bims-mitper 2023-01-01 papers

Issue of 2023‒01‒01
three papers selected by
Bradley Irizarry
Thomas Jefferson University

J Mol Cell Biol. 2022 Dec 24. pii: mjac074. [Epub ahead of print]

The ARTS of p53-dependent mitochondrial apoptosis.

Qian Hao, Jiaxiang Chen, Hua Lu, Xiang Zhou.

The tumor-suppressive activity of p53 is largely attributed to its ability to induce cell death, including apoptosis through transcription-dependent and -independent mechanisms. On the one hand, nuclear p53 transcriptionally activates the expression of a myriad of pro-apoptotic BCL-2 family genes, such as NOXA, PUMA, BID, BAD, BIK, BAX, etc., whereas inactivates the expression of anti-apoptotic BCL-2, BCL-XL, and MCL1, leading to mitochondrial apoptosis. On the other hand, cytoplasmic p53 also promotes mitochondrial apoptosis by directly associating with multiple BCL-2 family proteins in the mitochondria. Apoptosis-related protein in TGF-β signaling pathway (ARTS), a mitochondria-localized pro-apoptotic protein encoded by an alternative spliced variant of the SEPT4 gene, triggers apoptosis by facilitating proteasomal degradation of BCL-2 and XIAP upon pro-apoptotic stimuli. We recently identified SEPT4/ARTS as a new p53 target gene in response to genotoxic stress. ARTS in turn binds to p53, drives its mitochondrial localization, and enhances the interaction between p53 and BCL-XL, thereby promoting mitochondrial apoptosis. This review will illustrate the mechanisms of p53-induced mitochondrial apoptosis, offer some recently discovered new insights into the ARTS functions in regulating mitochondrial cell death, and discuss the clinical significance of ARTS in cancer and non-cancer diseases.

Keywords: ARTS; BCL-2 family; SEPT4; apoptosis; cancer therapy; p53

DOI: https://doi.org/10.1093/jmcb/mjac074

Zool Res. 2023 Jan 18. pii: 2095-8137(2023)01-0183-36. [Epub ahead of print]44(1): 183-218

Current understanding of the cGAS-STING signaling pathway: Structure, regulatory mechanisms, and related diseases.

Jing Pan, Chen-Jie Fei, Yang Hu, Xiang-Yu Wu, Li Nie, Jiong Chen.

The innate immune system protects the host from external pathogens and internal damage in various ways. The cGAS-STING signaling pathway, comprised of cyclic GMP-AMP synthase (cGAS), stimulator of interferon genes (STING), and downstream signaling adaptors, plays an essential role in protective immune defense against microbial DNA and internal damaged-associated DNA and is responsible for various immune-related diseases. After binding with DNA, cytosolic cGAS undergoes conformational change and DNA-linked liquid-liquid phase separation to produce 2'3'-cGAMP for the activation of endoplasmic reticulum (ER)-localized STING. However, further studies revealed that cGAS is predominantly expressed in the nucleus and strictly tethered to chromatin to prevent binding with nuclear DNA, and functions differently from cytosolic-localized cGAS. Detailed delineation of this pathway, including its structure, signaling, and regulatory mechanisms, is of great significance to fully understand the diversity of cGAS-STING activation and signaling and will be of benefit for the treatment of inflammatory diseases and cancer. Here, we review recent progress on the above-mentioned perspectives of the cGAS-STING signaling pathway and discuss new avenues for further study.

Keywords: Diseases; Post-translational modification; STING; Signaling; Structure; cGAS

Free Radic Biol Med. 2022 Dec 28. pii: S0891-5849(22)01109-1. [Epub ahead of print]195 103-120

Cell-free circulating mitochondrial DNA: An emerging biomarker for airborne particulate matter associated with cardiovascular diseases.

Afreen Rehman, Roshani Kumari, Arunika Kamthan, Rajnarayan Tiwari, Rupesh Kumar Srivastava, Francois H van der Westhuizen, Pradyumna Kumar Mishra.

The association of airborne particulate matter exposure with the deteriorating function of the cardiovascular system is fundamentally driven by the impairment of mitochondrial-nuclear crosstalk orchestrated by aberrant redox signaling. The loss of delicate balance in retrograde communication from mitochondria to the nucleus often culminates in the methylation of the newly synthesized strand of mitochondrial DNA (mtDNA) through DNA methyl transferases. In highly metabolic active tissues such as the heart, mtDNA's methylation state alteration impacts mitochondrial bioenergetics. It affects transcriptional regulatory processes involved in biogenesis, fission, and fusion, often accompanied by the integrated stress response. Previous studies have demonstrated a paradoxical role of mtDNA methylation in cardiovascular pathologies linked to air pollution. A pronounced alteration in mtDNA methylation contributes to systemic inflammation, an etiological determinant for several co-morbidities, including vascular endothelial dysfunction and myocardial injury. In the current article, we evaluate the state of evidence and examine the considerable promise of using cell-free circulating methylated mtDNA as a predictive biomarker to reduce the more significant burden of ambient air pollution on cardiovascular diseases.

Keywords: Environmental health; Mitochondria; Mitochondrial epigenetics; Oxidative stress; Translational research

DOI: https://doi.org/10.1016/j.freeradbiomed.2022.12.083