Cell Type-Specific Transcriptomics Reveals that Mutant Huntingtin Leads to Mitochondrial RNA Release and Neuronal Innate Immune Activation

Lee, Hyeseung; Fenster, Robert J.; Pineda, Sergio Sebastian; Gibbs, Whitney S.; Mohammadi, Shahin; Dávila-Velderrain, José; García, Francisco J.; Therrien, Martine; Novis, Hailey S.; Gao, Fan; Wilkinson, Hilary A.; Vogt, Thomas; Kellis, M; LaVoie, Matthew J.; Heiman, Myriam

doi:10.1016/j.neuron.2020.06.021

Cited by 187 publications

(262 citation statements)

References 98 publications

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“…In line with this, they provide stress mediators initiating cell death and autophagy, present adaptor molecules required for the transduction of cellular innate immune signals [ 2 , 3 ], and release mitochondrial components (e.g., mitochondrial DNA, mitochondrial RNA, cytochrome c, reactive oxygen species (ROS)) into the cytosol as danger signals [ 4 ] ( Figure 1 ). Mitochondrial DNA and RNA may activate intracellular sensors sensing pathogenic DNA and RNA (e.g., the retinoic-acid-inducible gene (RIG)-I-like proteins, protein kinase R (PKR), the stimulator of interferon genes (STING), mitochondrial antiviral signaling protein (MAVS), cyclic guanine monophosphate (GMP)—adenosine monophosphate (AMP) synthase [cGAS] and interferon-γ-inducible protein 16 (IFI16)) to detect intracellular pathogens [ 2 , 3 , 8 , 9 , 10 , 11 , 12 , 13 ]. Studies have found that mitochondrial DNA leaking from dysfunctioning or disrupted mitochondria directly activates STING providing a direct potential link between mitochondrial disease and inflammatory response [ 3 , 14 , 15 ].…”

Section: Introductionmentioning

confidence: 99%

Tricarboxylic Acid (TCA) Cycle Intermediates: Regulators of Immune Responses

Choi

Son

Baek

2021

Life

120

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The tricarboxylic acid cycle (TCA) is a series of chemical reactions used in aerobic organisms to generate energy via the oxidation of acetylcoenzyme A (CoA) derived from carbohydrates, fatty acids and proteins. In the eukaryotic system, the TCA cycle occurs completely in mitochondria, while the intermediates of the TCA cycle are retained inside mitochondria due to their polarity and hydrophilicity. Under cell stress conditions, mitochondria can become disrupted and release their contents, which act as danger signals in the cytosol. Of note, the TCA cycle intermediates may also leak from dysfunctioning mitochondria and regulate cellular processes. Increasing evidence shows that the metabolites of the TCA cycle are substantially involved in the regulation of immune responses. In this review, we aimed to provide a comprehensive systematic overview of the molecular mechanisms of each TCA cycle intermediate that may play key roles in regulating cellular immunity in cell stress and discuss its implication for immune activation and suppression.

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Section: Introductionmentioning

confidence: 99%

Tricarboxylic Acid (TCA) Cycle Intermediates: Regulators of Immune Responses

Choi

Son

Baek

2021

Life

120

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“…Pathological processes like oxidative stress or transcriptional dysregulation in HD cause immune system activation and inflammation in central and peripheral tissues [ 2 ]. In a recent report, Lee and colleagues [ 200 ] observed the release of mitochondrial RNA (mtRNA) specifically from striatal spiny projection neurons in HD patients and mouse models of HD. Cytoplasmic mtRNA induces strong innate immune responses [ 201 ].…”

Section: Conditioning Benefits On Mitochondrial Dysfunctions Oxidmentioning

confidence: 99%

“…Cytoplasmic mtRNA induces strong innate immune responses [ 201 ]. In the transcriptomics study of Lee and colleagues [ 200 ], components of the neurotrophin pathway were upregulated and elements of oxidative phosphorylation were downregulated in HD spiny projection neurons (of the striatopallidal “indirect pathway”) as a result.…”

Section: Conditioning Benefits On Mitochondrial Dysfunctions Oxidmentioning

confidence: 99%

A Rationale for Hypoxic and Chemical Conditioning in Huntington’s Disease

Burtscher

Maglione

Pardo

et al. 2021

IJMS

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Neurodegenerative diseases are characterized by adverse cellular environments and pathological alterations causing neurodegeneration in distinct brain regions. This development is triggered or facilitated by conditions such as hypoxia, ischemia or inflammation and is associated with disruptions of fundamental cellular functions, including metabolic and ion homeostasis. Targeting intracellular downstream consequences to specifically reverse these pathological changes proved difficult to translate to clinical settings. Here, we discuss the potential of more holistic approaches with the purpose to re-establish a healthy cellular environment and to promote cellular resilience. We review the involvement of important molecular pathways (e.g., the sphingosine, δ-opioid receptor or N-Methyl-D-aspartate (NMDA) receptor pathways) in neuroprotective hypoxic conditioning effects and how these pathways can be targeted for chemical conditioning. Despite the present scarcity of knowledge on the efficacy of such approaches in neurodegeneration, the specific characteristics of Huntington’s disease may make it particularly amenable for such conditioning techniques. Not only do classical features of neurodegenerative diseases like mitochondrial dysfunction, oxidative stress and inflammation support this assumption, but also specific Huntington’s disease characteristics: a relatively young age of neurodegeneration, molecular overlap of related pathologies with hypoxic adaptations and sensitivity to brain hypoxia. The aim of this review is to discuss several molecular pathways in relation to hypoxic adaptations that have potential as drug targets in neurodegenerative diseases. We will extract the relevance for Huntington’s disease from this knowledge base.

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“…Indeed, mitochondria provide stress mediators initiating cell death and autophagy, present adaptor molecules required for the transduction of cellular innate immune signals [2,3], and release mitochondrial components (e.g., mitochondrial DNA, mitochondrial RNA, cytochrome c, reactive oxygen species [ROS]) into the cytosol as danger signals [4] (Figure 1). Mitochondrial DNA and RNA may activate intracellular sensors sensing pathogenic DNA and RNA (e.g., the retinoic-acid-inducible gene [RIG]-I-like proteins, protein kinase R [PKR], the stimulator of interferon genes [STING], mitochondrial antiviral signaling protein [MAVS], cyclic GMP-AMP synthase [cGAS] and interferon-γinducible protein 16 [IFI16]) to detect intracellular pathogens [2,3,[8][9][10][11][12][13]. Researchers have demonstrated that mitochondrial DNA leaking from dysfunctioning or disrupted mitochondria directly activates STING providing a direct potential link between mitochondrial disease and inflammatory response [3,14,15].…”

Section: Introductionmentioning

confidence: 99%

“…Researchers have demonstrated that mitochondrial DNA leaking from dysfunctioning or disrupted mitochondria directly activates STING providing a direct potential link between mitochondrial disease and inflammatory response [3,14,15]. A more recent study showed that, under pathologic conditions, mitochondrial RNA is released from dysfunctioning mitochondria, in turn, triggering immune activation [13]. Under conditions of cell stress, mitochondria release cytochrome c and ROS inducing apoptosis and cell and tissue destruction [4].…”

Section: Introductionmentioning

confidence: 99%

Tricarboxylic Acid (TCA) Cycle Intermediates: Regulators of Immune Responses

Choi¹,

Son²,

Baek³

2020

Preprint

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Tricarboxylic acid cycle (TCA) is a series of chemical reactions in aerobic organisms used to generate energy via the oxidation of acetyl-CoA derived from carbohydrates, fatty acids, and proteins. In the eukaryotic system, the TCA cycle completely occurs in mitochondria, while the intermediates of the TCA cycle are retained in mitochondria due to their polarity and hydrophilicity. Under conditions of cell stress, mitochondria become disrupted and release their contents, which act as danger signals in the cytosol. Of note, the TCA cycle intermediates may also leak from dysfunctioning mitochondria and regulate cellular processes. Increasing evidence shows that the metabolites of the TCA cycle are substantially involved in the regulation of immune responses. In this review, we aimed to provide a comprehensive systematic overview of the molecular mechanisms of each TCA cycle intermediate that may play key roles in regulating cellular immunity in cell stress and discuss their implications for immune activation and suppression.

show abstract

Cell Type-Specific Transcriptomics Reveals that Mutant Huntingtin Leads to Mitochondrial RNA Release and Neuronal Innate Immune Activation

Cited by 187 publications

References 98 publications

Tricarboxylic Acid (TCA) Cycle Intermediates: Regulators of Immune Responses

Tricarboxylic Acid (TCA) Cycle Intermediates: Regulators of Immune Responses

A Rationale for Hypoxic and Chemical Conditioning in Huntington’s Disease

Tricarboxylic Acid (TCA) Cycle Intermediates: Regulators of Immune Responses

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