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Article ; Online: Mitochondrial dysfunction defines T cell exhaustion.

Soto-Heredero, Gonzalo / Desdín-Micó, Gabriela / Mittelbrunn, María

2021 Volume 33, Issue 3, Page(s) 470–472

Abstract: When T cells are exposed to continuous antigen stimulation, they become exhausted. Here, we preview findings from Scharping et al. (2021), who have illuminated the molecular mechanism by which the persistent antigen stimulation and severe hypoxic ... ...

Abstract	When T cells are exposed to continuous antigen stimulation, they become exhausted. Here, we preview findings from Scharping et al. (2021), who have illuminated the molecular mechanism by which the persistent antigen stimulation and severe hypoxic conditions in the intratumoral environment drive T cell exhaustion, losing their cytotoxic function and anticancer effects.
MeSH term(s)	CD8-Positive T-Lymphocytes/metabolism ; Mitochondria
Language	English
Publishing date	2021-03-03
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Comment
ZDB-ID	2176834-1
ISSN	1932-7420 ; 1550-4131
ISSN (online)	1932-7420
ISSN	1550-4131
DOI	10.1016/j.cmet.2021.02.010
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Article ; Online: Extremely Differentiated T Cell Subsets Contribute to Tissue Deterioration During Aging.

Soto-Heredero, Gonzalo / Gómez de Las Heras, Manuel M / Escrig-Larena, J Ignacio / Mittelbrunn, María

Annual review of immunology

2022 Volume 41, Page(s) 181–205

Abstract: There is a dramatic remodeling of the T cell compartment during aging. The most notorious changes are the reduction of the naive T cell pool and the accumulation of memory-like T cells. Memory-like T cells in older people acquire a phenotype of ... ...

Abstract	There is a dramatic remodeling of the T cell compartment during aging. The most notorious changes are the reduction of the naive T cell pool and the accumulation of memory-like T cells. Memory-like T cells in older people acquire a phenotype of terminally differentiated cells, lose the expression of costimulatory molecules, and acquire properties of senescent cells. In this review, we focus on the different subsets of age-associated T cells that accumulate during aging. These subsets include extremely cytotoxic T cells with natural killer properties, exhausted T cells with altered cytokine production, and regulatory T cells that gain proinflammatory features. Importantly, all of these subsets lose their lymph node homing capacity and migrate preferentially to nonlymphoid tissues, where they contribute to tissue deterioration and inflammaging.
MeSH term(s)	Humans ; Animals ; T-Lymphocyte Subsets ; Aging ; T-Lymphocytes, Regulatory ; Cell Differentiation
Language	English
Publishing date	2022-12-16
Publishing country	United States
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	604953-9
ISSN	1545-3278 ; 0732-0582
ISSN (online)	1545-3278
ISSN	0732-0582
DOI	10.1146/annurev-immunol-101721-064501
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Article ; Online: The Role of Extracellular Vesicles in Cutaneous Remodeling and Hair Follicle Dynamics.

Carrasco, Elisa / Soto-Heredero, Gonzalo / Mittelbrunn, María

International journal of molecular sciences

2019 Volume 20, Issue 11

Abstract: Extracellular vesicles (EVs), including exosomes, microvesicles, and apoptotic bodies, are cell-derived membranous structures that were originally catalogued as a way of releasing cellular waste products. Since the discovery of their function in ... ...

Abstract	Extracellular vesicles (EVs), including exosomes, microvesicles, and apoptotic bodies, are cell-derived membranous structures that were originally catalogued as a way of releasing cellular waste products. Since the discovery of their function in intercellular communication as carriers of proteins, lipids, and DNA and RNA molecules, numerous therapeutic approaches have focused on the use of EVs, in part because of their minimized risk compared to cell-based therapies. The skin is the organ with the largest surface in the body. Besides the importance of its body barrier function, much attention has been paid to the skin in regenerative medicine because of its cosmetic aspect, which is closely related to disorders affecting pigmentation and the presence or absence of hair follicles. The use of exosomes in therapeutic approaches for cutaneous wound healing has been reported and is briefly reviewed here. However, less attention has been paid to emerging interest in the potential capacity of EVs as modulators of hair follicle dynamics. Hair follicles are skin appendices that mainly comprise an epidermal and a mesenchymal component, with the former including a major reservoir of epithelial stem cells but also melanocytes and other cell types. Hair follicles continuously cycle, undergoing consecutive phases of resting, growing, and regression. Many biomolecules carried by EVs have been involved in the control of the hair follicle cycle and stem cell function. Thus, investigating the role of either naturally produced or therapeutically delivered EVs as signaling vehicles potentially involved in skin homeostasis and hair cycling may be an important step in the attempt to design future strategies towards the efficient treatment of several skin disorders.
MeSH term(s)	Animals ; Extracellular Vesicles/metabolism ; Hair Follicle/metabolism ; Humans ; Models, Biological ; Regenerative Medicine ; Signal Transduction ; Skin/metabolism
Language	English
Publishing date	2019-06-05
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms20112758
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Article ; Online: The Role of Extracellular Vesicles in Cutaneous Remodeling and Hair Follicle Dynamics

Elisa Carrasco / Gonzalo Soto-Heredero / María Mittelbrunn

International Journal of Molecular Sciences, Vol 20, Iss 11, p

2019 Volume 2758

Abstract	Extracellular vesicles (EVs), including exosomes, microvesicles, and apoptotic bodies, are cell-derived membranous structures that were originally catalogued as a way of releasing cellular waste products. Since the discovery of their function in intercellular communication as carriers of proteins, lipids, and DNA and RNA molecules, numerous therapeutic approaches have focused on the use of EVs, in part because of their minimized risk compared to cell-based therapies. The skin is the organ with the largest surface in the body. Besides the importance of its body barrier function, much attention has been paid to the skin in regenerative medicine because of its cosmetic aspect, which is closely related to disorders affecting pigmentation and the presence or absence of hair follicles. The use of exosomes in therapeutic approaches for cutaneous wound healing has been reported and is briefly reviewed here. However, less attention has been paid to emerging interest in the potential capacity of EVs as modulators of hair follicle dynamics. Hair follicles are skin appendices that mainly comprise an epidermal and a mesenchymal component, with the former including a major reservoir of epithelial stem cells but also melanocytes and other cell types. Hair follicles continuously cycle, undergoing consecutive phases of resting, growing, and regression. Many biomolecules carried by EVs have been involved in the control of the hair follicle cycle and stem cell function. Thus, investigating the role of either naturally produced or therapeutically delivered EVs as signaling vehicles potentially involved in skin homeostasis and hair cycling may be an important step in the attempt to design future strategies towards the efficient treatment of several skin disorders.
Keywords	extracellular vesicles ; exosomes ; apoptotic bodies ; skin ; hair follicles ; hair cycle ; stem cells ; immune cells ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	612
Language	English
Publishing date	2019-06-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: Interorganelle Communication between Mitochondria and the Endolysosomal System.

Soto-Heredero, Gonzalo / Baixauli, Francesc / Mittelbrunn, María

Frontiers in cell and developmental biology

2017 Volume 5, Page(s) 95

Abstract: The function of mitochondria and lysosomes has classically been studied separately. However, evidence has now emerged of intense crosstalk between these two organelles, such that the activity or stress status of one organelle may affect the other. Direct ...

Abstract	The function of mitochondria and lysosomes has classically been studied separately. However, evidence has now emerged of intense crosstalk between these two organelles, such that the activity or stress status of one organelle may affect the other. Direct physical contacts between mitochondria and the endolysosomal compartment have been reported as a rapid means of interorganelle communication, mediating lipid or other metabolite exchange. Moreover, mitochondrial derived vesicles can traffic obsolete mitochondrial proteins into the endolysosomal system for their degradation or secretion to the extracellular milieu as exosomes, representing an additional mitochondrial quality control mechanism that connects mitochondria and lysosomes independently of autophagosome formation. Here, we present what is currently known about the functional and physical communication between mitochondria and lysosomes or lysosome-related organelles, and their role in sustaining cellular homeostasis.
Language	English
Publishing date	2017-11-07
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2737824-X
ISSN	2296-634X
ISSN	2296-634X
DOI	10.3389/fcell.2017.00095
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Mitochondrial activity in T cells.

Desdín-Micó, Gabriela / Soto-Heredero, Gonzalo / Mittelbrunn, María

Mitochondrion

2017 Volume 41, Page(s) 51–57

Abstract: Mitochondria fulfill important and diverse roles during the different stages of T cell adaptive responses. Here we discuss the role of the mitochondria in T cells from the initial steps of activation at the immune synapse to their participation in memory ...

Abstract	Mitochondria fulfill important and diverse roles during the different stages of T cell adaptive responses. Here we discuss the role of the mitochondria in T cells from the initial steps of activation at the immune synapse to their participation in memory response and T cell exhaustion. Mitochondria are relocated to the immune synapse in order to supply local ATP and to aid calcium signaling. During expansion and proliferation, mitochondrial reactive oxygen species drive proliferation. Aerobic glycolysis, glutaminolysis and fatty acid oxidation regulate the program of differentiation into effector or regulatory T cell subsets, and mitochondrial remodeling proteins are required for the long-lasting phenotype of memory cells.
MeSH term(s)	Animals ; Energy Metabolism ; Humans ; Immunity, Innate/immunology ; Metabolic Diseases/immunology ; Metabolic Diseases/pathology ; Mitochondria/immunology ; Mitochondria/metabolism ; Mitochondria/pathology ; Signal Transduction ; T-Lymphocytes/immunology
Language	English
Publishing date	2017-10-12
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2056923-3
ISSN	1872-8278 ; 1567-7249
ISSN (online)	1872-8278
ISSN	1567-7249
DOI	10.1016/j.mito.2017.10.006
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Glycolysis – a key player in the inflammatory response

Soto‐Heredero, Gonzalo / Gómez de las Heras, Manuel M / Gabandé‐Rodríguez, Enrique / Oller, Jorge / Mittelbrunn, María

FEBS journal. 2020 Aug., v. 287, no. 16

2020

Abstract: The inflammatory response involves the activation of several cell types to fight insults caused by a plethora of agents, and to maintain the tissue homoeostasis. On the one hand, cells involved in the pro‐inflammatory response, such as inflammatory M1 ... ...

Abstract	The inflammatory response involves the activation of several cell types to fight insults caused by a plethora of agents, and to maintain the tissue homoeostasis. On the one hand, cells involved in the pro‐inflammatory response, such as inflammatory M1 macrophages, Th1 and Th17 lymphocytes or activated microglia, must rapidly provide energy to fuel inflammation, which is essentially accomplished by glycolysis and high lactate production. On the other hand, regulatory T cells or M2 macrophages, which are involved in immune regulation and resolution of inflammation, preferentially use fatty acid oxidation through the TCA cycle as a main source for energy production. Here, we discuss the impact of glycolytic metabolism at the different steps of the inflammatory response. Finally, we review a wide variety of molecular mechanisms which could explain the relationship between glycolytic metabolites and the pro‐inflammatory phenotype, including signalling events, epigenetic remodelling, post‐transcriptional regulation and post‐translational modifications. Inflammatory processes are a common feature of many age‐associated diseases, such as cardiovascular and neurodegenerative disorders. The finding that immunometabolism could be a master regulator of inflammation broadens the avenue for treating inflammation‐related pathologies through the manipulation of the vascular and immune cell metabolism.
Keywords	beta oxidation ; energy ; epigenetics ; glycolysis ; inflammation ; lactic acid ; macrophages ; metabolites ; neuroglia ; phenotype ; tricarboxylic acid cycle
Language	English
Dates of publication	2020-08
Size	p. 3350-3369.
Publishing place	John Wiley & Sons, Ltd
Document type	Article
Note	NAL-AP-2-clean ; REVIEW
ZDB-ID	2173655-8
ISSN	1742-4658 ; 1742-464X
ISSN (online)	1742-4658
ISSN	1742-464X
DOI	10.1111/febs.15327
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Interorganelle Communication between Mitochondria and the Endolysosomal System

Gonzalo Soto-Heredero / Francesc Baixauli / María Mittelbrunn

Frontiers in Cell and Developmental Biology, Vol

2017 Volume 5

Abstract	The function of mitochondria and lysosomes has classically been studied separately. However, evidence has now emerged of intense crosstalk between these two organelles, such that the activity or stress status of one organelle may affect the other. Direct physical contacts between mitochondria and the endolysosomal compartment have been reported as a rapid means of interorganelle communication, mediating lipid or other metabolite exchange. Moreover, mitochondrial derived vesicles can traffic obsolete mitochondrial proteins into the endolysosomal system for their degradation or secretion to the extracellular milieu as exosomes, representing an additional mitochondrial quality control mechanism that connects mitochondria and lysosomes independently of autophagosome formation. Here, we present what is currently known about the functional and physical communication between mitochondria and lysosomes or lysosome-related organelles, and their role in sustaining cellular homeostasis.
Keywords	lysosome ; exosomes ; autophagy ; quality control ; proteostasis ; aging ; Biology (General) ; QH301-705.5
Language	English
Publishing date	2017-11-01T00:00:00Z
Publisher	Frontiers Media S.A.
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Glycolysis - a key player in the inflammatory response.

Soto-Heredero, Gonzalo / Gómez de Las Heras, Manuel M / Gabandé-Rodríguez, Enrique / Oller, Jorge / Mittelbrunn, María

The FEBS journal

2020 Volume 287, Issue 16, Page(s) 3350–3369

Abstract: The inflammatory response involves the activation of several cell types to fight insults caused by a plethora of agents, and to maintain the tissue homoeostasis. On the one hand, cells involved in the pro-inflammatory response, such as inflammatory M1 ... ...

Abstract	The inflammatory response involves the activation of several cell types to fight insults caused by a plethora of agents, and to maintain the tissue homoeostasis. On the one hand, cells involved in the pro-inflammatory response, such as inflammatory M1 macrophages, Th1 and Th17 lymphocytes or activated microglia, must rapidly provide energy to fuel inflammation, which is essentially accomplished by glycolysis and high lactate production. On the other hand, regulatory T cells or M2 macrophages, which are involved in immune regulation and resolution of inflammation, preferentially use fatty acid oxidation through the TCA cycle as a main source for energy production. Here, we discuss the impact of glycolytic metabolism at the different steps of the inflammatory response. Finally, we review a wide variety of molecular mechanisms which could explain the relationship between glycolytic metabolites and the pro-inflammatory phenotype, including signalling events, epigenetic remodelling, post-transcriptional regulation and post-translational modifications. Inflammatory processes are a common feature of many age-associated diseases, such as cardiovascular and neurodegenerative disorders. The finding that immunometabolism could be a master regulator of inflammation broadens the avenue for treating inflammation-related pathologies through the manipulation of the vascular and immune cell metabolism.
MeSH term(s)	Animals ; Citric Acid Cycle/immunology ; Glycolysis/immunology ; Humans ; Inflammation/immunology ; Inflammation/metabolism ; Macrophage Activation/immunology ; Macrophages/classification ; Macrophages/immunology ; Macrophages/metabolism ; Neurodegenerative Diseases/immunology ; Neurodegenerative Diseases/metabolism ; T-Lymphocytes, Helper-Inducer/immunology ; T-Lymphocytes, Helper-Inducer/metabolism ; T-Lymphocytes, Regulatory/immunology ; T-Lymphocytes, Regulatory/metabolism
Language	English
Publishing date	2020-04-27
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2173655-8
ISSN	1742-4658 ; 1742-464X
ISSN (online)	1742-4658
ISSN	1742-464X
DOI	10.1111/febs.15327
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Article ; Online: T cells with dysfunctional mitochondria induce multimorbidity and premature senescence.

Desdín-Micó, Gabriela / Soto-Heredero, Gonzalo / Aranda, Juan Francisco / Oller, Jorge / Carrasco, Elisa / Gabandé-Rodríguez, Enrique / Blanco, Eva Maria / Alfranca, Arantzazu / Cussó, Lorena / Desco, Manuel / Ibañez, Borja / Gortazar, Arancha R / Fernández-Marcos, Pablo / Navarro, Maria N / Hernaez, Bruno / Alcamí, Antonio / Baixauli, Francesc / Mittelbrunn, María

Science (New York, N.Y.)

2020 Volume 368, Issue 6497, Page(s) 1371–1376

Abstract: The effect of immunometabolism on age-associated diseases remains uncertain. In this work, we show that T cells with dysfunctional mitochondria owing to mitochondrial transcription factor A (TFAM) deficiency act as accelerators of senescence. In mice, ... ...

Abstract	The effect of immunometabolism on age-associated diseases remains uncertain. In this work, we show that T cells with dysfunctional mitochondria owing to mitochondrial transcription factor A (TFAM) deficiency act as accelerators of senescence. In mice, these cells instigate multiple aging-related features, including metabolic, cognitive, physical, and cardiovascular alterations, which together result in premature death. T cell metabolic failure induces the accumulation of circulating cytokines, which resembles the chronic inflammation that is characteristic of aging ("inflammaging"). This cytokine storm itself acts as a systemic inducer of senescence. Blocking tumor necrosis factor-α signaling or preventing senescence with nicotinamide adenine dinucleotide precursors partially rescues premature aging in mice with
MeSH term(s)	Aging, Premature/genetics ; Aging, Premature/immunology ; Aging, Premature/prevention & control ; Animals ; Cytokine Release Syndrome/immunology ; DNA-Binding Proteins/deficiency ; DNA-Binding Proteins/genetics ; Female ; Gene Deletion ; Inflammation/genetics ; Inflammation/immunology ; Longevity ; Male ; Mice ; Mice, Mutant Strains ; Mitochondria/metabolism ; Mitochondrial Proteins/deficiency ; Mitochondrial Proteins/genetics ; Multimorbidity ; NAD/administration & dosage ; NAD/pharmacology ; Physical Fitness ; T-Lymphocytes/metabolism ; T-Lymphocytes/ultrastructure ; Transcription Factors/deficiency ; Transcription Factors/genetics ; Tumor Necrosis Factor-alpha/antagonists & inhibitors
Chemical Substances	DNA-Binding Proteins ; Mitochondrial Proteins ; Transcription Factors ; Tumor Necrosis Factor-alpha ; mitochondrial transcription factor A ; NAD (0U46U6E8UK)
Language	English
Publishing date	2020-05-21
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	128410-1
ISSN	1095-9203 ; 0036-8075
ISSN (online)	1095-9203
ISSN	0036-8075
DOI	10.1126/science.aax0860
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