bims-miptne 2025-12-07 papers

Toxicol Rep. 2025 Dec;15 102156

Comparative effects of antimalarial drugs on oxidative phosphorylation, mitochondrial dynamics and mitophagy in Plasmodium berghei-infected mice.

John Oludele Olanlokun, Oluseye Osovehe Yahaya, Cecilia Opeyemi Babarinde, Oluwakemi Marvellous Oloke, Paul Steenkamp, Gerhard Prinsloo.

Mitochondria occupy prominent position in cell metabolism. Information on changes in host mitochondrial capacity in electron transport system, dynamics and mitophagy in mice infected with resistant Plasmodium berghei and thereafter treated with some orthodox drugs, is critical to the survival and the organelles' metabolism. In this study, the effects of some antimalarial drugs were investigated on mitochondrial permeability transition (mPT) pore opening, FoF1 ATPase and lipid peroxidation, oxidative phosphorylation and mitochondrial dynamics in mice infected with chloroquine resistant (ANKA) strain of Plasmodium berghei. Thirty-five Swiss-mice (18 ± 3 g) were infected intraperitoneally with chloroquine resistant (ANKA) strain of Plasmodium berghei and treated orally and once daily with (10 mg/kg) dose of Amodiaquine artesunate (AA), Artemether-Lemefantrine (AL), Sulfadoxine- pyrimethamine (SP) and Artesunate (ART), On day 6, animals were sacrificed and livers were removed. Liver mitochondria were isolated and mitochondrial permeability transition (mPT) pore opening, F0F1 ATPase (mATPase) and lipid peroxidation (mLPO) were determined spectrophotometrically. Gene expressions on liver mitochondrial complexes I, II, III, IV and V, DNM1L, DRP1, OPA 1 Mitofusin 1 and 2, PINK 1, FUNDC1, PGC-1α and prohibitins 1 and 2 were determined using gel electrophoresis. AA, AL and SP did not significantly open the mPT pore while ART caused its opening (7 fold) and enhance mitochondrial FoF1 ATPase (P < 0.01), SP and AA induced peroxidation of mitochondrial membrane phospholipids (P < 0.01) when compared to the infected control. SP and AA significantly silenced the expressions of mitochondrial complexes. The effects of these drugs on mitochondrial fission and fusion vary significantly: AA down-regulated the expressions of DRP1, OPA 1 while AA, AL and ART decreased the expression of Mitofusin 2 as observed in the infected control. Significant down-regulation in the expressions of PINK 1 by SP, FUNDC1 by AA and AL, DNM1L by ART, PGC-1α by AA, AL, and ART, and prohibitins 1 and 2 by AA and AL similar to the infected control were observed. This study showed that host mitochondria respond differently to antimalarial drugs.

Keywords: Electron transport; Fission; Fusion; Mitochondrial dynamics; Permeability transition Plasmodium berghei

DOI: https://doi.org/10.1016/j.toxrep.2025.102156

ACS Nano. 2025 Nov 30.

Sequential Mitochondrial Transplantation for Myocardial Ischemia-Reperfusion Injury Treatment.

Ziyu Wu, Zichun Zhao, Ronghuang Yu, Yuning Sun, Wenyan Guo, Jun Wang, Chun Mao, Mimi Wan, Min Zhou.

The treatment of myocardial ischemia-reperfusion injury (IRI) requires urgent improvement of mitochondrial dysfunction and sustained energy supply to restore cardiac function, but currently, there is a lack of effective strategies to meet these needs. Here, we transplanted mitochondria to treat myocardial IRI by a sequential administration approach. First, nanomotors with chemotactic target ability are modified on the surface of mitochondria to obtain engineered mitochondrial nanomotors. Then, denatured bovine serum albumin is modified outside the nanomotor, enabling mitochondria to hitchhike on activated neutrophils to accumulate in the damaged heart. During reperfusion, immediate intramyocardial injection of these mitochondria can stabilize energy supply and rescue dying cardiomyocytes from IRI. In the subsequent tissue repair stage, the mitochondria injected intravenously can achieve stepwise targeting to the damaged heart by hitchhiking on activated neutrophils and chemotactic behavior of nanomotors, thereby continuously supplementing energy to cardiomyocytes and enhancing cardiac function. In addition, in vivo results show that sequential administration reduces adverse reactions such as arrhythmia caused by high-dose mitochondrial transplantation. Compared with existing treatment methods, this design of sequential administration is a special strategy targeting the specific needs and inflammatory microenvironment of myocardial IRI, better promoting the clinical translation of mitochondrial transplantation.

Keywords: mitochondrial transplantation; myocardial ischemia-reperfusion injury; nanomotor; neutrophil hitchhiking; sequential therapy

DOI: https://doi.org/10.1021/acsnano.5c10203

ACS Appl Mater Interfaces. 2025 Dec 04.

Thiosulfate-Enhanced Fenton-Like Nanocatalyst for Synergistic Chemodynamic Therapy and Calcium Death in Tumor Treatment.

Zhaomin Tang, Yudong Wang, Kanglin Chen, Yaning Ou, Wenxin Liao, PinJia Zhong, Huangzhao Wei, Qiuye Jin.

To enhance chemodynamic therapy (CDT) and induce calcium overload in tumor cells, we developed a novel nanocatalyst, Cu/ZIF-8@CaS2O3@PEG (CZCaP) via a dual-pathway strategy. The system was constructed based on a biocompatible ZIF-8 scaffold, which incorporated Cu2+ ions as the catalytic center and was loaded with calcium thiosulfate (CaS2O3) as a therapeutic agent. The surface of the nanocatalyst was modified with PEG to enable a tumor microenvironment (TME)-responsive drug release. Under acidic TME conditions, CZCaP dissociated to release CaS2O3 and Cu2+. The thiosulfate ions (S2O32-) acted as a cocatalyst by donating electrons to hydroperoxyl (•OOH) radicals generated from H2O2 decomposition. This reaction accelerated the Cu(II)/Cu(I) redox cycling, leading to an enhanced production of hydroxyl radicals (•OH). Consequently, glutathione (GSH) was depleted, compromising the antioxidant capacity of tumor cells. Simultaneously, •OH-mediated oxidative damage impaired PMCA4, a calcium efflux pump, resulting in intracellular accumulation of Ca2+ and ultimately calcium overload. Furthermore, •OH downregulated the antiapoptotic protein Bcl-2, collapsed the mitochondrial membrane potential, and promoted calcium influx into mitochondria, thereby inducing apoptosis. By integrating inorganic cocatalysis with the disruption of calcium signaling, this system overcomes the limitation of conventional CDT and presents an innovative multimodal strategy for tumor therapy.

Keywords: calcium overload; chemodynamic therapy; hydroxyl radicals; nanocatalyst; tumor microenvironment

DOI: https://doi.org/10.1021/acsami.5c18937

Mol Cell. 2025 Dec 03. pii: S1097-2765(25)00909-8. [Epub ahead of print]

The landscape of regulated cell death: It's all downhill from here.

Andreas Aufschnaiter, Teak-Jung Oh, Andrew Oberst.

Cells can die via any of several forms of regulated cell death (RCD), including apoptosis, pyroptosis, and necroptosis. We now appreciate that there is substantial crosstalk between them, allowing for a high degree of plasticity downstream of cell death triggers. Understanding this is essential to delineate roles of RCD in development, homeostasis, tumor biology, and immunity; however, this crosstalk can make the fate of individual cells difficult to visualize. Here, we present a conceptual framework that builds on Waddington's landscape model of lineage commitment. On the landscape of RCD, live cells begin atop a "mountain," from which they roll down via "valleys" representing different cell death programs, potentially being diverted or even raised back to the summit by regulators of these processes. While acknowledging that, like any conceptual framework, this visualization is imperfect, we hope it presents a succinct approach to understand the complexities and interconnections of cell death regulation.

Keywords: apoptosis; necroptosis; programmed cell death; pyroptosis; regulated cell death

DOI: https://doi.org/10.1016/j.molcel.2025.11.013

Life Sci. 2025 Nov 29. pii: S0024-3205(25)00763-5. [Epub ahead of print]385 124127

Mitochondria at the crossroads of aging and cardiovascular disease.

Olubodun Michael Lateef, Sodiq Fakorede, Chanel Harris, Adeola Mariam Lateef, Ayodeji Folorunsho Ajayi.

Mitochondrial dysfunction plays a critical role in cardiovascular aging and is a key player in the development of cardiovascular diseases (CVDs) such as hypertension, arteriosclerosis, aneurysms, and heart failure. Aging disrupts mitochondrial function through impaired oxidative phosphorylation, excessive reactive oxygen species generation, mitochondrial DNA mutations, endoplasmic reticulum stress, mitochondrial enzyme dysregulation, and impaired calcium homeostasis. These alterations drive endothelial dysfunction, arterial stiffening, cardiac remodeling, and ultimately exacerbate age-related cardiovascular decline. Despite extensive research, the precise mechanisms by which mitochondrial aging impairs the function of endothelial cells, vascular smooth muscle cells, and cardiomyocytes remain poorly understood. Therefore, this review synthesizes current evidence on how aging-associated mitochondrial dysfunction contributes to endothelial dysfunction, arterial stiffening and remodeling, and cardiac dysfunction. It also outlines emerging pathophysiological mechanisms linking mitochondrial dysfunction to age-related CVDs, offering insights into potential therapeutic targets to promote cardiovascular health in aging populations. This review highlights key biomarkers of declining mitochondrial function to facilitate early diagnosis of CVD-related mitochondrial dysfunction. We show that aging disrupts key regulators of mitochondrial dynamics and quality control in the vasculature and heart across human studies and preclinical models of aging. Recent evidence indicates that impaired mitochondrial function in aging cardiomyocytes results in valvular degeneration, left ventricular hypertrophy, diastolic dysfunction, atrial fibrillation, and diminished exercise capacity. Therefore, understanding the pathophysiological mechanisms linking mitochondrial dysfunction to cardiovascular aging may guide the development of new therapeutic strategies for mitigating age-related cardiovascular decline in older adults.

Keywords: Arterial disease; Cardiomyopathy; Cardiovascular aging; Endothelial dysfunction; Mitochondrial dysfunction

DOI: https://doi.org/10.1016/j.lfs.2025.124127