bims-miptne 2025-08-17 papers

Cells. 2025 Jul 25. pii: 1148. [Epub ahead of print]14(15):

Intranasal Mitochondrial Transplantation Restores Mitochondrial Function and Modulates Glial-Neuronal Interactions in a Genetic Parkinson's Disease Model of UQCRC1 Mutation.

Jui-Chih Chang, Chin-Hsien Lin, Cheng-Yi Yeh, Mei-Fang Cheng, Yi-Chieh Chen, Chi-Han Wu, Hui-Ju Chang, Chin-San Liu.

The intranasal delivery of exogenous mitochondria is a potential therapy for Parkinson's disease (PD). The regulatory mechanisms and effectiveness in genetic models remains uncertain, as well as the impact of modulating the mitochondrial permeability transition pore (mPTP) in grafts. Utilizing UQCRC1 (p.Tyr314Ser) knock-in mice, and a cellular model, this study validated the transplantation of mitochondria with or without cyclosporin A (CsA) preloading as a method to treat mitochondrial dysfunction and improve disease progression through intranasal delivery. Liver-derived mitochondria were labeled with bromodeoxyuridine (BrdU), incubated with CsA to inhibit mPTP opening, and were administered weekly via the nasal route to 6-month-old mice for six months. Both treatment groups showed significant locomotor improvements in open-field tests. PET imaging showed increased striatal tracer uptake, indicating enhanced dopamine synthesis capacity. The immunohistochemical analysis revealed increased neuron survival in the dentate gyrus, a higher number of tyrosine hydroxylase (TH)-positive neurons in the substantia nigra (SN) and striatum (ST), and a thicker granule cell layer. In SN neurons, the function of mitochondrial complex III was reinstated. Additionally, the CsA-accumulated mitochondria reduced more proinflammatory cytokine levels, yet their therapeutic effectiveness was similar to that of unmodified mitochondria. External mitochondria were detected in multiple brain areas through BrdU tracking, showing a 3.6-fold increase in the ST compared to the SN. In the ST, about 47% of TH-positive neurons incorporated exogenous mitochondria compared to 8% in the SN. Notably, GFAP-labeled striatal astrocytes (ASTs) also displayed external mitochondria, while MBP-labeled striatal oligodendrocytes (OLs) did not. On the other hand, fewer ASTs and increased OLs were noted, along with lower S100β levels, indicating reduced reactive gliosis and a more supportive environment for OLs. Intranasally, mitochondrial transplantation showed neuroprotective effects in genetic PD, validating a noninvasive therapeutic approach. This supports mitochondrial recovery and is linked to anti-inflammatory responses and glial modulation.

Keywords: Parkinson’s disease; UQCRC1 mutation (p.Tyr314Ser) knock-in mice; cyclosporine A; glial modulation; inflammatory cytokines; intranasal delivery; mitochondrial function; mitochondrial transplantation; neuroprotection; striatal astrocytes; striatal oligodendrocytes

DOI: https://doi.org/10.3390/cells14151148

J Nutr Biochem. 2025 Aug 07. pii: S0955-2863(25)00214-1. [Epub ahead of print] 110059

Isosteviol attenuates myocardial ischemia-reperfusion damage by modulating Akt/GSK3β phosphorylation and mitochondrial permeability transition pore opening in female rats.

Victoria Evangelina Mestre Cordero, Romina Hermann, María de Las Mercedes Fernández Pazos, Federico Joaquín Reznik, Lucia Sánchez, Julieta Mourglia, Juliana Perego, Débora Elisabet Vélez, Juan Manuel Prieto, María Gabriela Marina Prendes.

Presently, numerous studies are exploring the cardioprotective effects of compounds from native plants. In particular, research suggests that isosteviol may exert potential cardioprotective effects, linked to Protein Kinase B (Akt) activation. This study aimed to explore the role of Akt and GSK-3β in the cardioprotective effects mediated by the acute administration of isosteviol in Langendorff-perfused female rat hearts subjected to ischemia-reperfusion (Is-Rs). Hearts from female Wistar rats underwent Is-Rs. Isosteviol (5 µM) was added to the perfusate 10 minutes before ischemia. Wortmannin, a phosphatidylinositol 3-kinase (PI3K)/Akt inhibitor (100 nM), was added 15 minutes before ischemia. Mitochondrial ultrastructure was analyzed by electron microscopy, and the phosphorylation profile of Akt and GSK-3β were studied by western blot. Effects on mitochondrial permeability transition pore (MPTP) was assessed by calcium retention capacity (CRC). Docking studies using AutoDock4-Bias were performed, to explore potential interactions between isosteviol and Akt or GSK-3β. ANOVA, n=6/group. Isosteviol improved cardiac post-ischemic mechanical recovery and decreased infarct size. It also increased the phosphorylation of Akt and GSK-3β after Is-Rs. Isosteviol treatment prevented MPTP opening, evidenced, by the increase in CRC, and preserved mitochondria from the expected deterioration toward the end of Is-Rs protocol. All these beneficial effects were prevented, at least in part, by wortmannin. Finally, the results showed that isosteviol interacted with favorable binding energies at the phosphoinositide-binding site of Akt and the kinase site of GSK-3β. These results suggest that cardioprotective effects of isosteviol could be partly mediated by Akt activation, GSK-3β phosphorylation and the inhibition of MPTP opening.

Keywords: Akt; GSK-3β; Isosteviol; MPTP; ischemia-reperfusion; molecular docking

DOI: https://doi.org/10.1016/j.jnutbio.2025.110059

Sci Rep. 2025 Aug 12. 15(1): 29469

2-aminoethoxydiphenylborane intervenes intracellular calcium signaling and attenuates myocardial ischemia-reperfusion injury in mice through ITPR1/MCU pathway.

Hailong Bao, Xin Chen, Xi Hu, Zhaoxing Cao, Wei Zhou, Bingxiu Chen, Fujun Liao, Fang Wei, Runze Huang, Wei Li, Zhangrong Chen.

Myocardial ischemia-reperfusion (MI/R) injury frequently occurs during the clinical management of ischemic heart disease. The underlying mechanism includes neutrophil infiltration, heightened intracellular Ca2+ levels, mitochondrial energy metabolism disorder. This study investigated the pathological role of the inositol 1,4,5-trisphosphate receptor/mitochondrial calcium uniporter (ITPR1/MCU) pathway in regulating disturbances in intracellular calcium ([Ca2+]i) and mitochondrial calcium ([Ca2+]m) levels during MI/R injury. Furthermore, the study explored the potential of 2-aminoethoxydiphenylborane (2-APB) as a cardioprotective agent against MI/R injury. The outcomes of this investigation demonstrated that the ITPR1/MCU pathway was activated after MI/R, leading to [Ca2+]i/[Ca2+]m overload, impairing mitochondrial structure and function, and promoting cardiomyocyte death. The administered treatment attenuates myocardial injury after MI/R by reversing the [Ca2+]i/[Ca2+]m imbalance, maintaining cardiomyocyte mitochondrial homeostasis and promoting cardiomyocyte survival. Furthermore, the administration of 2-APB exerted a suppressive effect on MCU expression. Notably, the activation of MCU abolished the cardioprotective impact mediated by 2-APB. These results suggest that 2-APB intervenes [Ca2+]i/[Ca2+]m balance and maintains mitochondrial function through the ITPR1/MCU pathway. The strategic manipulation of this pathway holds promise as a prospective avenue for the clinical treatment of MI/R injury.

Keywords: 2-aminoethoxydiphenylborane; Calcium overload; Inositol 1,4,5-trisphosphate receptor; Mitochondria; Mitochondrial calcium uniporter; Myocardial ischemia-reperfusion

DOI: https://doi.org/10.1038/s41598-025-14822-2

Front Cardiovasc Med. 2025 ;12 1596757

Cardioprotective effect of Yiqi Huoxue decoction on post-myocardial infarction injury mediated by Ca2+ flux through MAMs.

Yufei Li, Tianhui Du, Yunshu Zhang, Yang Lu, Xinyi Li, Weibin Xie, Shuwen Guo.

Background: Mitochondria-associated membranes (MAMs) regulate cellular Ca2+ and contribute to cardiovascular disease pathogenesis. The IP3R-GRP75-VDAC1 complex is the primary MAMs pathway regulating Ca2+ flux and cardiomyocyte calcium homeostasis. Yiqi Huoxue decoction (YQHX), a Traditional Chinese Medicine formula, shows potential for myocardial infarction (MI) prevention and treatment. However, YQHX's regulation of MAMs and associated Ca2+ mechanisms in MI remains unclear.
Methods: MI rat and oxygen-glucose deprivation cardiomyocytes model were used to mimic myocardial ischemia in human. in vivo, Rats were randomly divided into Sham, Model, YQHX (8.2 g/kg) and Perindopril (10 mg/kg) groups. 28 days after MI, echocardiography, HE, Masson staining and transmission electron microscopy detections were performed to observe cardiac functions and morphology. The effects of YQHX on H9c2 cell viability, mPTP and Ca2+ levels were examined in vitro. Proteins located at MAMs including Cyclophilin D (CypD), Mitochondrial Calcium Uniporter (MCU), Sigma-1 Receptor (Sig-1R), and Neurite Outgrowth Inhibitor B (NOGO-B) are abundantly expressed in myocardial tissue. Consequently, these proteins, along with components of the IP3Rs-GRP75-VDAC1 complex, were detected using WB and qPCR. Mitofusin 2 (Mfn2), which regulates mitochondrial function and Ca2+ flux and is widely expressed at MAMs, was assessed using immunofluorescence.MKT-077, an agent known to disrupt the IP3Rs-GRP75-VDAC1 complex, was employed to investigate the mechanism of YQHX on the complex.
Results: YQHX improved cardiac function and attenuated pathological changes in vivo. It ameliorated MAMs ultrastructure and function, enhancing CypD, MCU, Sig-1R, and NOGO-B expression while reducing IP3R2, GRP75, and VDAC1. in vitro, YQHX significantly increased viability, reduced oxygen-glucose deprivation-induced mPTP opening and Ca2+ levels, upregulated CypD, MCU, Sig-1R, and NOGO-B, and downregulated IP3R2, GRP75, and VDAC1. YQHX also restored MAMs morphology, decreased mPTP opening and Ca2+ levels, and reversed GRP75 downregulation blocked by MKT-077 under oxygen-glucose deprivation.
Conclusions: YQHX exerts cardioprotection against hypoxia by regulating Ca2+ homeostasis and preserving MAMs structure, function, and associated protein expression.

Keywords: IP3Rs-GRP75-VDAC1 complex; MAMS; Yiqi Huoxue decoction (YQHX); cardiomyocytes; myocardial infarction (MI)

DOI: https://doi.org/10.3389/fcvm.2025.1596757

Chem Biol Interact. 2025 Aug 08. pii: S0009-2797(25)00330-8. [Epub ahead of print] 111700

Neonatal sevoflurane anesthesia induces persistent cognitive deficits in mice through CypD-dependent mitochondrial impairment in parvalbumin interneurons.

Xiaoyuan Zhang, Lulu Wang, Xuezhu Zou, Chengyuan Xu, Wenli Qu, Kang Peng, Xianwen Hu, Li Zhang.

Repeated neonatal sevoflurane anesthesia induces cognitive impairment in adulthood, but its neuropathological mechanisms remain unclear. Parvalbumin (PV) interneurons, which rely heavily on mitochondrial stability, are susceptible to anesthesia. Mitochondrial matrix protein Cyclophilin D (CypD) is involved in cognition by regulating the mitochondrial function. To investigate the role of CypD in PV interneurons in neonatal sevoflurane-induced cognitive impairment, postnatal day 6-8 mice were exposed to 3% sevoflurane 2 hours daily in 30% oxygen/70% air. Behavioral tests revealed that repeated sevoflurane exposure induced persistent deficits in novel object recognition, social interaction, and Morris water maze performance; however, these cognitive impairments were prevented in mice with conditional CypD knockout in PV interneurons (PpifF/F-PVCre). Immunofluorescence and Western blot analysis of hippocampal tissues demonstrated upregulated CypD expression in PV interneurons following anesthesia, accompanied by downregulation of vesicular GABA transporter (VGAT); however, these effects were absent in PpifF/F-PVCre mice. Furthermore, sevoflurane reduced mitochondrial membrane potential (MMP) and enhanced oxidative stress. Calcium imaging showed that sevoflurane disrupted mitochondrial calcium homeostasis. Nevertheless, CypD ablation preserved MMP, attenuated oxidative stress, and maintained calcium homeostasis. Synaptic plasticity evaluation using Golgi staining and whole-cell patch-clamp recordings confirmed that sevoflurane reduced dendritic spine density and decreased frequency and amplitude of miniature inhibitory postsynaptic currents (mIPSCs), which was rescued by PV-interneuron-specific CypD deletion. These findings indicate that neonatal exposure to sevoflurane impairs cognition through CypD-dependent mitochondrial dysfunction in PV interneurons, and that targeting CypD in these neurons represents a viable neuroprotective strategy.

Keywords: Cognitive deficits; Cyclophilin D; Mitochondrial function; Parvalbumin interneuron; Sevoflurane anesthesia; Synaptic plasticity

DOI: https://doi.org/10.1016/j.cbi.2025.111700