bims-miptne 2024-10-27 papers

bims-miptne

Biomed News

on Mitochondrial permeability transition pore-dependent necrosis

Issue of 2024–10–27
seven papers selected by
Oluwatobi Samuel Adegbite, University of Liverpool

Cyclophilin D plays a critical role in the survival of senescent cells.
Mitoception, or transfer of normal cell mitochondria to cancer cells, reverses remodeling of store-operated Ca2+ entry in tumor cells.
Urolithin A improves myocardial ischemia-reperfusion injury by attenuating oxidative stress and ferroptosis through Nrf2 pathway.
Naringin alleviates fluoride-induced neurological impairment: A focus on the regulation of energy metabolism mediated by mitochondrial permeability transition pore.
Decreased Mrpl42 expression exacerbates myocardial ischemia and reperfusion injury by inhibiting mitochondrial translation.
Aristolochic acid I induced mitochondrial Ca2+ accumulation triggers the production of MitoROS and activates Src/FAK pathway in hepatocellular carcinoma cells.
Galectin-3/Gelatin Electrospun Scaffolds Modulate Collagen Synthesis in Skin Healing but Do Not Improve Wound Closure Kinetics.

EMBO J. 2024 Oct 24.

Cyclophilin D plays a critical role in the survival of senescent cells.

Margherita Protasoni, Vanessa López-Polo, Camille Stephan-Otto Attolini, Julian Brandariz, Nicolas Herranz, Joaquin Mateo, Sergio Ruiz, Oscar Fernandez-Capetillo, Marta Kovatcheva, Manuel Serrano.

  Senescent cells play a causative role in many diseases, and their elimination is a promising therapeutic strategy. Here, through a genome-wide CRISPR/Cas9 screen, we identify the gene PPIF, encoding the mitochondrial protein cyclophilin D (CypD), as a novel senolytic target. Cyclophilin D promotes the transient opening of the mitochondrial permeability transition pore (mPTP), which serves as a failsafe mechanism for calcium efflux. We show that senescent cells exhibit a high frequency of transient CypD/mPTP opening events, known as 'flickering'. Inhibition of CypD using genetic or pharmacologic tools, including cyclosporin A, leads to the toxic accumulation of mitochondrial Ca2+ and the death of senescent cells. Genetic or pharmacological inhibition of NCLX, another mitochondrial calcium efflux channel, also leads to senolysis, while inhibition of the main Ca2+ influx channel, MCU, prevents senolysis induced by CypD inhibition. We conclude that senescent cells are highly vulnerable to elevated mitochondrial Ca2+ ions, and that transient CypD/mPTP opening is a critical adaptation mechanism for the survival of senescent cells.

Keywords:  Cellular Senescence; Cyclophilin D; Mitochondria; Senolytic Therapy; mPTP Flickering

DOI:  https://doi.org/10.1038/s44318-024-00259-2
Biochim Biophys Acta Mol Cell Res. 2024 Oct 20. pii: S0167-4889(24)00205-2. [Epub ahead of print]1872(1): 119862

Mitoception, or transfer of normal cell mitochondria to cancer cells, reverses remodeling of store-operated Ca2+ entry in tumor cells.

Verónica Feijóo, Sendoa Tajada, Alejandra Méndez-Mena, Lucía Núñez, Carlos Villalobos.

  Most cancer cells show the Warburg effect, the rewiring of aerobic metabolism to glycolysis due to defective mitochondrial ATP synthesis. As a consequence, tumor cells display enhanced mitochondrial potential (∆Ψ), the driving force for mitochondrial Ca2+ uptake. Mitochondria control the Ca2+-dependent inactivation of store-operated channels (SOCs), leading to enhanced and sustained store-operated Ca2+ entry (SOCE) involved in cancer hallmarks. We asked here whether the transfer of mitochondria (mitoception) from normal cells to tumor cells may reverse SOCE remodeling in cancer cells. For this end, we labeled mitochondria in normal NCM460 human colonic cells, isolated them and transferred them to tumor HT29 cells. We tested the viability and efficiency of mitoception using flow cytometry and confocal microscopy, as well as calcium imaging to investigate the effects of mitoception on SOCE. Our results show that mitoception of tumor HT29 cells with normal mitochondria restores a low ∆Ψ and SOCE. Conversely, self-mitoception of tumor HT29 cells with tumor cell mitochondria increases further ∆Ψ and SOCE, thus excluding the possibility that effects of mitoception are due to increased mitochondrial mass. Strikingly, mitoception of normal NCM460 cells with tumor cell mitochondria has no effects on either ∆Ψ or SOCE. These results are consistent with the previous proposal that transformed mitochondria may modulate SOC channels involved in SOCE. Further research is warranted to test whether mitoception of cancer cells with normal mitochondria may reverse Ca2+ remodeling associated to cancer.

Keywords:  Colon cancer; Mitoception; Mitochondria; Store-operated Ca(2+) entry

DOI:  https://doi.org/10.1016/j.bbamcr.2024.119862
Int Immunopharmacol. 2024 Oct 21. pii: S1567-5769(24)01916-7. [Epub ahead of print]143(Pt 2): 113394

Urolithin A improves myocardial ischemia-reperfusion injury by attenuating oxidative stress and ferroptosis through Nrf2 pathway.

Zhe Su, Peihui Li, Wei Ding, Yufang Gao.

  Ischemia/reperfusion (I/R) injury has been demonstrated to exert a significant role in acute myocardial infarction (AMI), which constitutes a crucial cause of AMI. Ferroptosis represents a novel form of cell death that is intimately linked to myocardial ischemia-reperfusion (MIR) injury. Urolithin A (UA), an intestinal metabolite of ellagitannins, has not been fully elucidated for its role in MIR injury. In the present study, we analyzed the effects of UA on ischemia-reperfusion-induced oxidative stress and ferroptosis both in vitro and in vivo, and explored the potential mechanisms of UA action. The results indicated that UA was capable of protecting the heart from ischemia-reperfusion injury and enhancing cardiac function both in vitro and in vivo. In addition, UA also attenuated oxidative stress, mitochondrial damage, and ferroptosis during MIR. Mechanistically, UA not only augmented the Nrf2 expression but also promoted Nrf2 entry into the nucleus and activated the downstream antioxidant defense system. Moreover, after the inhibition of Nrf2, the myocardial protective function of UA was lost, and its function of attenuating oxidative stress and ferroptosis was suppressed. In conclusion, we found that UA protected the heart from ischemia-reperfusion injury by attenuating oxidative stress and ferroptosis through the Nrf2 signaling pathway, suggesting that UA might be a potential therapeutic agent for the treatment of AMI.

Keywords:  Ferroptosis; Myocardial ischemia–reperfusion; Nrf2; Urolithin A

DOI:  https://doi.org/10.1016/j.intimp.2024.113394
Sci Total Environ. 2024 Oct 22. pii: S0048-9697(24)07230-9. [Epub ahead of print] 177073

Naringin alleviates fluoride-induced neurological impairment: A focus on the regulation of energy metabolism mediated by mitochondrial permeability transition pore.

Yuhui Du, Guoqing Wang, Bin Liu, Meng Guo, Xi Yan, Ming Dou, Fangfang Yu, Yue Ba, Guoyu Zhou.

  The neurological impairment induced by fluoride is associated with mitochondrial dysfunction. Normal mitochondrial permeability transition pore (mPTP) opening plays a pivotal role in mitochondrial function. However, it remains unclear whether p53-dependent mPTP-related mitochondrial apoptosis is associated with fluoride-induced neurological impairment, and the alleviation of naringin on those. In vivo, NaF-treated rats had impaired learning and memory abilities, damaged hippocampal structure, and higher respiratory exchange rates (RER). In vitro, the increased apoptosis rates, excessive opening of mPTP, and decreased mitochondrial membrane potential (MMP) were observed in PC12 cells treated with NaF. The protein expressions of p53, CytoC, and cleaved caspase 3 were significantly increased in hippocampi of rats treated with 50 mg/L and 100 mg/L NaF and in 40 mg/L and 80 mg/L NaF-treated PC12 cells, while the protein expression of CypD remains stable. And the changes of p53 and CypD were also confirmed by the immunofluorescence staining in vivo. After inhibiting the expression of p53 with pifithrin-α and p53-siRNA, the decreased apoptosis rates and mPTP opening, increased MMP, and decreased protein expressions of p53, CytoC, and cleaved caspase 3 were observed in NaF-treated PC12 cells. Rats, treated with NaF and naringin, had alleviated impaired neurological function, and had lower RER than rats treated with NaF alone. And compared with those in the NaF group, the decreased apoptosis rates and mPTP opening, and increased MMP were also found in PC12 cells treated with NaF and naringin. Furthermore, hippocampi of rats and PC12 cells treated with NaF and naringin had decreased protein expressions of p53, CytoC, and cleaved caspase 3. Our results indicate that fluoride activates the p53-dependent mPTP-related mitochondrial apoptosis, which then affects energy metabolism, resulting in neurological impairment. Additionally, naringin can alleviate this damage, and further studies on the potential health benefits of naringin are needed.

Keywords:  Energy metabolism; Fluoride; Naringin; mPTP; p53

DOI:  https://doi.org/10.1016/j.scitotenv.2024.177073
Cell Signal. 2024 Oct 22. pii: S0898-6568(24)00457-1. [Epub ahead of print] 111482

Decreased Mrpl42 expression exacerbates myocardial ischemia and reperfusion injury by inhibiting mitochondrial translation.

Xiaomeng Zhang, Xiaoqian Chang, Jingyu Deng, Congye Li, Yuan Li, Yangzhi Zheng, Rongjin Yang, Xiaoming Xu, Wenjun Yan, Fuyang Zhang, Yunlong Xia, Huishou Zhao, Pingping Xing, Guigao Guo, Fengyue Ding, Ling Tao, Shan Wang.

  Mammalian mitochondrial DNA (mtDNA) encodes a total of 13 proteins, all of which are subunits of enzyme complexes of the oxidative phosphorylation. The mtDNA-encoded protein synthesis depends on the mitochondrial ribosomal proteins (MRPs), which assemble to form a specialized form of ribosome. Some mtDNA-encoded proteins have been reported to be reduced after myocardial ischemic injury. However, the molecular mechanisms responsible for this decrease and whether this decrease is involved in myocardial ischemia/reperfusion (I/R) injury remains unknown. Here, we found that the mtDNA-encoded protein levels were significantly decreased after I/R injury, while the mRNA levels of these genes were either increased or had no significant change. Subsequently, by querying and analyzing public database resources, we found that the expression of many mitochondrial translation-related proteins tended to decrease after myocardial infarction injury, and the reduction in the expression of these proteins was most obvious for Mrpl42. Furthermore, we found that cardiac Mrpl42 knockdown aggravated I/R-induced cardiac contractile dysfunction and cardiomyocyte death, while restoring Mrpl42 expression in the heart reduced I/R injury. Mrpl42 knockdown impaired the translation of mtDNA-encoded genes, ultimately led to aberrations in mitochondrial morphology and respiratory function. In addition, we found that the decrease in the expression of Mrpl42 after I/R injury was caused by the downregulation of Nrf2, which directly regulates Mrpl42 transcription. Our study revealed that ischemic downregulation of Mrpl42 expression and subsequent inhibition of mitochondrial translation contribute to cardiac I/R injury. Targeting Mrpl42 may be a novel therapeutic intervention for cardiac I/R injury and myocardial infarction.

Keywords:  Mitochondria encoded gene; Mitochondria translation; Mrpl42; Myocardial ischemia/reperfusion injury

DOI:  https://doi.org/10.1016/j.cellsig.2024.111482
Chem Biol Interact. 2024 Oct 17. pii: S0009-2797(24)00415-0. [Epub ahead of print] 111269

Aristolochic acid I induced mitochondrial Ca2+ accumulation triggers the production of MitoROS and activates Src/FAK pathway in hepatocellular carcinoma cells.

Yongkang Hu, Qi Zhang, Wenjuan Jiang, Xian Wang, Xinlong Guo, Langqun Chen, Siyu Cheng, Jiahui Ying, Jing Ye, Zhang Liang.

  Aristolochic acid I (AAI) is one of the nephrotoxic and carcinogenic compounds in Aristolochic acids (AAs). Recent studies have reported its promoting effect on hepatocellular carcinoma. However, the underlying mechanisms of AAI for the development of HCC is still unclear. Here, we found that AAI exposure caused alterations in mitochondrial function, which featured with increased ATP level and mitochondrial membrane potential, accumulation of mitochondrial Ca2+ and mitochondrial ROS (MitoROS) in Hepa1-6 and HepG2 cells. The restriction of mitochondrial Ca2+ uptake alleviated these effects. Our results showed that increased MitoROS was associated with AAI-induced migration and invasion in HCC cells. MitoROS/Src/FAK pathway was involved in the AAI-induced migration and invasion of HCC cells. In summary, our study showed that AAI affected mitochondrial metabolism of HCC cells by promoting the accumulation of mitochondrial Ca2+. These effects resulted in the activation of the MitoROS/SRC/FAK pathway in AAI-treated HCC cells, which in turn induced cell migration and invasion.

Keywords:  Aristolochic acid I; hepatocellular carcinoma; invasion; migration; mitochondrial Ca(2+); mitochondrial reactive oxygen species

DOI:  https://doi.org/10.1016/j.cbi.2024.111269
Bioengineering (Basel). 2024 Sep 25. pii: 960. [Epub ahead of print]11(10):

Galectin-3/Gelatin Electrospun Scaffolds Modulate Collagen Synthesis in Skin Healing but Do Not Improve Wound Closure Kinetics.

Karrington A McLeod, Madeleine Di Gregorio, Dylan Tinney, Justin Carmichael, David Zuanazzi, Walter L Siqueira, Amin Rizkalla, Douglas W Hamilton.

  Chronic wounds remain trapped in a pro-inflammatory state, with strategies targeted at inducing re-epithelialization and the proliferative phase of healing desirable. As a member of the lectin family, galectin-3 is implicated in the regulation of macrophage phenotype and epithelial migration. We investigated if local delivery of galectin-3 enhanced skin healing in a full-thickness excisional C57BL/6 mouse model. An electrospun gelatin scaffold loaded with galectin-3 was developed and compared to topical delivery of galectin-3. Electrospun gelatin/galectin-3 scaffolds had an average fiber diameter of 200 nm, with 83% scaffold porosity approximately and an average pore diameter of 1.15 μm. The developed scaffolds supported dermal fibroblast adhesion, matrix deposition, and proliferation in vitro. In vivo treatment of 6 mm full-thickness excisional wounds with gelatin/galectin-3 scaffolds did not influence wound closure, re-epithelialization, or macrophage phenotypes, but increased collagen synthesis. In comparison, topical delivery of galectin-3 [6.7 µg/mL] significantly increased arginase-I cell density at day 7 versus untreated and gelatin/galectin-3 scaffolds (p < 0.05). A preliminary assessment of increasing the concentration of topical galectin-3 demonstrated that at day 7, galectin-3 [12.5 µg/mL] significantly increased both epithelial migration and collagen content in a concentration-dependent manner. In conclusion, local delivery of galectin 3 shows potential efficacy in modulating skin healing in a concentration-dependent manner.

Keywords:  arginase-I; keratin 17; keratinocytes; lectins; macrophage; matricellular proteins; re-epithelialization; wound chronicity

DOI:  https://doi.org/10.3390/bioengineering11100960