bims-miptne Biomed News
on Mitochondrial permeability transition pore-dependent necrosis
Issue of 2024–05–19
six papers selected by
Oluwatobi Samuel Adegbite, University of Liverpool
  1. Coumarin-Furoxan Hybrid Suppressed the Proliferation and Metastasis of Triple-Negative Breast Cancer by Activating Mitochondrial Stress and Cell Apoptosis.
  2. MICU3 Regulates Mitochondrial Calcium and Cardiac Hypertrophy.
  3. Calcium signaling crosstalk between the endoplasmic reticulum and mitochondria, a new drug development strategies of kidney diseases.
  4. Cytoplasmic Ca2+ influx mediates iron- and reactive oxygen species-dependent ferroptotic cell death in rice immunity.
  5. Induction of mitochondrial toxicity by non-steroidal anti-inflammatory drugs (NSAIDs): The ultimate trade-off governing the therapeutic merits and demerits of these wonder drugs.
  6. Caffeine improves mitochondrial dysfunction in the white matter of neonatal rats with hypoxia-ischemia through deacetylation: a proteomic analysis of lysine acetylation.
  1. ACS Pharmacol Transl Sci. 2024 May 10. 7(5): 1278-1290
    Coumarin-Furoxan Hybrid Suppressed the Proliferation and Metastasis of Triple-Negative Breast Cancer by Activating Mitochondrial Stress and Cell Apoptosis.
    Mengru Li, Fan Cao, Weijie Wang, Yulei Ma, Zhihui Yu, Ke Wang, Ying Chen, Hongrui Liu.
      Triple-negative breast cancer (TNBC) typically manifests as higher invasive carcinoma correlated with a worse prognosis that primarily relies on chemotherapy. There is growing evidence that nitric oxide (NO) donor drugs have the potential for anticancer therapy. On this basis, we constructed and evaluated a novel coumarin-furoxan hybrid 4A93 as an effective antitumor candidate drug. 4A93 exhibits low IC50 values in three TNBC cell lines and inhibits colony formation and DNA synthesis, probably due to the release of high concentrations of NO in mitochondria, which induces oxidative stress, mitochondrial dysfunction, and apoptosis. Further research suggests that 4A93 might destroy mitochondria by opening the mitochondrial permeability transition pore (mPTP), depolarizing the mitochondrial membrane potential (MMP), and promoting the release of cytochrome c into the cytoplasm. Intrinsic apoptosis is induced finally, along with Akt/Erk signaling suppression. Additionally, 4A93 underregulates the Epithelial-mesenchymal transition process to inhibit cell migration and invasion. In 4T1 subcutaneous and hematogenous models of mice, 4A93 therapy suppresses the tumor growth and prevented lung metastasis with favorable biosafety. Our results provide insights into 4A93 in TNBC treatment and validate the contribution of NO donors in tumor therapy.
    DOI:  https://doi.org/10.1021/acsptsci.3c00329
  2. Circ Res. 2024 May 15.
    MICU3 Regulates Mitochondrial Calcium and Cardiac Hypertrophy.
    Barbara Roman, Yusuf Mastoor, Junhui Sun, Hector Chapoy Villanueva, Gabriela Hinojosa, Danielle Springer, Julia C Liu, Elizabeth Murphy.
       BACKGROUND: Calcium (Ca2+) uptake by mitochondria occurs via the mitochondrial Ca2+ uniporter. Mitochondrial Ca2+ uniporter exists as a complex, regulated by 3 MICU (mitochondrial Ca2+ uptake) proteins localized in the intermembrane space: MICU1, MICU2, and MICU3. Although MICU3 is present in the heart, its role is largely unknown.
    METHODS: We used CRISPR-Cas9 to generate a mouse with global deletion of MICU3 and an adeno-associated virus (AAV9) to overexpress MICU3 in wild-type mice. We examined the role of MICU3 in regulating mitochondrial calcium ([Ca2+]m) in ex vivo hearts using an optical method following adrenergic stimulation in perfused hearts loaded with a Ca2+-sensitive fluorophore. Additionally, we studied how deletion and overexpression of MICU3, respectively, impact cardiac function in vivo by echocardiography and the molecular composition of the mitochondrial Ca2+ uniporter complex via Western blot, immunoprecipitation, and Blue native-PAGE analysis. Finally, we measured MICU3 expression in failing human hearts.
    RESULTS: Knock out MICU3 hearts and cardiomyocytes exhibited a significantly smaller increase in [Ca2+]m than wild-type hearts following acute isoproterenol infusion. In contrast, overexpression of MICU3 hearts exhibited an enhanced increase in [Ca2+]m compared with control hearts. Echocardiography analysis showed no significant difference in cardiac function in knock out MICU3 mice relative to wild-type mice at baseline. However, overexpression of MICU3 animals exhibited significantly reduced ejection fraction and fractional shortening compared with control mice. We observed a significant increase in the ratio of heart weight to tibia length in overexpression of MICU3 hearts compared with controls, consistent with hypertrophy. We also found a significant decrease in MICU3 protein and expression in failing human hearts.
    CONCLUSIONS: Our results indicate that increased and decreased expression of MICU3 enhances and reduces, respectively, the uptake of [Ca2+]m in the heart. We conclude that MICU3 plays an important role in regulating [Ca2+]m physiologically, and overexpression of MICU3 is sufficient to induce cardiac hypertrophy, making MICU3 a possible therapeutic target.
    Keywords:  calcium; cardiomegaly; echocardiography; mitochondria; myocytes, cardiac
    DOI:  https://doi.org/10.1161/CIRCRESAHA.123.324026
  3. Biochem Pharmacol. 2024 May 11. pii: S0006-2952(24)00261-2. [Epub ahead of print]225 116278
    Calcium signaling crosstalk between the endoplasmic reticulum and mitochondria, a new drug development strategies of kidney diseases.
    Wen-Di Ge, Tian-Tian Du, Cao-Yang Wang, Lu-Ning Sun, Yong-Qing Wang.
      Calcium (Ca2+) acts as a second messenger and constitutes a complex and large information exchange system between the endoplasmic reticulum (ER) and mitochondria; this process is involved in various life activities, such as energy metabolism, cell proliferation and apoptosis. Increasing evidence has suggested that alterations in Ca2+ crosstalk between the ER and mitochondria, including alterations in ER and mitochondrial Ca2+ channels and related Ca2+ regulatory proteins, such as sarco/endoplasmic reticulum Ca2+-ATPase (SERCA), inositol 1,4,5-trisphosphate receptor (IP3R), and calnexin (CNX), are closely associated with the development of kidney disease. Therapies targeting intracellular Ca2+ signaling have emerged as an emerging field in the treatment of renal diseases. In this review, we focused on recent advances in Ca2+ signaling, ER and mitochondrial Ca2+ monitoring methods and Ca2+ homeostasis in the development of renal diseases and sought to identify new targets and insights for the treatment of renal diseases by targeting Ca2+ channels or related Ca2+ regulatory proteins.
    Keywords:  Calcium; Endoplasmic Reticulum; Kidney Diseases; Mitochondria; Mitochondrial Associated Membranes
    DOI:  https://doi.org/10.1016/j.bcp.2024.116278
  4. Front Plant Sci. 2024 ;15 1339559
    Cytoplasmic Ca2+ influx mediates iron- and reactive oxygen species-dependent ferroptotic cell death in rice immunity.
    Juan Wang, Won-Gyu Choi, Nam Khoa Nguyen, Dongping Liu, Su-Hwa Kim, Dongyeol Lim, Byung Kook Hwang, Nam-Soo Jwa.
      Iron- and reactive oxygen species (ROS)-dependent ferroptosis occurs in plant cells. Ca2+ acts as a conserved key mediator to control plant immune responses. Here, we report a novel role of cytoplasmic Ca2+ influx regulating ferroptotic cell death in rice immunity using pharmacological approaches. High Ca2+ influx triggered iron-dependent ROS accumulation, lipid peroxidation, and subsequent hypersensitive response (HR) cell death in rice (Oryza sativa). During Magnaporthe oryzae infection, 14 different Ca2+ influx regulators altered Ca2+, ROS and Fe2+ accumulation, glutathione reductase (GR) expression, glutathione (GSH) depletion and lipid peroxidation, leading to ferroptotic cell death in rice. High Ca2+ levels inhibited the reduction of glutathione isulphide (GSSG) to GSH in vitro. Ca2+ chelation by ethylene glycol-bis (2-aminoethylether)-N, N, N', N'-tetra-acetic acid (EGTA) suppressed apoplastic Ca2+ influx in rice leaf sheaths during infection. Blocking apoplastic Ca2+ influx into the cytoplasm by Ca2+ chelation effectively suppressed Ca2+-mediated iron-dependent ROS accumulation and ferroptotic cell death. By contrast, acibenzolar-S-methyl (ASM), a plant defense activator, significantly enhanced Ca2+ influx, as well as ROS and iron accumulation to trigger ferroptotic cell death in rice. The cytoplasmic Ca2+ influx through calcium-permeable cation channels, including the putative resistosomes, could mediate iron- and ROS-dependent ferroptotic cell death under reduced GR expression levels in rice immune responses.
    Keywords:  Ca2+ influx; GR expression; Magnaporthe oryzae; ROS; ferroptotic cell death; iron; rice
    DOI:  https://doi.org/10.3389/fpls.2024.1339559
  5. Biochem Pharmacol. 2024 May 13. pii: S0006-2952(24)00266-1. [Epub ahead of print] 116283
    Induction of mitochondrial toxicity by non-steroidal anti-inflammatory drugs (NSAIDs): The ultimate trade-off governing the therapeutic merits and demerits of these wonder drugs.
    Somnath Mazumder, Samik Bindu, Subhashis Debsharma, Uday Bandyopadhyay.
      Non-steroidal anti-inflammatory drugs (NSAIDs) are most extensively used over-the-counter FDA-approved analgesic medicines for treating inflammation, musculoskeletal pain, arthritis, pyrexia and menstrual cramps. Moreover, aspirin is widely used against cardiovascular complications. Owing to their non-addictive nature, NSAIDs are also commissioned as safer opioid-sparing alternatives in acute trauma and post-surgical treatments. In fact, therapeutic spectrum of NSAIDs is expanding. These "wonder-drugs" are now repurposed against lung diseases, diabetes, neurodegenerative disorders, fungal infections and most notably cancer, due to their efficacy against chemoresistance, radio-resistance and cancer stem cells. However, prolonged NSAID treatment accompany several adverse effects. Mechanistically, apart from cyclooxygenase inhibition, NSAIDs directly target mitochondria to induce cell death. Interestingly, there are also incidences of dose-dependent effects where NSAIDs are found to improve mitochondrial health thereby suggesting plausible mitohormesis. While mitochondria-targeted effects of NSAIDs are discretely studied, a comprehensive account emphasizing the multiple dimensions in which NSAIDs affect mitochondrial structure-function integrity, leading to cell death, is lacking. This review discusses the current understanding of NSAID-mitochondria interactions in the pathophysiological background. This is essential for assessing the risk-benefit trade-offs of NSAIDs for judiciously strategizing NSAID-based approaches to manage pain and inflammation as well as formulating effective anti-cancer strategies. We also discuss recent developments constituting selective mitochondria-targeted NSAIDs including theranostics, mitocans, chimeric small molecules, prodrugs and nanomedicines that rationally optimize safer application of NSAIDs. Thus, we present a comprehensive understanding of therapeutic merits and demerits of NSAIDs with mitochondria at its cross roads. This would help in NSAID-based disease management research and drug development.
    Keywords:  Apoptosis; Cancer; Gastropathy; Inflammation; Mitochondria; Non-steroidal anti-inflammatory drug; Oxidative stress
    DOI:  https://doi.org/10.1016/j.bcp.2024.116283
  6. Front Mol Neurosci. 2024 ;17 1394886
    Caffeine improves mitochondrial dysfunction in the white matter of neonatal rats with hypoxia-ischemia through deacetylation: a proteomic analysis of lysine acetylation.
    Yajun Zhang, Yuqian Wang, Haiping Dou, Shanshan Wang, Danyang Qu, Xin Peng, Ning Zou, Liu Yang.
       Aims: White matter damage (WMD) is linked to both cerebral palsy and cognitive deficits in infants born prematurely. The focus of this study was to examine how caffeine influences the acetylation of proteins within the neonatal white matter and to evaluate its effectiveness in treating white matter damage caused by hypoxia-ischemia.
    Main methods: We employed a method combining affinity enrichment with advanced liquid chromatography and mass spectrometry to profile acetylation in proteins from the white matter of neonatal rats grouped into control (Sham), hypoxic-ischemic (HI), and caffeine-treated (Caffeine) groups.
    Key findings: Our findings included 1,999 sites of lysine acetylation across 1,123 proteins, with quantifiable changes noted in 1,342 sites within 689 proteins. Analysis of these patterns identified recurring sequences adjacent to the acetylation sites, notably YKacN, FkacN, and G * * * GkacS. Investigation into the biological roles of these proteins through Gene Ontology analysis indicated their involvement in a variety of cellular processes, predominantly within mitochondrial locations. Further analysis indicated that the acetylation of tau (Mapt), a protein associated with microtubules, was elevated in the HI condition; however, caffeine treatment appeared to mitigate this over-modification, thus potentially aiding in reducing oxidative stress, inflammation in the nervous system, and improving mitochondrial health. Caffeine inhibited acetylated Mapt through sirtuin 2 (SITR2), promoted Mapt nuclear translocation, and improved mitochondrial dysfunction, which was subsequently weakened by the SIRT2 inhibitor, AK-7.
    Significance: Caffeine-induced changes in lysine acetylation may play a key role in improving mitochondrial dysfunction and inhibiting oxidative stress and neuroinflammation.
    Keywords:  caffeine; high performance liquid chromatography; lysine acetylation; microtubule associated protein tau; tandem mass spectrometry; white matter damage
    DOI:  https://doi.org/10.3389/fnmol.2024.1394886
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