Mitochondria as intracellular signaling platforms in health and disease

Jay X. Tan; Toren Finkel

doi:10.1083/jcb.202002179

Mitochondria as intracellular signaling platforms in health and disease

The Journal of Cell Biology ◽

10.1083/jcb.202002179 ◽

2020 ◽

Vol 219 (5) ◽

Cited By ~ 5

Author(s):

Jay X. Tan ◽

Toren Finkel

Keyword(s):

Cell Fate ◽

Intracellular Signaling ◽

Redox Homeostasis ◽

Innate Immune ◽

Signaling Cascades ◽

Cell Fate Determination ◽

Age Related ◽

Mitochondrial Signaling ◽

Health And Disease ◽

Multiple Signaling

Mitochondria, long viewed solely in the context of bioenergetics, are increasingly emerging as critical hubs for intracellular signaling. Due to their bacterial origin, mitochondria possess their own genome and carry unique lipid components that endow these organelles with specialized properties to help orchestrate multiple signaling cascades. Mitochondrial signaling modulates diverse pathways ranging from metabolism to redox homeostasis to cell fate determination. Here, we review recent progress in our understanding of how mitochondria serve as intracellular signaling platforms with a particular emphasis on lipid-mediated signaling, innate immune activation, and retrograde signaling. We further discuss how these signaling properties might potentially be exploited to develop new therapeutic strategies for a range of age-related conditions.

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Signals Getting Crossed in the Entanglement of Redox and Phosphorylation Pathways: Phosphorylation of Peroxiredoxin Proteins Sparks Cell Signaling

Antioxidants ◽

10.3390/antiox8020029 ◽

2019 ◽

Vol 8 (2) ◽

pp. 29 ◽

Cited By ~ 6

Author(s):

John Skoko ◽

Shireen Attaran ◽

Carola Neumann

Keyword(s):

Cell Signaling ◽

Cell Fate ◽

Intracellular Signaling ◽

Redox Homeostasis ◽

Three Dimensional ◽

Cysteine Residue ◽

Signaling Cascades ◽

Dimensional Structure ◽

Post Translational Modification ◽

Downstream Signaling

Reactive oxygen and nitrogen species have cell signaling properties and are involved in a multitude of processes beyond redox homeostasis. The peroxiredoxin (Prdx) proteins are highly sensitive intracellular peroxidases that can coordinate cell signaling via direct reactive species scavenging or by acting as a redox sensor that enables control of binding partner activity. Oxidation of the peroxidatic cysteine residue of Prdx proteins are the classical post-translational modification that has been recognized to modulate downstream signaling cascades, but increasing evidence supports that dynamic changes to phosphorylation of Prdx proteins is also an important determinant in redox signaling. Phosphorylation of Prdx proteins affects three-dimensional structure and function to coordinate cell proliferation, wound healing, cell fate and lipid signaling. The advent of large proteomic datasets has shown that there are many opportunities to understand further how phosphorylation of Prdx proteins fit into intracellular signaling cascades in normal or malignant cells and that more research is necessary. This review summarizes the Prdx family of proteins and details how post-translational modification by kinases and phosphatases controls intracellular signaling.

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Carotenoid metabolism in mitochondrial function

Food Quality and Safety ◽

10.1093/fqsafe/fyaa023 ◽

2020 ◽

Vol 4 (3) ◽

pp. 115-122

Author(s):

Peiran Lu ◽

Siau Yen Wong ◽

Lei Wu ◽

Dingbo Lin

Keyword(s):

Human Health ◽

Cell Fate ◽

Mitochondrial Function ◽

Redox Homeostasis ◽

Future Research ◽

Mitochondrial Structure ◽

Carotenoid Metabolism ◽

Health And Disease ◽

Eukaryotic Organisms ◽

And Function

Abstract Mitochondria are highly dynamic organelles that are found in most eukaryotic organisms. It is broadly accepted that mitochondria originally evolved from prokaryotic bacteria, e.g. proteobacteria. The mitochondrion has its independent genome that encodes 37 genes, including 13 genes for oxidative phosphorylation. Accumulative evidence demonstrates that mitochondria are not only the powerhouse of the cells by supplying adenosine triphosphate, but also exert roles as signalling organelles in the cell fate and function. Numerous factors can affect mitochondria structurally and functionally. Carotenoids are a large group of fat-soluble pigments commonly found in our diets. Recently, much attention has been paid in carotenoids as dietary bioactives in mitochondrial structure and function in human health and disease, though the mechanistic research is limited. Here, we update the recent progress in mitochondrial functioning as signalling organelles in human health and disease, summarize the potential roles of carotenoids in regulation of mitochondrial redox homeostasis, biogenesis, and mitophagy, and discuss the possible approaches for future research in carotenoid regulation of mitochondrial function.

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TOX Provides a Link Between Calcineurin Activation and CD8 Lineage Commitment

Journal of Experimental Medicine ◽

10.1084/jem.20040051 ◽

2004 ◽

Vol 199 (8) ◽

pp. 1089-1099 ◽

Cited By ~ 48

Author(s):

Parinaz Aliahmad ◽

Emmett O'Flaherty ◽

Peggy Han ◽

Olivia D. Goularte ◽

Beverley Wilkinson ◽

...

Keyword(s):

T Cell ◽

Positive Selection ◽

Cell Fate ◽

Cell Receptor ◽

Signaling Cascades ◽

Double Positive ◽

Nuclear Factors ◽

Nuclear Changes ◽

Thymocyte Differentiation ◽

Multiple Signaling

T cell development is dependent on the integration of multiple signaling pathways, although few links between signaling cascades and downstream nuclear factors that play a role in thymocyte differentiation have been identified. We show here that expression of the HMG box protein TOX is sufficient to induce changes in coreceptor gene expression associated with β-selection, including CD8 gene demethylation. TOX expression is also sufficient to initiate positive selection to the CD8 lineage in the absence of MHC–TCR interactions. TOX-mediated positive selection is associated with up-regulation of Runx3, implicating CD4 silencing in the process. Interestingly, a strong T cell receptor–mediated signal can modify this cell fate. We further demonstrate that up-regulation of TOX in double positive thymocytes is calcineurin dependent, linking this critical signaling pathway to nuclear changes during positive selection.

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TAK1 kinase switches cell fate from apoptosis to necrosis following TNF stimulation

The Journal of Cell Biology ◽

10.1083/jcb.201305070 ◽

2014 ◽

Vol 204 (4) ◽

pp. 607-623 ◽

Cited By ~ 60

Author(s):

Sho Morioka ◽

Peter Broglie ◽

Emily Omori ◽

Yuka Ikeda ◽

Giichi Takaesu ◽

...

Keyword(s):

Cell Fate ◽

Intracellular Signaling ◽

Signaling Cascades ◽

Caspase 8 ◽

Interacting Protein ◽

Cellular Context ◽

Biological Event ◽

Apoptosis And Necrosis

TNF activates three distinct intracellular signaling cascades leading to cell survival, caspase-8–mediated apoptosis, or receptor interacting protein kinase 3 (RIPK3)–dependent necrosis, also called necroptosis. Depending on the cellular context, one of these pathways is activated upon TNF challenge. When caspase-8 is activated, it drives the apoptosis cascade and blocks RIPK3-dependent necrosis. Here we report the biological event switching to activate necrosis over apoptosis. TAK1 kinase is normally transiently activated upon TNF stimulation. We found that prolonged and hyperactivation of TAK1 induced phosphorylation and activation of RIPK3, leading to necrosis without caspase activation. In addition, we also demonstrated that activation of RIPK1 and RIPK3 promoted TAK1 activation, suggesting a positive feedforward loop of RIPK1, RIPK3, and TAK1. Conversely, ablation of TAK1 caused caspase-dependent apoptosis, in which Ripk3 deletion did not block cell death either in vivo or in vitro. Our results reveal that TAK1 activation drives RIPK3-dependent necrosis and inhibits apoptosis. TAK1 acts as a switch between apoptosis and necrosis.

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Absence of Mal/TIRAP Results in Abrogated Imidazoquinolinones-Dependent Activation of IRF7 and Suppressed IFNβ and IFN-I Activated Gene Production

International Journal of Molecular Sciences ◽

10.3390/ijms21238925 ◽

2020 ◽

Vol 21 (23) ◽

pp. 8925

Author(s):

Ewa Leszczyńska ◽

Edyta Makuch ◽

Małgorzata Mitkiewicz ◽

Izabella Jasyk ◽

Miwako Narita ◽

...

Keyword(s):

Immune Response ◽

Transcription Factor ◽

Intracellular Signaling ◽

Innate Immune ◽

Signaling Cascades ◽

Signaling Cascade ◽

Type I ◽

Type I Ifns ◽

Activation Of Transcription ◽

Intracellular Signaling Molecules

Activation of TLR7 by small imidazoquinoline molecules such as R848 or R837 initiates signaling cascades leading to the activation of transcription factors, such as AP-1, NF-κB, and interferon regulatory factors (IRFs) and afterward to the induction of cytokines and anti-viral Type I IFNs. In general, TLRs mediate these effects by utilizing different intracellular signaling molecules, one of them is Mal. Mal is a protein closely related to the antibacterial response, and its role in the TLR7 pathways remains poorly understood. In this study, we show that Mal determines the expression and secretion of IFNβ following activation of TLR7, a receptor that recognizes ssRNA and imidazoquinolines. Moreover, we observed that R848 induces Mal-dependent IFNβ production via ERK1/2 activation as well as the transcription factor IRF7 activation. Although activation of TLR7 leads to NF-κB-dependent expression of IRF7, this process is independent of Mal. We also demonstrate that secretion of IFNβ regulated by TLR7 and Mal in macrophages and dendritic cells leads to the IP-10 chemokine expression. In conclusion, our data demonstrate that Mal is a critical regulator of the imidazoquinolinones-dependent IFNβ production via ERK1/2/IRF7 signaling cascade which brings us closer to understanding the molecular mechanism’s regulation of innate immune response.

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Mitochondrial Oxidative Stress and “Mito-Inflammation”: Actors in the Diseases

Biomedicines ◽

10.3390/biomedicines9020216 ◽

2021 ◽

Vol 9 (2) ◽

pp. 216

Author(s):

Simone Patergnani ◽

Esmaa Bouhamida ◽

Sara Leo ◽

Paolo Pinton ◽

Alessandro Rimessi

Keyword(s):

Redox Homeostasis ◽

Innate Immune ◽

Signaling Cascades ◽

Oxygen Species ◽

Mitochondrial Oxidative Stress ◽

Beneficial Effects ◽

Innate Immune Signaling ◽

Mitochondrial Ros ◽

Wide Range ◽

Key Aspects

A decline in mitochondrial redox homeostasis has been associated with the development of a wide range of inflammatory-related diseases. Continue discoveries demonstrate that mitochondria are pivotal elements to trigger inflammation and stimulate innate immune signaling cascades to intensify the inflammatory response at front of different stimuli. Here, we review the evidence that an exacerbation in the levels of mitochondrial-derived reactive oxygen species (ROS) contribute to mito-inflammation, a new concept that identifies the compartmentalization of the inflammatory process, in which the mitochondrion acts as central regulator, checkpoint, and arbitrator. In particular, we discuss how ROS contribute to specific aspects of mito-inflammation in different inflammatory-related diseases, such as neurodegenerative disorders, cancer, pulmonary diseases, diabetes, and cardiovascular diseases. Taken together, these observations indicate that mitochondrial ROS influence and regulate a number of key aspects of mito-inflammation and that strategies directed to reduce or neutralize mitochondrial ROS levels might have broad beneficial effects on inflammatory-related diseases.

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Metabolite Transporters as Regulators of Immunity

Metabolites ◽

10.3390/metabo10100418 ◽

2020 ◽

Vol 10 (10) ◽

pp. 418

Author(s):

Hauke J. Weiss ◽

Stefano Angiari

Keyword(s):

Intracellular Signaling ◽

Cell Function ◽

Immune Cell ◽

Innate Immune ◽

Signaling Cascades ◽

Effector Functions ◽

Immunological Responses ◽

The Face ◽

Specific Receptors

In the past decade, the rise of immunometabolism has fundamentally reshaped the face of immunology. As the functions and properties of many (immuno)metabolites have now been well described, their exchange among cells and their environment have only recently sparked the interest of immunologists. While many metabolites bind specific receptors to induce signaling cascades, some are actively exchanged between cells to communicate, or induce metabolic reprograming. In this review, we give an overview about how active metabolite transport impacts immune cell function and shapes immunological responses. We present some examples of how specific transporters feed into metabolic pathways and initiate intracellular signaling events in immune cells. In particular, we focus on the role of metabolite transporters in the activation and effector functions of T cells and macrophages, as prototype adaptive and innate immune cell populations.

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Extracellular matrix: the gatekeeper of tumor angiogenesis

Biochemical Society Transactions ◽

10.1042/bst20190653 ◽

2019 ◽

Vol 47 (5) ◽

pp. 1543-1555 ◽

Cited By ~ 10

Author(s):

Maurizio Mongiat ◽

Simone Buraschi ◽

Eva Andreuzzi ◽

Thomas Neill ◽

Renato V. Iozzo

Keyword(s):

Extracellular Matrix ◽

Tumor Angiogenesis ◽

Signaling Cascades ◽

Cancer Growth ◽

Cell Behavior ◽

Metastatic Progression ◽

Surface Receptors ◽

The Matrix ◽

Multiple Signaling

Abstract The extracellular matrix is a network of secreted macromolecules that provides a harmonious meshwork for the growth and homeostatic development of organisms. It conveys multiple signaling cascades affecting specific surface receptors that impact cell behavior. During cancer growth, this bioactive meshwork is remodeled and enriched in newly formed blood vessels, which provide nutrients and oxygen to the growing tumor cells. Remodeling of the tumor microenvironment leads to the formation of bioactive fragments that may have a distinct function from their parent molecules, and the balance among these factors directly influence cell viability and metastatic progression. Indeed, the matrix acts as a gatekeeper by regulating the access of cancer cells to nutrients. Here, we will critically evaluate the role of selected matrix constituents in regulating tumor angiogenesis and provide up-to-date information concerning their primary mechanisms of action.

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