bims-miptne 2024-06-09 papers

FASEB Bioadv. 2024 Jun;6(6): 143-158

The effects of oxidative stress and intracellular calcium on mitochondrial permeability transition pore formation in equine spermatozoa.

Zamira Gibb, Robert J Aitken, Alecia R Sheridan, Brandan Holt, Stephanie Waugh, Aleona Swegen.

The in vitro storage of stallion spermatozoa for use in artificial insemination leads to oxidative stress and imbalances in calcium homeostasis that trigger the formation of the mitochondrial permeability transition pore (mPTP), resulting in premature cell death. However, little is understood about the dynamics and the role of mPTP formation in mammalian spermatozoa. Here, we identify an important role for mPTP in stallion sperm Ca2+ homeostasis. We show that stallion spermatozoa do not exhibit "classical" features of mPTP; specifically, they are resistant to cyclosporin A-mediated inhibition of mPTP formation, and they do not require exogenous Ca2+ to form the mPTP. However, chelation of endogenous Ca2+ prevented mPTP formation, indicating a role for intracellular Ca2+ in this process. Furthermore, our findings suggest that this cell type can mobilize intracellular Ca2+ stores to form the mPTP in response to low Ca2+ environments and that under oxidative stress conditions, mPTP formation preceded a measurable increase in intracellular Ca2+, and vice versa. Contrary to previous work that identified mitochondrial membrane potential (MMP) as a proxy for mPTP formation, here we show that a loss of MMP can occur independently of mPTP formation, and thus MMP is not an appropriate proxy for the detection of mPTP formation. In conclusion, the mPTP plays a crucial role in maintaining Ca2+ and reactive oxygen species homeostasis in stallion spermatozoa, serving as an important regulatory mechanism for normal sperm function, thereby contraindicating the in vitro pharmacological inhibition of mPTP formation to enhance sperm longevity.

Keywords: JC‐1; horse; mitochondrial permeability transition pore; oxidative stress; spermatozoa

DOI: https://doi.org/10.1096/fba.2023-00051

Mitochondrion. 2024 Jun 05. pii: S1567-7249(24)00066-7. [Epub ahead of print] 101908

The role of mitochondrial genes in ischemia-reperfusion injury: A systematic review of experimental studies.

Zeyu Jennifer Chen, Daniel Rayner, Robert Morton, Laura Banfield, Guillaume Paré, Michael Chong.

Mitochondrial dysfunction contributes to pathological conditions like ischemia-reperfusion (IR) injury. To address the lack of effective therapeutic interventions for IR injury and potential knowledge gaps in the current literature, we systematically reviewed 3800 experimental studies across 5 databases and identified 20 mitochondrial genes impacting IR injury in various organs. Notably, CyPD, Nrf2, and GPX4 are well-studied genes consistently influencing IR injury outcomes. Emerging genes like ALDH2, BNIP3, and OPA1 are supported by human genetic evidence, thereby warranting further investigation. Findings of this review can inform future research directions and inspire therapeutic advancements.

Keywords: In vitro; In vivo; Ischemia-reperfusion injury; Mitochondria; Oxidative stress

DOI: https://doi.org/10.1016/j.mito.2024.101908

Neurochem Res. 2024 Jun 06.

Aerobic Exercise Ameliorates Cognitive Disorder and Declined Oxidative Stress via Modulating the Nrf2 Signaling Pathway in D-galactose Induced Aging Mouse Model.

Guangjing Xie, Zixuan Xu, Feizhou Li, Meng Kong, Ping Wang, Yuping Shao.

The aim of this research was to explore the potential of treadmill exercise in preventing brain aging and neurodegenerative diseases caused by oxidative stress, by studying its effects on D-galactose-induced mice and the mechanisms involved. The results showed that C57BL/6 mice induced with D-gal exhibited cognitive impairment and oxidative stress damage, which was ameliorated by treadmill exercise. The Morris water maze also showed that exercise improved cognitive performance in aging mice and alleviated hippocampal and mitochondrial damage. The study also found that treadmill exercise increased the expression of nuclear factor Nrf2, p-GSK3β, HO-1, NQO1, BDNF, and Bcl-2 proteins while decreasing the expression of Bax. Furthermore, there was a substantial increase in the levels of CAT, GSH-PX and SOD in the serum, along with a decrease in MDA levels. The outcomes propose that aerobic exercise has the potential to hinder oxidative stress and cell death in mitochondria through the modulation of the Nrf2/GSK3β signaling pathway, thus improving cognitive impairment observed in the aging model induced by D-galactose. It appears that treadmill exercise could potentially serve as an effective therapeutic approach to mitigating brain aging and neurodegenerative diseases triggered by oxidative stress.

Keywords: Aerobic exercise; Aging; Cognition; Nrf2 signaling; Oxidative stress

DOI: https://doi.org/10.1007/s11064-024-04164-2

Sci Rep. 2024 06 04. 14(1): 12766

Suppressing mitochondrial inner membrane protein (IMMT) inhibits the proliferation of breast cancer cells through mitochondrial remodeling and metabolic regulation.

Li Liu, Qingqing Zhao, Daigang Xiong, Dan Li, Jie Du, Yunfei Huang, Yan Yang, Rui Chen.

Metabolic reprogramming is widely recognized as a hallmark of malignant tumors, and the targeting of metabolism has emerged as an appealing approach for cancer treatment. Mitochondria, as pivotal organelles, play a crucial role in the metabolic regulation of tumor cells, and their morphological and functional alterations are intricately linked to the biological characteristics of tumors. As a key regulatory subunit of mitochondria, mitochondrial inner membrane protein (IMMT), plays a vital role in degenerative diseases, but its role in tumor is almost unknown. The objective of this research was to investigate the roles that IMMT play in the development and progression of breast cancer (BC), as well as to elucidate the underlying biological mechanisms that drive these effects. In this study, it was confirmed that the expression of IMMT in BC tissues was significantly higher than that in normal tissues. The analysis of The Cancer Genome Atlas (TCGA) database revealed that IMMT can serve as an independent prognostic factor for BC patients. Additionally, verification in clinical specimens of BC demonstrated a positive association between high IMMT expression and larger tumor size (> 2 cm), Ki-67 expression (> 15%), and HER-2 status. Furthermore, in vitro experiments have substantiated that the suppression of IMMT expression resulted in a reduction in cell proliferation and alterations in mitochondrial cristae, concomitant with the liberation of cytochrome c, but it did not elicit mitochondrial apoptosis. Through Gene Set Enrichment Analysis (GSEA) analysis, we have predicted the associated metabolic genes and discovered that IMMT potentially modulates the advancement of BC through its interaction with 16 metabolic-related genes, and the changes in glycolysis related pathways have been validated in BC cell lines after IMMT inhibition. Consequently, this investigation furnishes compelling evidence supporting the classification of IMMT as prognostic marker in BC, and underscoring its prospective utility as a novel target for metabolic therapy.

Keywords: Breast cancer; Metabolic reprogramming; Mitochondria remodeling; Mitochondrial inner membrane protein (IMMT); Prognostic marker

DOI: https://doi.org/10.1038/s41598-024-63427-8

Cell Mol Neurobiol. 2024 Jun 05. 44(1): 49

Urine Proteomic Signatures of Mild Hypothermia Treatment in Cerebral Ischemia-Reperfusion Injury in Rats.

Dandan Zhang, Dapeng Li, Xueting Wang, Yanyan Sui, Fuguo Ma, Yuting Dai, Mingshan Wang, Weiwei Qin.

Mild hypothermia (MH) is an effective measure to alleviate cerebral ischemia-reperfusion (I/R) injury. However, the underlying biological mechanisms remain unclear. This study set out to investigate dynamic changes in urinary proteome due to MH in rats with cerebral I/R injury and explore the neuroprotective mechanisms of MH. A Pulsinelli's four-vessel occlusion (4-VO) rat model was used to mimic global cerebral I/R injury. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was employed to profile the urinary proteome of rats with/without MH (32 °C) treatment after I/R injury. Representative differentially expressed proteins (DEPs) associated with MH were validated by western blotting in hippocampus. A total of 597 urinary proteins were identified, among which 119 demonstrated significant changes associated with MH. Gene Ontology (GO) annotation of the DEPs revealed that MH significantly enriched in endopeptidase activity, inflammatory response, aging, response to oxidative stress and reactive oxygen species, blood coagulation, and cell adhesion. Notably, changes in 12 DEPs were significantly reversed by MH treatment. Among them, 8 differential urinary proteins were previously reported to be closely associated with brain disease, including NP, FZD1, B2M, EPCR, ATRN, MB, CA1and VPS4A. Two representative proteins (FZD1, B2M) were further validated by western blotting in the hippocampus and the results were shown to be consistent with urinary proteomic analysis. Overall, this study strengthens the idea that urinary proteome can sensitively reflect pathophysiological changes in the brain, and appears to be the first study to explore the neuroprotective effects of MH by urinary proteomic analysis. FZD1 and B2M may be involved in the most fundamental molecular biological mechanisms of MH neuroprotection.

Keywords: Animal model; Cerebral ischemia–reperfusion injury; LC–MS/MS; Mild hypothermia; Urine proteome

DOI: https://doi.org/10.1007/s10571-024-01483-4