High-fat diet exacerbates 1-Bromopropane-induced loss of dopaminergic neurons in the substantia nigra of mice through mitochondrial damage associated necroptotic pathway DOI Creative Commons

Mingxue Song,

Yalong Qiang,

Shuai Wang

и другие.

Ecotoxicology and Environmental Safety, Год журнала: 2024, Номер 276, С. 116280 - 116280

Опубликована: Апрель 3, 2024

In recent years, accumulating evidence supports that occupational exposure to solvents is associated with an increased incidence of Parkinson's disease (PD) among workers. The neurotoxic effects 1-bromopropane (1-BP), a widely used new-type solvent, are well-established, yet data on its relationship the etiology PD remain limited. Simultaneously, high-fat consumption in modern society recognized as significant risk factor for PD. However, whether there synergistic effect between diet and 1-BP remains unclear. this study, adult C57BL/6 mice were fed either chow or 18 weeks prior 12-week treatment. Subsequent neurobehavioral neuropathological examinations conducted assess parkinsonian pathology. results demonstrated produced obvious abnormalities dopaminergic degeneration nigral region mice. Importantly, further exacerbated impact motor cognitive Mechanistic investigation revealed mitochondrial damage mtDNA release induced by activate NLRP3 cGAS-STING pathway- mediated neuroinflammatory response, ultimately lead necroptosis neurons. summary, our study unveils potential link chronic PD-like pathology no-motor defects experimental animals, long-term can promote neurotoxicity, which underscores pivotal role environmental factors

Язык: Английский

Cooperative sensing of mitochondrial DNA by ZBP1 and cGAS promotes cardiotoxicity DOI Creative Commons
Yuanjiu Lei,

Jordyn J. VanPortfliet,

Yifan Chen

и другие.

Cell, Год журнала: 2023, Номер 186(14), С. 3013 - 3032.e22

Опубликована: Июнь 22, 2023

Mitochondrial DNA (mtDNA) is a potent agonist of the innate immune system; however, exact immunostimulatory features mtDNA and kinetics detection by cytosolic nucleic acid sensors remain poorly defined. Here, we show that mitochondrial genome instability promotes Z-form accumulation. Z-DNA binding protein 1 (ZBP1) stabilizes nucleates complex containing cGAS, RIPK1, RIPK3 to sustain STAT1 phosphorylation type I interferon (IFN-I) signaling. Elevated mtDNA, ZBP1 expression, IFN-I signaling are observed in cardiomyocytes after exposure Doxorubicin, first-line chemotherapeutic agent induces frequent cardiotoxicity cancer patients. Strikingly, mice lacking or protected from Doxorubicin-induced cardiotoxicity. Our findings reveal as cooperative partner for cGAS sustains responses highlight potential target heart failure other disorders where stress contributes interferon-related pathology.

Язык: Английский

Процитировано

120
Mitochondria at the crossroads of health and disease DOI Creative Commons
Anu Suomalainen, Jodi Nunnari

Cell, Год журнала: 2024, Номер 187(11), С. 2601 - 2627

Опубликована: Май 1, 2024

Mitochondria reside at the crossroads of catabolic and anabolic metabolism—the essence life. How their structure function are dynamically tuned in response to tissue-specific needs for energy, growth repair, renewal is being increasingly understood. respond intrinsic extrinsic stresses can alter cell organismal by inducing metabolic signaling within cells distal tissues. Here, we review how centrality mitochondrial functions manifests health a broad spectrum diseases aging.

Язык: Английский

Процитировано

94
Mitochondrial DNA-triggered innate immune response: mechanisms and diseases DOI Creative Commons

Ming-Ming Hu,

Hong‐Bing Shu

Cellular and Molecular Immunology, Год журнала: 2023, Номер 20(12), С. 1403 - 1412

Опубликована: Ноя. 7, 2023

Abstract Various cellular stress conditions trigger mitochondrial DNA (mtDNA) release from mitochondria into the cytosol. The released mtDNA is sensed by cGAS-MITA/STING pathway, resulting in induced expression of type I interferon and other effector genes. These processes contribute to innate immune response viral infection factors. deregulation these causes autoimmune diseases, inflammatory metabolic disorders cancer. Therefore, pathway a potential target for intervention infectious, diseases as well In this review, we focus on mechanisms underlying mtDNA-triggered activation effects under various physiological pathological conditions, advances development drugs that cGAS MITA/STING.

Язык: Английский

Процитировано

51
Mitochondrial DNA replication stress triggers a pro-inflammatory endosomal pathway of nucleoid disposal DOI
Laura Newman, Sammy Weiser Novak,

Gladys R. Rojas

и другие.

Nature Cell Biology, Год журнала: 2024, Номер 26(2), С. 194 - 206

Опубликована: Фев. 1, 2024

Язык: Английский

Процитировано

39
TFAM is an autophagy receptor that limits inflammation by binding to cytoplasmic mitochondrial DNA DOI
Hao Liu,

Cien Zhen,

Jianming Xie

и другие.

Nature Cell Biology, Год журнала: 2024, Номер 26(6), С. 878 - 891

Опубликована: Май 23, 2024

Язык: Английский

Процитировано

33
Microglial CMPK2 promotes neuroinflammation and brain injury after ischemic stroke DOI Creative Commons
Xin‐Yuan Guan,

Sitong Zhu,

Jin‐Qian Song

и другие.

Cell Reports Medicine, Год журнала: 2024, Номер 5(5), С. 101522 - 101522

Опубликована: Май 1, 2024

Neuroinflammation plays a significant role in ischemic injury, which can be promoted by oxidized mitochondrial DNA (Ox-mtDNA). Cytidine/uridine monophosphate kinase 2 (CMPK2) regulates mtDNA replication, but its neuroinflammation and injury remains unknown. Here, we report that CMPK2 expression is upregulated monocytes/macrophages microglia post-stroke humans mice, respectively. Microglia/macrophage knockdown using the Cre recombination-dependent adeno-associated virus suppresses inflammatory responses brain, reduces infarcts, improves neurological outcomes CX3CR1Cre/ERT2 mice. Mechanistically, limits newly synthesized Ox-mtDNA formation subsequently blocks NLRP3 inflammasome activation microglia/macrophages. Nordihydroguaiaretic acid (NDGA), as inhibitor, discovered to reduce mice prevent primary human monocytes from patients. Thus, these findings identify promising therapeutic target for stroke other brain disorders associated with neuroinflammation.

Язык: Английский

Процитировано

20
Chromosomal instability as a driver of cancer progression DOI

Xuelan Chen,

Albert S. Agustinus, Jun Li

и другие.

Nature Reviews Genetics, Год журнала: 2024, Номер 26(1), С. 31 - 46

Опубликована: Июль 29, 2024

Язык: Английский

Процитировано

17
Mitochondria complex III–generated superoxide is essential for IL-10 secretion in macrophages DOI Creative Commons
Joshua S. Stoolman, Rogan A. Grant,

Leah K. Billingham

и другие.

Science Advances, Год журнала: 2025, Номер 11(4)

Опубликована: Янв. 22, 2025

Mitochondrial electron transport chain (ETC) function modulates macrophage biology; however, mechanisms underlying mitochondria ETC control of immune responses are not fully understood. Here, we report that mutant mice with complex III (CIII)–deficient macrophages exhibit increased susceptibility to influenza A virus (IAV) and LPS-induced endotoxic shock. Cultured bone marrow–derived (BMDMs) isolated from these CIII–deficient released less IL-10 than controls following TLR3 or TLR4 stimulation. Unexpectedly, restoring mitochondrial respiration without generating superoxide using alternative oxidase (AOX) was sufficient reverse shock restore release. However, activation protein kinase (PKA) rescued release in CIII-deficient BMDMs LPS In addition, CIII deficiency did affect BMDM interleukin-4 (IL-4) Thus, our results highlight the essential role CIII–generated anti-inflammatory response TLR

Язык: Английский

Процитировано

3
Inflammatory signaling in NASH driven by hepatocyte mitochondrial dysfunctions DOI Creative Commons
Melissa Myint, Francesca Oppedisano, Valeria De Giorgi

и другие.

Journal of Translational Medicine, Год журнала: 2023, Номер 21(1)

Опубликована: Окт. 26, 2023

Abstract Liver steatosis, inflammation, and variable degrees of fibrosis are the pathological manifestations nonalcoholic steatohepatitis (NASH), an aggressive presentation most prevalent chronic liver disease in Western world known as fatty (NAFL). Mitochondrial hepatocyte dysfunction is a primary event that triggers affecting Kupffer hepatic stellate cell behaviour. Here, we consider role impaired mitochondrial function caused by lipotoxicity during oxidative stress hepatocytes. Dysfunction phosphorylation ROS production cause release damage-associated molecular patterns from dying hepatocytes, leading to activation innate immunity trans-differentiation cells, thereby driving NASH.

Язык: Английский

Процитировано

22
Release of mitochondrial dsRNA into the cytosol is a key driver of the inflammatory phenotype of senescent cells DOI Creative Commons
Vanessa López-Polo, Máté Maus, Emmanouil Zacharioudakis

и другие.

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Авг. 27, 2024

The escape of mitochondrial double-stranded dsRNA (mt-dsRNA) into the cytosol has been recently linked to a number inflammatory diseases. Here, we report that release mt-dsRNA is general feature senescent cells and critical driver their secretome, known as senescence-associated secretory phenotype (SASP). Inhibition RNA polymerase, sensors RIGI MDA5, or master signaling protein MAVS, all result in reduced expression SASP, while broadly preserving other hallmarks senescence. Moreover, are hypersensitized mt-dsRNA-driven inflammation due levels PNPT1 ADAR1, two proteins for mitigating accumulation potency dsRNA, respectively. We find mitofusin MFN1, but not MFN2, important activation mt-dsRNA/MAVS/SASP axis and, accordingly, genetic pharmacologic MFN1 inhibition attenuates SASP. Finally, within fibrotic aged tissues present foci, polymerase reduces systemic associated In conclusion, uncover mt-dsRNA/MAVS/MFN1 key SASP identify novel therapeutic strategies authors show

Язык: Английский

Процитировано

11