bims-miptne 2026-01-11 papers

Cell Mol Neurobiol. 2026 Jan 09.

Genetic Deletion of Cyclophilin D Results in Enhanced Hypoxia Tolerance in Mice.

Yanying Liu, Haiyang Jiang, Lisha Cao, Jiayi Li, Ziya Zhang, Zuoyingjie Dong, Xiao-Ping Wang, Peng-Cheng Wang.

Hypoxic preconditioning (HPC) activates intracellular anti-hypoxia molecular defense mechanisms through short-term non-lethal repeated hypoxic stimulation, leading to the subsequent acquisition of high tolerance to lethal hypoxic damage in cells. Cyclophilin D (CypD) regulates the function of mitochondria by controlling the opening of the mitochondrial permeability transition pore. However, the mechanism of action of CypD in hypoxia and HPC is poorly understood. Here, we examined the role of CypD under HPC using both wild-type (WT) and Ppif gene knockout (KO) mice. The results showed that HPC could induce increased hypoxia tolerance in WT and KO mice. Compared to the WT group, KO mice showed a more significant improvement in hypoxia tolerance. Moreover, there are differences in the activation time of HIF-1α and the number of apoptotic cells in the brain tissues of WT and KO mice. Further investigation indicated that proteins related to cell apoptosis, as well as the expression levels of MAPKs, including JNK and ERK, were changed in the brains of mice. The above results demonstrate that the key regulatory role of mitochondrial function-related protein CypD in HPC processes affects cell survival. This study will provide valuable support for the selection of CypD as a key new target for the future treatment of hypoxia and hypoxia-related diseases.

Keywords: Apoptosis; Cyclophilin D; HIF-1α; Hypoxic preconditioning; Mitochondrial permeability transition pore

DOI: https://doi.org/10.1007/s10571-025-01649-8

Redox Biol. 2025 Dec 11. pii: S2213-2317(25)00488-4. [Epub ahead of print]89 103975

Fetal programming of the cardiac mitochondrial permeability transition pore in male offspring from hypoxic pregnancies.

Kerri L M Smith, Philippe Pasdois, Mafalda Pires, Mitchell C Lock, Gina L J Galli.

A lack of oxygen during fetal development (fetal hypoxia) permanently alters the structure and function of the heart, leading to increased susceptibility to ischemia reperfusion (IR) injury in adulthood. However, the underlying cellular mechanisms are incompletely understood. In this study, we used a rat model to understand the role of calcium, reactive oxygen species and the mitochondrial permeability transition pore (MPTP) in programming IR sensitivity in offspring from hypoxic pregnancies. Pregnant Wistar rats were subjected to either ambient oxygen (∼21 %) throughout gestation, 13 % oxygen from gestational day 6-20, or 10.5 % oxygen from gestational day 15-20 (rat term ∼ 22 days). Offspring were raised to adulthood and hearts were subjected to ex vivo IR injury during Langendorff perfusion, whilst measuring ventricular pressure, intracellular calcium, oxidative stress and NAD(P)H autofluorescence. In addition, calcium retention capacity (CRC) and MPTP components were measured in isolated mitochondria, as well as basal H2O2 emission and electron transport system activity. Exposure to fetal hypoxia (10.5 % oxygen) increased IR sensitivity in adult offspring, demonstrated by increased diastolic pressure (p < 0.05), lipid peroxidation (p < 0.05), and an increased rate of NAD(P)H oxidation (p < 0.05) at reperfusion. This increased sensitivity to IR was associated with a decreased CRC (p < 0.01), increased basal H2O2 emission (p < 0.05) and decreased basal respiratory capacity linked to complex IV (p < 0.01). Additionally, both models of fetal hypoxia (13 % and 10.5 %) increased the abundance of the MPTP regulatory protein cyclophilin D in adult hearts (p < 0.01 and <0.001, respectively). Together, these data suggest that exposure to hypoxia during fetal development can programme MPTP calcium sensitivity by altering factors that modulate the pore (e.g. H2O2 emission, electron transport system activity, NAD(P)H oxidation and CypD content). These data could help to explain why individuals from hypoxic pregnancies are more susceptible to myocardial infarction, and other cardiovascular diseases.

Keywords: Fetal; Heart; Hypoxia; MPTP; Programming; ROS

DOI: https://doi.org/10.1016/j.redox.2025.103975

Cell Death Dis. 2026 Jan 08. 17(1): 10

Calcium overload induced mitochondrial and lysosomal dysfunction is regulated by Tousled-like kinase in a-synucleinopathy.

Fangyan Gong, Qi Cheng.

As a pathological hallmark of Parkinson's disease (PD), a-synucleinopathy induces various cellular damages, including calcium overload, mitochondrial and autophagic dysfunction, ultimately resulting in dopaminergic neuron death. However, the hierarchy of these detrimental events remains unclear. It is well established that a-synuclein can induce calcium overload through diverse mechanisms. To assess whether calcium overload plays a crucial detrimental role, we established a calcium overload model in Drosophila and conducted genetic screening. Our findings indicate that calcium overload caused mitochondrial damage and lysosomal dysfunction, leading to cell death, and these cytotoxic processes were significantly mitigated by the loss of Tousled-like kinase (TLK). Notably, the loss of TLK also ameliorated defects induced by a-synuclein overexpression in Drosophila. This suggests that calcium overload is a critical event in a-synucleinopathy. In mammalian cells and mice, calcium overload activated TLK2 (the homologue of Drosophila TLK) by enhancing TLK2 phosphorylation, which increases TLK2 kinase activity. Increased TLK2 phosphorylation was detected in the brains of GluR1Lc and a-synuclein overexpression mice, suggesting that TLK2 is activated under these pathological conditions. Furthermore, TLK2 knockout mice exhibited rescue of multi-aspect cytotoxicity induced by calcium overload and a-synuclein overexpression. Our research demonstrates that TLK2 activation by calcium overload appears to be a pivotal step in the progression of PD. This finding provides a potential link between calcium overload, the subsequent mitochondrial and lysosomal dysfunction observed in the disease.

DOI: https://doi.org/10.1038/s41419-025-08213-8

Biochem Biophys Res Commun. 2025 Dec 24. pii: S0006-291X(25)01916-3. [Epub ahead of print]799 153200

Design-driven optimization of mitochondrial protein phosphatases for in vitro studies.

Mariana L Gabas, Luca P Otvos, Naira B O Almeida, Sofia O Farias, Giovanna S Val, Luciana E S F Machado.

Molecular cloning and heterologous protein expression are essential for investigating protein function and interactions with ligands such as small molecules, drugs, and other proteins. Studies on the redox regulation, intermolecular interactions, structural determination, and structural dynamics of mitochondrial protein phosphatases require high-yield expression of soluble, catalytically active enzymes. Accordingly, the aim of this study was to optimize the cloning, expression, and soluble purification of mitochondrial protein phosphatases in their monomeric and active forms. We designed 22 expression constructs encoding the mitochondrial protein phosphatases PTPMT1, PP2Cm, PPTc7, and PGAM5, incorporating variations with or without the mitochondrial targeting sequence (MTS) and solubility-enhancing fusion tags. Our results demonstrate that, for matrix localized phosphatases, MTS removal combined with a soluble fusion tag is essential for obtaining soluble, structurally stable, properly folded, and catalytically active proteins. In contrast, intermembrane space phosphatase PGAM5 was well structured and active across constructs, thoug MTS presence reduced expression yields and increased protein instability. Overall, this work underscores the critical role of rational construct design for the successful production of mitochondrial protein phosphatases suitable for in vitro biochemical and structural studies.

Keywords: Mitochondrial targeting signal; PGAM5; PP2Cm; PPTc7; PTPMT1; Protein phosphatase; Solubility

DOI: https://doi.org/10.1016/j.bbrc.2025.153200

Nat Cell Biol. 2026 Jan 06.

Mitotic errors as triggers of cell death and inflammation.

Dario Rizzotto, Christian Zierhut, Andreas Villunger.

Bursts of cell proliferation after infection, injury or transformation can coincide with DNA damage and spindle assembly defects. These increase the risk of cell cycle arrest in mitosis, during which many cellular processes are uniquely regulated. Ultimately, cells arrested during mitosis may die, but adaptive mechanisms also allow their escape into the next interphase. This step can have variable consequences, including chromosome missegregation, polyploidization and centrosome amplification. Escaping cells can also initiate innate immune signalling, enter senescence or engage cell death, which in turn alert the microenvironment through nucleic acid sensing mechanisms and/or the release of danger-associated molecular patterns. Here we discuss the causes and consequences of deregulated mitosis and postmitotic cell fate, highlighting the impact of DNA damage repair, the spindle assembly checkpoint and extra centrosomes on genome integrity, as well as inflammatory signalling. Finally, we attempt to reconcile conflicting observations and propose variable modes that activate innate immune responses after mitotic perturbations.

DOI: https://doi.org/10.1038/s41556-025-01785-9