxide between the blood and air. Alveolar epithelial type 2 (AT2) cells serve as a partially committed stem cell population, producing AT1 cells during postnatal alveolar development and repair after influenza A and SARS-CoV-2 pneumonia 1–6 . Little is known about the metabolic regulation of the fate of lung epithelial cells. Here we report that deleting the mitochondrial electron transport chain complex I subunit Ndufs2 in lung epithelial cells during mouse gestation led to death during postnatal alveolar development. Affected mice displayed hypertrophic cells with AT2 and AT1 cell features, known as transitional cells. Mammalian mitochondrial complex I, comprising 45 subunits, regenerates NAD + and pumps protons. Conditional expression of yeast NADH dehydrogenase (NDI1) protein that regenerates NAD + without proton pumping 7,8 was sufficient to correct abnormal alveolar development and avert lethality. Single-cell RNA sequencing revealed enrichment of integrated stress response (ISR) genes in transitional cells. Administering an ISR inhibitor 9,10 or NAD + precursor reduced ISR gene signatures in epithelial cells and partially rescued lethality in the absence of mitochondrial complex I function. Notably, lung epithelial-specific loss of mitochondrial electron transport chain complex II subunit Sdhd , which maintains NAD + regeneration, did not trigger high ISR activation or lethality. These findings highlight an unanticipated requirement for mitochondrial complex I-dependent NAD + regeneration in directing cell fate during postnatal alveolar development by preventing pathological ISR induction.

10.1038/s41586-023-06423-8

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Citations (55)

Carotid body chemosensory responses in mice deficient of TASK channels

The Journal of General Physiology (2010)

Patricia Ortega‐Sáenz Konstantín L. Levitsky María T. Marcos-Almaraz Victoria Bonilla Alberto Pascual

Background K+ channels of the TASK family are believed to participate in sensory transduction by chemoreceptor (glomus) cells of the carotid body (CB). However, studies on the systemic CB-mediated ventilatory response to hypoxia and hypercapnia in TASK1- and/or TASK3-deficient mice have yielded conflicting results. We have characterized the glomus cell phenotype of TASK-null mice and studied the responses of individual cells to hypoxia and other chemical stimuli. CB morphology and glomus cell size were normal in wild-type as well as in TASK1−/− or double TASK1/3−/− mice. Patch-clamped TASK1/3-null glomus cells had significantly higher membrane resistance and less hyperpolarized resting potential than their wild-type counterpart. These electrical parameters were practically normal in TASK1−/− cells. Sensitivity of background currents to changes of extracellular pH was drastically diminished in TASK1/3-null cells. In contrast with these observations, responsiveness to hypoxia or hypercapnia of either TASK1−/− or double TASK1/3−/− cells, as estimated by the amperometric measurement of catecholamine release, was apparently normal. TASK1/3 knockout cells showed an enhanced secretory rate in basal (normoxic) conditions compatible with their increased excitability. Responsiveness to hypoxia of TASK1/3-null cells was maintained after pharmacological blockade of maxi-K+ channels. These data in the TASK-null mouse model indicate that TASK3 channels contribute to the background K+ current in glomus cells and to their sensitivity to external pH. They also suggest that, although TASK1 channels might be dispensable for O2/CO2 sensing in mouse CB cells, TASK3 channels (or TASK1/3 heteromers) could mediate hypoxic depolarization of normal glomus cells. The ability of TASK1/3−/− glomus cells to maintain a powerful response to hypoxia even after blockade of maxi-K+ channels, suggests the existence of multiple sensor and/or effector mechanisms, which could confer upon the cells a high adaptability to maintain their chemosensory function.

Glomus cell

Cell type

Hypoxia

10.1085/jgp.200910302

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Citations (89)

Combined oxygen and glucose sensing in the carotid body.

PubMed (2004)

Ricardo Pardal José López‐Barneo

Source

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Citations (4)

Differential proteomic analysis of adrenal gland during postnatal development

PROTEOMICS (2009)

Alberto Pascual Antonio Romero‐Ruíz José López‐Barneo

The adrenal glands (AGs) are endocrine organs essential for life. They undergo a fetal to adult developmental maturation process, occurring in rats during the first postnatal month. The molecular modifications underlying these ontogenic changes are essentially unknown. Here we report the results of a comparative proteomic analysis performed on neonatal (Postnatal day 3) versus adult (Postnatal day 30) AGs, searching for proteins with a relative higher abundance at each age. We have identified a subset of proteins with relevant expression in each developmental period using 2-DE and DIGE analysis. The identified proteins belong to several functional categories, including proliferation/differentiation, cell metabolism, and steroid biosynthesis. To study if the changes in the proteome are correlated with changes at the mRNA level, we have randomly selected several proteins with differential expression and measured their relative mRNA levels using quantitative RT-PCR. Cell-cycle regulating proteins (retinoblastoma binding protein 9 and prohibitin) with contrasting effects on proliferation are expressed differentially in neonatal and adult AG. Progesterone metabolizing enzymes, up-regulated in the neonatal gland, might contribute to the hyporesponsiveness of the adrenal cortex characteristic of this developmental period. We have also observed in the adult gland a marked up-regulation of enzymes involved in NAD(P)H production, thus providing the reducing power necessary for steroid hormone biosynthesis.

Proteome

Prohibitin

Steroid biosynthesis

10.1002/pmic.200800748

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Citations (8)

Sdhd ablation promotes thyroid tumorigenesis by inducing a stem-like phenotype

Endocrine Related Cancer (2017)

Amruta Ashtekar Danielle J. Huk Alexa Magner Krista La Perle Xiaoli Zhang

Mutations in genes encoding enzymes in the tricarboxylic acid cycle (TCA, also known as the Krebs cycle) have been implicated as causative genetic lesions in a number of human cancers, including renal cell cancers, glioblastomas and pheochromocytomas. In recent studies, missense mutations in the succinate dehydrogenase (SDH) complex have also been proposed to cause differentiated thyroid cancer. In order to gain mechanistic insight into this process, we generated mice lacking the SDH subunit D (Sdhd) in the thyroid. We report that these mice develop enlarged thyroid glands with follicle hypercellularity and increased proliferation. In vitro , human thyroid cell lines with knockdown of SDHD exhibit an enhanced migratory capability, despite no change in proliferative capacity. Interestingly, these cells acquire stem-like features which are also observed in the mouse tumors. The stem-like characteristics are reversed by α-ketoglutarate, suggesting that SDH-associated tumorigenesis results from dedifferentiation driven by an imbalance in cellular metabolites of the TCA cycle. The results of this study reveal a metabolic vulnerability for potential future treatment of SDH-associated neoplasia.

SDHD

10.1530/erc-17-0229

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Citations (3)

Selective Glial Cell Line-Derived Neurotrophic Factor Production in Adult Dopaminergic Carotid Body CellsIn Situand after Intrastriatal Transplantation

Journal of Neuroscience (2005)

Javier Villadiego Simón Méndez‐Ferrer Teresa Valdés‐Sánchez Inmaculada Silos‐Santiago Isabel Fariñas

Glial cell line-derived neurotrophic factor (GDNF) exerts a notable protective effect on dopaminergic neurons in rodent and primate models of Parkinson's disease (PD). The clinical applicability of this therapy is, however, hampered by the need of a durable and stable GDNF source allowing the safe and continuous delivery of the trophic factor into the brain parenchyma. Intrastriatal carotid body (CB) autografting is a neuroprotective therapy potentially useful in PD. It induces long-term recovery of parkinsonian animals through a trophic effect on nigrostriatal neurons and causes amelioration of symptoms in some PD patients. Moreover, the adult rodent CB has been shown to express GDNF. Here we show, using heterozygous GDNF/lacZ knock-out mice, that unexpectedly CB dopaminergic glomus, or type I, cells are the source of CB GDNF. Among the neural or paraneural cells tested, glomus cells are those that synthesize and release the highest amount of GDNF in the adult rodent (as measured by standard and in situ ELISA). Furthermore, GDNF expression by glomus cells is maintained after intrastriatal grafting and in CB of aged and parkinsonian 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated animals. Thus, glomus cells appear to be prototypical abundant sources of GDNF, ideally suited to be used as biological pumps for the endogenous delivery of trophic factors in PD and other neurodegenerative diseases.

10.1523/jneurosci.4312-04.2005

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Citations (67)

Neuroprotective and reparative effects of carotid body grafts in a chronic MPTP model of Parkinson's disease

Neurobiology of Aging (2012)

Ana B. Muñoz‐Manchado Javier Villadiego Nela Suárez‐Luna Alfonso Bermejo‐Navas Pablo Garrido‐Gil

MPTP

Neurotoxin

10.1016/j.neurobiolaging.2012.06.001

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Citations (31)