Oxidized DNA fragments exit mitochondria via mPTP- and VDAC-dependent channels to activate NLRP3 inflammasome and interferon signaling

Xian, Hongxu; Watari, Kosuke; Sánchez-López, Elsa; Offenberger, Joseph; Onyuru, Janset; Sampath, Harini; Wang, Ying; Hoffman, Hal M.; Shadel, Gerald S.; Karin, Michael

doi:10.1016/j.immuni.2022.06.007

Cited by 309 publications

(204 citation statements)

References 74 publications

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“…Additionally, other sensors represented by cGAS and AIM2 can directly recognize mtDNA with their specific DNA‐binding domain and activate IFN‐relative pathways (Kim et al , 2019; Yu et al , 2020) and AIM2‐inflammasomes (Wang et al , 2021), respectively. Recently, Xian et al (2022) found that upon the stimulations of NLRP3 activators, ox‐mtDNA reaches the cytosol via mPTP‐ and VDAC‐ dependent channels and activates NLRP3‐inflammasomes and cGAS‐STING pathways. However, the results from our laboratory (not shown) and other laboratories show the limitations of using 8‐OH‐dG to stain ox‐mtDNA.…”

Section: Discussionmentioning

confidence: 99%

Prohibitin 1 regulates mtDNA release and downstream inflammatory responses

Liu

Fan

et al. 2022

The EMBO Journal

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Exposure of mitochondrial DNA (mtDNA) to the cytosol activates innate immune responses. But the mechanisms by which mtDNA crosses the inner mitochondrial membrane are unknown. Here, we found that the inner mitochondrial membrane protein prohibitin 1 (PHB1) plays a critical role in mtDNA release by regulating permeability across the mitochondrial inner membrane. Loss of PHB1 results in alterations in mitochondrial integrity and function. PHB1deficient macrophages, serum from myeloid-specific PHB1 KO (Phb1MyeKO) mice, and peripheral blood mononuclear cells from neonatal sepsis patients show increased interleukin-1b (IL-1b) levels. PHB1 KO mice are also intolerant of lipopolysaccharide shock. Phb1-depleted macrophages show increased cytoplasmic release of mtDNA and inflammatory responses. This process is suppressed by cyclosporine A and VBIT-4, which inhibit the mitochondrial permeability transition pore (mPTP) and VDAC oligomerization. Inflammatory stresses downregulate PHB1 expression levels in macrophages. Under normal physiological conditions, the inner mitochondrial membrane proteins, AFG3L2 and SPG7, are tethered to PHB1 to inhibit mPTP opening. Downregulation of PHB1 results in enhanced interaction between AFG3L2 and SPG7, mPTP opening, mtDNA release, and downstream inflammatory responses.

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Section: Discussionmentioning

confidence: 99%

Prohibitin 1 regulates mtDNA release and downstream inflammatory responses

Liu

Fan

et al. 2022

The EMBO Journal

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“…The OGG1 inhibitor, TH5487, prevents TNF-α-induced OGG1 interactions with nuclear DNA to decrease NF-κB binding 62 . Oxidized mtDNA within mitochondria, if not readily repaired by OGG1, fragments and exits the organelle to initiate inflammation 63 . Nonetheless, allosteric activation by small molecules is favorable to drug discovery.…”

Section: Discussionmentioning

confidence: 99%

Small molecule-mediated allosteric activation of the base excision repair enzyme 8-oxoguanine DNA glycosylase and its impact on mitochondrial function

Tian

Katchur

Jiang

et al. 2022

Sci Rep

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Abstract8-Oxoguanine DNA glycosylase (OGG1) initiates base excision repair of the oxidative DNA damage product 8-oxoguanine. OGG1 is bifunctional; catalyzing glycosyl bond cleavage, followed by phosphodiester backbone incision via a β-elimination apurinic lyase reaction. The product from the glycosylase reaction, 8-oxoguanine, and its analogues, 8-bromoguanine and 8-aminoguanine, trigger the rate-limiting AP lyase reaction. The precise activation mechanism remains unclear. The product-assisted catalysis hypothesis suggests that 8-oxoguanine and analogues bind at the product recognition (PR) pocket to enhance strand cleavage as catalytic bases. Alternatively, they may allosterically activate OGG1 by binding outside of the PR pocket to induce an active-site conformational change to accelerate apurinic lyase. Herein, steady-state kinetic analyses demonstrated random binding of substrate and activator. 9-Deazaguanine, which can’t function as a substrate-competent base, activated OGG1, albeit with a lower Emax value than 8-bromoguanine and 8-aminoguanine. Random compound screening identified small molecules with Emax values similar to 8-bromoguanine. Paraquat-induced mitochondrial dysfunction was attenuated by several small molecule OGG1 activators; benefits included enhanced mitochondrial membrane and DNA integrity, less cytochrome c translocation, ATP preservation, and mitochondrial membrane dynamics. Our results support an allosteric mechanism of OGG1 and not product-assisted catalysis. OGG1 small molecule activators may improve mitochondrial function in oxidative stress-related diseases.

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“…Thus, linear double-strand mtDNA with a diameter of 2.3 nm appears to be threaded through the pore and released into the cytoplasm. Mitochondrial FEN1 nuclease has been shown to be activated by oxidative stress and to hydrolyze oxidized mtDNA into 500–650 base pair fragments released through the mPTP into the intermembrane space [ 91 ]. Mitochondrial outer membrane VDAC pores can also transport solutes such as double-strand DNA with a diameter less than 3 nm between the intermembrane space and the cytoplasm [ 92 ].…”

Section: Interventional Strategies To Correct Dysfunctional Mqc and D...mentioning

confidence: 99%

NADPH and Mitochondrial Quality Control as Targets for a Circadian-Based Fasting and Exercise Therapy for the Treatment of Parkinson’s Disease

Curtis

Seeds²,

Mattson

et al. 2022

Cells

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Dysfunctional mitochondrial quality control (MQC) is implicated in the pathogenesis of Parkinson’s disease (PD). The improper selection of mitochondria for mitophagy increases reactive oxygen species (ROS) levels and lowers ATP levels. The downstream effects include oxidative damage, failure to maintain proteostasis and ion gradients, and decreased NAD+ and NADPH levels, resulting in insufficient energy metabolism and neurotransmitter synthesis. A ketosis-based metabolic therapy that increases the levels of (R)-3-hydroxybutyrate (BHB) may reverse the dysfunctional MQC by partially replacing glucose as an energy source, by stimulating mitophagy, and by decreasing inflammation. Fasting can potentially raise cytoplasmic NADPH levels by increasing the mitochondrial export and cytoplasmic metabolism of ketone body-derived citrate that increases flux through isocitrate dehydrogenase 1 (IDH1). NADPH is an essential cofactor for nitric oxide synthase, and the nitric oxide synthesized can diffuse into the mitochondrial matrix and react with electron transport chain-synthesized superoxide to form peroxynitrite. Excessive superoxide and peroxynitrite production can cause the opening of the mitochondrial permeability transition pore (mPTP) to depolarize the mitochondria and activate PINK1-dependent mitophagy. Both fasting and exercise increase ketogenesis and increase the cellular NAD+/NADH ratio, both of which are beneficial for neuronal metabolism. In addition, both fasting and exercise engage the adaptive cellular stress response signaling pathways that protect neurons against the oxidative and proteotoxic stress implicated in PD. Here, we discuss how intermittent fasting from the evening meal through to the next-day lunch together with morning exercise, when circadian NAD+/NADH is most oxidized, circadian NADP+/NADPH is most reduced, and circadian mitophagy gene expression is high, may slow the progression of PD.

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Oxidized DNA fragments exit mitochondria via mPTP- and VDAC-dependent channels to activate NLRP3 inflammasome and interferon signaling

Cited by 309 publications

References 74 publications

Prohibitin 1 regulates mtDNA release and downstream inflammatory responses

Prohibitin 1 regulates mtDNA release and downstream inflammatory responses

Small molecule-mediated allosteric activation of the base excision repair enzyme 8-oxoguanine DNA glycosylase and its impact on mitochondrial function

NADPH and Mitochondrial Quality Control as Targets for a Circadian-Based Fasting and Exercise Therapy for the Treatment of Parkinson’s Disease

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