Mitochondrial <scp>RNA</scp>, a new trigger of the innate immune system

Grochowska, Joanna; Czerwińska, Jolanta; Borowski, Lukasz S.; Szczęsny, Roman J.

doi:10.1002/wrna.1690

Cited by 15 publications

(10 citation statements)

References 148 publications

(206 reference statements)

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“…Mitophagy is an essential way that tumor cells rely on to deal with the damaged mitochondria and protect themselves from chemotherapy-induced cell death 37 . Recently, mitochondrial DNA (mtDNA) and RNA (mtRNA) released during mitophagy have been characterized as novel triggers of tumor-intrinsic immune response 38 , 39 . Of note, our shift ability analysis revealed multiple MEK inhibitors, such as selumetinib and PD-0325901 can induce dramatic R-to-S shifting in melanoma, lung adenocarcinoma, colorectal cancer, and breast cancer cell lines ( Supplementary Table 6 ).…”

Section: Resultsmentioning

confidence: 99%

Systematic investigation of chemo-immunotherapy synergism to shift anti-PD-1 resistance in cancer

Yang,

Wang,

Pattarayan

et al. 2023

Preprint

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Chemo-immunotherapy combinations have been regarded as one of the most practical ways to improve immunotherapy response in cancer patients. In this study, we integrated the transcriptomics data from immunotherapy-treated tumors and compound-treated cell lines to systematically identify chemo-immunotherapy synergisms and their underlying mechanisms. Through analyzing anti-PD-1 treatment induced expression changes in patient tumors, we developed a shift ability score that can measure whether a chemotherapy treatment shifts anti-PD-1 response. By applying the shift ability analysis on 41,321 compounds and 16,853 shRNA treated cancer cell line expression profiles, we characterized a systematic landscape of chemo-immunotherapy synergism and prioritized 17 potential synergy targets. Further investigation of the treatment induced transcriptomic data revealed that a mitophagy-dsRNA-MAVS-dependent activation of type I IFN signaling may be a novel mechanism for chemo-immunotherapy synergism. Our study represents the first comprehensive effort to mechanistically characterize chemo-immunotherapy synergism and will facilitate future pre-clinical and clinical studies.

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Section: Resultsmentioning

confidence: 99%

Systematic investigation of chemo-immunotherapy synergism to shift anti-PD-1 resistance in cancer

Yang,

Wang,

Pattarayan

et al. 2023

Preprint

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“…mt-dsRNA is a critical mt-DAMP, and under some pathophysiological conditions, mt-dsRNA released to the cytoplasm is implicated in triggering innate immune responses [ 32 ] and eliciting the pro-inflammatory activity of KC in an alcoholic liver disease model [ 25 ]. The released mt-dsRNA moves from hepatocyte to KC and triggers pro-inflammatory signaling in a TLR3-dependent manner [ 25 ].…”

Section: Discussionmentioning

confidence: 99%

Heat Shock Protein 60 Restricts Release of Mitochondrial dsRNA to Suppress Hepatic Inflammation and Ameliorate Non-Alcoholic Fatty Liver Disease in Mice

Huang

Wang

et al. 2022

IJMS

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Non-alcoholic fatty liver disease (NAFLD), the most common cause of chronic liver disease, consists of fat deposited (steatosis) in the liver due to causes besides excessive alcohol use. The folding activity of heat shock protein 60 (HSP60) has been shown to protect mitochondria from proteotoxicity under various types of stress. In this study, we investigated whether HSP60 could ameliorate experimental high-fat diet (HFD)-induced obesity and hepatitis and explored the potential mechanism in mice. The results uncovered that HSP60 gain not only alleviated HFD-induced body weight gain, fat accumulation, and hepatocellular steatosis, but also glucose tolerance and insulin resistance according to intraperitoneal glucose tolerance testing and insulin tolerance testing in HSP60 transgenic (HSP60Tg) compared to wild-type (WT) mice by HFD. Furthermore, overexpression of HSP60 in the HFD group resulted in inhibited release of mitochondrial dsRNA (mt-dsRNA) compared to WT mice. In addition, overexpression of HSP60 also inhibited the activation of toll-like receptor 3 (TLR3), melanoma differentiation-associated gene 5 (MDA5), and phosphorylated-interferon regulatory factor 3 (p-IRF3), as well as inflammatory biomarkers such as mRNA of il-1β and il-6 expression in the liver in response to HFD. The in vitro study also confirmed that the addition of HSP-60 mimics in HepG2 cells led to upregulated expression level of HSP60 and restricted release of mt-dsRNA, as well as downregulated expression levels of TLR3, MDA5, and pIRF3. This study provides novel insight into a hepatoprotective effect, whereby HSP60 inhibits the release of dsRNA to repress the TLR3/MDA5/pIRF3 pathway in the context of NAFLD or hepatic inflammation. Therefore, HSP60 may serve as a possible therapeutic target for improving NAFLD.

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“…We assessed the performance of our mtDNAcn assay by three-way comparison to the commercial assay and lpWGS results obtained from three samples using DNA (2ng/replicate) obtained from a subset of the same buccal swab specimens from the Your Baby study. We were only able to perform this 3-way comparison on this subset of samples due to (1) limited amounts of DNA remaining and (2) limited quantities of the commercial assay.…”

Section: Methodsmentioning

confidence: 99%

A method for measuring mitochondrial DNA copy number in pediatric populations

Maggo,

North,

Ozuna

et al. 2024

Preprint

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The mitochondrion is a multifunctional organelle that modulates multiple systems critical for homeostasis during pathophysiological stress. Variation in mitochondrial DNA (mtDNA) copy number (mtDNAcn), a key mitochondrial change associated with chronic stress, is an emerging biomarker for disease pathology and progression. mtDNAcn can be quantified from whole blood samples using qPCR to determine the ratio of nuclear DNA to mtDNA. However, the collection of blood samples in pediatric populations, particularly in infants and young children, can be technically challenging, yield much smaller volume samples, and can be distressing for the patients and their caregivers. Therefore, we have validated a mtDNAcn assay utilizing DNA from simple buccal swabs (Isohelix SK-2S) and report here it’s performance in specimens from infants (age = <12 months). Utilizing qPCR to amplify ∼200bp regions from two mitochondrial (ND1, ND6) and two nuclear (BECN1, NEB) genes, we demonstrated absolute (100%) concordance with results from low-pass whole genome sequencing (lpWGS). We believe that this method overcomes key obstacles to measuring mtDNAcn in pediatric populations and creates the possibility for development of clinical assays to measure mitochondrial change during pathophysiological stress.

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Mitochondrial RNA, a new trigger of the innate immune system

Cited by 15 publications

References 148 publications

Systematic investigation of chemo-immunotherapy synergism to shift anti-PD-1 resistance in cancer

Systematic investigation of chemo-immunotherapy synergism to shift anti-PD-1 resistance in cancer

Heat Shock Protein 60 Restricts Release of Mitochondrial dsRNA to Suppress Hepatic Inflammation and Ameliorate Non-Alcoholic Fatty Liver Disease in Mice

A method for measuring mitochondrial DNA copy number in pediatric populations

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