bims-miptne 2024-06-02 papers

Curr Pharm Des. 2024 May 27.

Reactive Oxygen Species and Mitochondrial Calcium's Roles in the Development of Atherosclerosis.

K P Helan, Krishna Priya Jha, Nitesh Kumar, Sanjiv Singh.

In the last decade, there has been increasing evidence connecting mitochondrial dysfunction to the onset and advancement of atherosclerosis. Both reactive oxygen species (ROS) and the disruption of mitochondrial calcium (Ca2+) regulation have garnered significant attention due to their involvement in various stages of atherosclerosis. This abstract discusses the potential therapeutic applications of targeting mitochondrial calcium (Ca2+) and reactive oxygen species (ROS), while also providing an overview of their respective roles in atherosclerosis. The abstract underscores the importance of mitochondrial Ca2+ homeostasis in cellular physiology, including functions such as energy production, cell death signaling, and maintaining redox balance. Alterations in the mitochondria's Ca2+ handling disrupt all these procedures and speed up the development of atherosclerosis. Reactive oxygen species (ROS), generated during mitochondrial respiration, are widely recognized as significant contributors to the development of atherosclerosis. Through modulating the function of calcium ion (Ca2+) transport proteins, ROS can impact the regulation of mitochondrial Ca2+ handling. These oxidative modifications lead to vascular remodeling and plaque formation by impairing endothelial function, encouraging the recruitment of inflammatory cells, and promoting smooth muscle cell proliferation. Preclinical investigations indicate that interventions aimed at regulating the production and elimination of reactive oxygen species (ROS) hold promise for mitigating atherosclerosis. Targeting mitochondrial processes represents a prospective therapeutic strategy for addressing this condition. Further research is necessary to elucidate the intricate molecular mechanisms associated with mitochondrial dysfunction in atherosclerosis and develop effective therapeutic strategies to decelerate disease progression.

Keywords: Reactive oxygen species; atherosclerosis; endothelial dysfunction; mechanisms.; mitochondrial Ca2+; mitochondrial respiration

DOI: https://doi.org/10.2174/0113816128303026240514111200

J Cardiovasc Transl Res. 2024 May 28.

Mitochondria-Associated Organelle Crosstalk in Myocardial Ischemia/Reperfusion Injury.

Hui Yao, Yuxin Xie, Chaoquan Li, Wanting Liu, Guanghui Yi.

Organelle damage is a significant contributor to myocardial ischemia/reperfusion (I/R) injury. This damage often leads to disruption of endoplasmic reticulum protein regulatory programs and dysfunction of mitochondrial energy metabolism. Mitochondria and endoplasmic reticulum are seamlessly connected through the mitochondrial-associated endoplasmic reticulum membrane (MAM), which serves as a crucial site for the exchange of organelles and metabolites. However, there is a lack of reports regarding the communication of information and metabolites between mitochondria and related organelles, which is a crucial factor in triggering myocardial I/R damage. To address this research gap, this review described the role of crosstalk between mitochondria and the correlative organelles such as endoplasmic reticulum, lysosomal and nuclei involved in reperfusion injury of the heart. In summary, this review aims to provide a comprehensive understanding of the crosstalk between organelles in myocardial I/R injury, with the ultimate goal of facilitating the development of targeted therapies based on this knowledge.

Keywords: Cell nucleus; Lysosomes; Mitochondria; Mitochondria-associated endoplasmic reticulum membrane (MAM); Myocardial ischemia/reperfusion (I/R) injury; Organelle crosstalk

DOI: https://doi.org/10.1007/s12265-024-10523-9

Mol Neurobiol. 2024 May 31.

Resveratrol Inhibits VDAC1-Mediated Mitochondrial Dysfunction to Mitigate Pathological Progression in Parkinson's Disease Model.

Shenglan Feng, Jianjun Gui, Bingqing Qin, Junjie Ye, Qiang Zhao, Ai Guo, Ming Sang, Xiaodong Sun.

An increase in α-synuclein (α-syn) levels and mutations in proteins associated with mitochondria contribute to the development of familial Parkinson's disease (PD); however, the involvement of α-syn and mitochondria in idiopathic PD remains incompletely understood. The voltage-dependent anion channel I (VDAC1) protein, which serves as a crucial regulator of mitochondrial function and a gatekeeper, plays a pivotal role in governing cellular destiny through the control of ion and respiratory metabolite flux. The ability of resveratrol (RES), which is a potent phytoalexin with antioxidant and anti-inflammatory properties, to regulate VDAC1 in PD is unknown. The objective of this study was to evaluate the role of VDAC1 in the pathological process of PD and to explore the mechanism by which resveratrol protects dopaminergic neurons by regulating VDAC1 to maintain the mitochondrial permeability transition pore (mPTP) and calcium ion balance. The effects of RES on the motor and cognitive abilities of A53T mice were evaluated by using small animal behavioral tests. Various techniques, including immunofluorescence staining, transmission electron microscopy, enzyme-linked immunoadsorption, quantitative polymerase chain reaction (PCR), and Western blotting, among others, were employed to assess the therapeutic impact of RES on neuropathy associated with PD and its potential in regulating mitochondrial VDAC1. The findings showed that RES significantly improved motor and cognitive dysfunction and restored mitochondrial function, thus reducing oxidative stress levels in A53T mice. A significant positive correlation was observed between the protein expression level of VDAC1 and mitochondrial α-syn expression, as well as disease progression, whereas no such correlation was found in VDAC2 and VDAC3. Administration of RES resulted in a significant decrease in the protein expression of VDAC1 and in the protein expression of α-syn both in vivo and in vitro. In addition, we found that RES prevents excessive opening of the mPTP in dopaminergic neurons. This may prevent the abnormal aggregation of α-syn in mitochondria and the release of mitochondrial apoptosis signals. Furthermore, the activation of VDAC1 reversed the resveratrol-induced decrease in the accumulation of α-syn in the mitochondria. These findings highlight the potential of VDAC1 as a therapeutic target for PD and identify the mechanism by which resveratrol alleviates PD-related pathology by modulating mitochondrial VDAC1.

Keywords: Mitochondria; Parkinson’s disease; Resveratrol; VDAC1; α-Synuclein

DOI: https://doi.org/10.1007/s12035-024-04234-0

Cell Mol Life Sci. 2024 May 25. 81(1): 236

EFHD1 promotes osteosarcoma proliferation and drug resistance by inhibiting the opening of the mitochondrial membrane permeability transition pore (mPTP) by binding to ANT3.

Xin Shen, Mengjun Ma, Rujia Mi, Jiahao Zhuang, Yihui Song, Wen Yang, Hongyu Li, Yixuan Lu, Biao Yang, Yinliang Liu, Yanfeng Wu, Huiyong Shen.

Chemoresistance is the main obstacle in the clinical treatment of osteosarcoma (OS). In this study, we investigated the role of EF-hand domain-containing protein 1 (EFHD1) in OS chemotherapy resistance. We found that the expression of EFHD1 was highly correlated with the clinical outcome after chemotherapy. We overexpressed EFHD1 in 143B cells and found that it increased their resistance to cell death after drug treatment. Conversely, knockdown of EFHD1 in 143BR cells (a cisplatin-less-sensitive OS cell line derived from 143B cells) increased their sensitivity to treatment. Mechanistically, EFHD1 bound to adenine nucleotide translocase-3 (ANT3) and inhibited its conformational change, thereby inhibiting the opening of the mitochondrial membrane permeability transition pore (mPTP). This effect could maintain mitochondrial function, thereby favoring OS cell survival. The ANT3 conformational inhibitor carboxyatractyloside (CATR), which can promote mPTP opening, enhanced the chemosensitivity of EFHD1-overexpressing cells when combined with cisplatin. The ANT3 conformational inhibitor bongkrekic acid (BKA), which can inhibit mPTP opening, restored the resistance of EFHD1 knockdown cells. In conclusion, our results suggest that EFHD1-ANT3-mPTP might be a promising target for OS therapy in the future.

Keywords: ANT3; Chemoresistance; EFHD1; Osteosarcoma; mPTP

DOI: https://doi.org/10.1007/s00018-024-05254-8

Stem Cell Res Ther. 2024 May 31. 15(1): 157

Bridging the gap between in vitro and in vivo models: a way forward to clinical translation of mitochondrial transplantation in acute disease states.

MITO2i-MbD Mitochondrial Transplant Consortium

Mitochondrial transplantation and transfer are being explored as therapeutic options in acute and chronic diseases to restore cellular function in injured tissues. To limit potential immune responses and rejection of donor mitochondria, current clinical applications have focused on delivery of autologous mitochondria. We recently convened a Mitochondrial Transplant Convergent Working Group (CWG), to explore three key issues that limit clinical translation: (1) storage of mitochondria, (2) biomaterials to enhance mitochondrial uptake, and (3) dynamic models to mimic the complex recipient tissue environment. In this review, we present a summary of CWG conclusions related to these three issues and provide an overview of pre-clinical studies aimed at building a more robust toolkit for translational trials.

Keywords: Ischemia–reperfusion injury; Joint-on-a-chip; Mitochondria; Mitochondrial transplant; Organ-on-a-chip

DOI: https://doi.org/10.1186/s13287-024-03771-8