Sepsis-induced acute lung injury is associated with lung epithelial cell injury. This study analyzed the role of the antimicrobial peptide LL37 with mitochondrial DNA (LL37-mtDNA) and its potential mechanism of action in lipopolysaccharide (LPS)-treated rat type II alveolar epithelial cells (RLE-6TN cells). RLE-6TN cells were treated with LPS alone or with LL37-mtDNA, followed by transcriptome sequencing. Differentially expressed and pivotal genes were screened using bioinformatics tools. The effects of LL37-mtDNA on cell viability, inflammation, apoptosis, reactive oxygen species (ROS) production, and autophagy-related hallmark expression were evaluated in LPS-treated RLE-6TN cells. Additionally, the effects of Hsp90aa1 silencing following LL37-mtDNA treatment were investigated in vitro. LL37-mtDNA further suppressed cell viability, augmented apoptosis, promoted the release of inflammatory cytokines, increased ROS production, and elevated LC3B expression in LPS-treated RLE-6TN cells. Using transcriptome sequencing and bioinformatics, ten candidate genes were identified, of which three core genes were verified to be upregulated in the LPS + LL37-mtDNA group. Additionally, Hsp90aa1 downregulation attenuated the effects of LL37-mtDNA on LPS-treated RLE-6TN cells. Hsp90aa1 silencing possibly acted as a crucial target to counteract the effects of LL37-mtDNA on viability, apoptosis, inflammation, and autophagy activation in LPS-treated RLE-6TN cells.

BACKGROUND: Liver surgery during the perioperative period often leads to a significant complication known as hepatic ischemia-reperfusion (I/R) injury. Hepatic I/R injury is linked to the innate immune response. The cGAS-STING pathway triggers the activation of innate immune through the detection of DNA within cells. Nevertheless, the precise mechanism and significance of the cGAS-STING pathway in hepatic I/R injury are yet to be investigated.
METHODS: Mouse model of hepatic I/R injury was used in the C57BL/6 WT mice and the STING knockout (STING-KO) mice. In addition, purified primary hepatocytes were used to construct oxygen-glucose deprivation reperfusion (OGD-Rep) treatment models.
RESULTS: Our research revealed a notable increase in mRNA and protein levels of cGAS and STING in liver during I/R injury. Interestingly, the lack of STING exhibited a safeguarding impact on hepatic I/R injury by suppressing the elevation of liver enzymes, liver cell death, and inflammation. Furthermore, pharmacological cGAS and STING inhibition recapitulated these phenomena. Macrophages play a crucial role in the activation of the cGAS-STING pathway during hepatic I/R injury. The cGAS-STING pathway experiences a significant decrease in activity and hepatic I/R injury is greatly diminished following the elimination of macrophages. Significantly, we demonstrate that the activation of the cGAS-STING pathway is primarily caused by the liberation of mitochondrial DNA (mtDNA) rather than nuclear DNA (nDNA). Moreover, the safeguarding of the liver against I/R injury is also attributed to the hindrance of mtDNA release through the utilization of inhibitors targeting mPTP and VDAC oligomerization.
CONCLUSIONS: The results of our study suggest that the release of mtDNA plays a significant role in causing damage to liver by activating the cGAS-STING pathway during I/R injury. Furthermore, inhibiting the release of mtDNA can provide effective protection against hepatic I/R injury.

Hepatocellular carcinoma (HCC) is the most common form of liver cancer with poor prognosis. The available drugs for advanced HCC are limited and substantial therapeutic advances including new drugs and new combination therapies are still in urgent need. In this study, we found that the major metabolite of Lactobacillus reuteri (L. reuteri), reuterin showed great anti-HCC potential and could help in sorafenib treatment. Reuterin treatment impaired mitophagy and caused the aberrant clustering of mitochondrial nucleoids to block mitochondrial DNA (mtDNA) replication and mitochondrial fission, which could promote mtDNA leakage and subsequent STING activation in HCC cells. STING could activate pyroptosis and necroptosis, while reuterin treatment also induced caspase 8 expression to inhibit necroptosis through cleaving RIPK3 in HCC cells. Thus, pyroptosis was the main death form in reuterin-treated HCC cells and STING suppression remarkably rescued the growth inhibitory effect of reuterin and concurrently knockdown caspase 8 synergized to restrain the induction of pyroptosis. In conclusion, our study explains the detailed molecular mechanisms of the antitumor effect of reuterin and reveals its potential to perform as a combinational drug for HCC treatment.

The relationship between maternal peripheral blood mitochondrial DNA and adverse pregnancy outcomes, specifically preterm birth (PTB), remains uncertain. To investigate the effects of preconception mitochondrial DNA copy number (mtDNAcn) on the association between prenatal air pollutants exposure and PTB risk, a total of 1871 expectant mothers from six regions in Henan Province were recruited. Information regarding air pollutants was obtained from 151 environmental monitoring sites, and relative mtDNAcn was evaluated using real-time PCR analysis. After adjusting for potential confounding variables, it was determined that the risk of PTB increased with elevated levels of inhalable particulate matter (PM10), fine particulate matter (PM2.5), sulfur dioxide (SO2), carbon monoxide (CO) and ozone (O3) exposure (P < 0.05) but decreased with higher nitrogen dioxide (NO2) exposure (0.05 < P < 0.10) during the entire pregnancy. Additionally, the preconception relative mtDNAcn was lower in the PTB group (0.82 ± 0.23) compared to the term group (0.92 ± 0.29). Furthermore, for each 0.1-unit increase in preconception mtDNAcn, the risk of PTB decreased by 14.8%. Stratified analyses revealed that the risk of PTB rose with increasing O3 concentrations, regardless of the relative mtDNAcn. Moreover, the study found a significant association between PTB risk and prenatal exposure to elevated PM10, PM2.5, SO2, and CO, particularly in mothers with low mtDNAcn (≤0.88) (P < 0.05). Conversely, a decrease in the PTB risk was observed with elevated NO2 exposure in mothers with high mtDNAcn (>0.88). Interaction analysis revealed that exposure to PM10, PM2.5, SO2, NO2, and CO interacted with mtDNAcn, respectively, affecting PTB risk (P-interaction<0.05). These findings indicate a noteworthy association between PTB risk and prenatal air pollutants exposure, which is influenced by the preconception mtDNAcn.

Rationale: The treatment of ulcerative colitis (UC) presents an ongoing clinical challenge. Emerging research has implicated that the cGAS-STING pathway promotes the progression of UC, but conflicting results have hindered the development of STING as a therapeutic target. In the current study, we aim to comprehensively elucidate the origins, downstream signaling and pathogenic roles of myeloid STING in colitis and colitis-associated carcinoma (CAC). Methods: Tmem173 fl/fl Lyz2-Cre ert2 mice were constructed for inducible myeloid-specific deletion of STING. RNA-sequencing, flow cytometry, and multiplex immunohistochemistry were employed to investigate immune responses in DSS-induced colitis or AOM/DSS-induced carcinogenesis. Colonic organoids, primary bone marrow derived macrophages and dendritic cells, and splenic T cells were used for in vitro studies. Results: We observed that myeloid STING knockout in adult mice inhibited macrophage maturation, reduced DC cell activation, and suppressed pro-inflammatory Th1 and Th17 cells, thereby protecting against both acute and chronic colitis and CAC. However, myeloid STING deletion in neonatal or tumor-present mice exhibited impaired immune tolerance and anti-tumor immunity. Furthermore, we found that TFAM-associated mtDNA released from damaged colonic organoids, rather than bacterial products, activates STING in dendritic cells in an extracellular vesicle-independent yet endocytosis-dependent manner. Both IRF3 and NF-κB are required for STING-mediated expression of IL-12 family cytokines, promoting Th1 and Th17 differentiation and contributing to excessive inflammation in colitis. Conclusions: Detection of the TFAM-mtDNA complex from damaged intestinal epithelium by myeloid STING exacerbates colitis through IL-12 cytokines, providing new evidence to support the development of STING as a therapeutic target for UC and CAC.

The primary functions of mitochondria are to produce energy and participate in the apoptosis of cells, with them being highly conserved among eukaryotes. However, the composition of mitochondrial genomes, mitochondrial DNA (mtDNA) replication, and mitochondrial inheritance varies significantly among animals, plants, and fungi. Especially in fungi, there exists a rich diversity of mitochondrial genomes, as well as various replication and inheritance mechanisms. Therefore, a comprehensive understanding of fungal mitochondria is crucial for unraveling the evolutionary history of mitochondria in eukaryotes. In this review, we have organized existing reports to systematically describe and summarize the composition of yeast-like fungal mitochondrial genomes from three perspectives: mitochondrial genome structure, encoded genes, and mobile elements. We have also provided a systematic overview of the mechanisms in mtDNA replication and mitochondrial inheritance during bisexual mating. Additionally, we have discussed and proposed open questions that require further investigation for clarification.

The role of the senescence-associated secretory phenotype (SASP) in the development of age-related diseases is significant, and its control promises to have a tremendous positive impact on health. A recent study has identified a new mechanism for SASP regulation, titled miMOMP. Failure to regulate SASP would dramatically increase the risk of various age-related health problems. Nonetheless, we have not completely comprehended how to modulate SASP. In this commentary, we summarise the specific mechanisms by which miMOMP regulates SASP and outline possible future research directions. Moreover, potential risks and obstacles to the clinical translation of miMOMP are also presented.

BACKGROUND: Z-DNA binding protein 1 (ZBP1) is a nucleic acid sensor that is involved in multiple inflammatory diseases, but whether and how it contributes to osteoarthritis (OA) are unclear.
METHODS: Cartilage tissues were harvested from patients with OA and a murine model of OA to evaluate ZBP1 expression. Subsequently, the functional role and mechanism of ZBP1 were examined in primary chondrocytes, and the role of ZBP1 in OA was explored in mouse models.
RESULTS: We showed the upregulation of ZBP1 in articular cartilage originating from OA patients and mice with OA after destabilization of the medial meniscus (DMM) surgery. Specifically, knockdown of ZBP1 alleviated chondrocyte damage and protected mice from DMM-induced OA. Mechanistically, tumor necrosis factor alpha induced ZBP1 overexpression in an interferon regulatory factor 1 (IRF1)-dependent manner and elicited the activation of ZBP1 via mitochondrial DNA (mtDNA) release and ZBP1 binding. The upregulated and activated ZBP1 could interact with receptor-interacting protein kinase 1 and activate the transforming growth factor-beta-activated kinase 1-NF-κB signaling pathway, which led to chondrocyte inflammation and extracellular matrix degradation. Moreover, inhibition of the mtDNA-IRF1-ZBP1 axis with Cyclosporine A, a blocker of mtDNA release, could delay the progression of DMM-induced OA.
CONCLUSIONS: Our data revealed the pathological role of the mtDNA-IRF1-ZBP1 axis in OA chondrocytes, suggesting that inhibition of this axis could be a viable therapeutic approach for OA.

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Examining patterns of genetic diversity are crucial for conservation planning on endangered species, while inferring the underlying process of recent anthropogenic habitat modifications in the context potential long-term demographic changes remains challenging. The globally endangered scaly-sided merganser (SSME), Mergus squamatus, is endemic to a narrow range in Northeast Asia, and its population has recently been contracted into two main breeding areas. Although low genetic diversity has been suggested in the Russian population, the genetic status and demographic history of these individuals have not been fully elucidated. We therefore examined the genetic diversity and structure of the breeding populations of the SSME and investigated the relative importance of historical and recent demographic changes to the present-day pattern of genetic diversity. Using 10 nuclear microsatellite (SSR) markers and mitochondrial DNA (mtDNA) control region sequences, we found limited female-inherited genetic diversity and a high level of nuclear genetic diversity. In addition, analysis of both markers consistently revealed significant but weak divergence between the breeding populations. Inconsistent demographic history parameters calculated from mtDNA and bottleneck analysis results based on SSR suggested a stable historical effective population size. By applying approximate Bayesian computation, it was estimated that populations started to genetically diverge from each other due to recent fragmentation events caused by anthropogenic effects rather than isolation during Last Glacial Maximum (LGM) and post-LGM recolonization. These results suggest that limited historical population size and shallow evolutionary history may be potential factors contributing to the contemporary genetic diversity pattern of breeding SSME populations. Conservation efforts should focus on protecting the current breeding habitats from further destruction, with priority given to both the Russian and Chinese population, as well as restoring the connected suitable breeding grounds.