bims-miptne 2025-09-21 papers

Front Immunol. 2025 ;16 1575242

Cyclophilin D (PPIF) and MPTP in hepatic ischemia-reperfusion injury: insights into mechanisms.

Jingxin Liu, Chengyu Wu, Ziyun Lin, Maomao Ma, Wei Ma, Xuefeng Yu, Kai Wang, Bin Zeng.

Hepatic ischemia-reperfusion injury (HIRI) is a major complication in liver transplantation, hepatic surgeries, and shock-induced acute liver failure. This injury is characterized by mitochondrial dysfunction, oxidative stress, and calcium overload, with the mitochondrial permeability transition pore (mPTP) playing a pivotal role in mediating hepatocyte death. Cyclophilin D (CypD), a key regulator of mPTP opening, has long been associated with the exacerbation of HIRI. However, recent research has uncovered a protective aspect of CypD, revealing that it can regulate intermittent or "flickering" mPTP openings to control calcium overload, preserve mitochondrial integrity, and mitigate damage during ischemic stress. This review highlights the dual role of CypD in regulating mitochondrial damage through mPTP dynamics and its complex interplay with autophagy, specifically mitophagy, in liver injury. We also explore the emerging pharmacological and genetic approaches targeting PPIF, offering potential avenues for mitigating liver injury in clinical settings. This review integrates recent findings on PPIF's role in mPTP regulation, inflammation, autophagy, and mitophagy, proposing a nuanced view of its therapeutic potential in managing hepatic ischemia-reperfusion injury.

Keywords: MPTP; calcium overload; cyclophilin D (CypD); hepatic ischemia-reperfusion injury; inflammatary disease; mechanisms; mitophagy

DOI: https://doi.org/10.3389/fimmu.2025.1575242

Commun Biol. 2025 Sep 19. 8(1): 1348

Interaction of the mitochondrial calcium/proton exchanger TMBIM5 with MICU1.

Li Zhang, Benjamin Gottschalk, Felicia Dietsche, Sara Bitar, Diones Bueno, Liliana Rojas-Charry, Anshu Kumari, Vivek Garg, Wolfgang F Graier, Axel Methner.

Ion transport within mitochondria influences their structure, energy production, and cell death regulation. TMBIM5, a conserved calcium/proton exchanger in the inner mitochondrial membrane, contributes to mitochondrial structure, ATP synthesis, and apoptosis regulation. The relationship of TMBIM5 with the mitochondrial calcium uniporter complex formed by MCU, MICU1-3, and EMRE remains undefined. We generated Tmbim5-deficient Drosophila that exhibit disrupted cristae architecture, premature mitochondrial permeability transition pore opening, reduced calcium uptake, and mitochondrial swelling - resulting in impaired mobility and shortened lifespan. Crossing these with flies lacking mitochondrial calcium uniporter complex proteins was generally detrimental, but partial MICU1 depletion ameliorated the Tmbim5-deficiency phenotype. In human cells, MICU1 rescues morphological defects in TMBIM5-knockout mitochondria, while TMBIM5 overexpression exacerbates size reduction in MICU1-knockout mitochondria. Both proteins demonstrated opposing effects on submitochondrial localization and coexisted in the same macromolecular complex. Our findings establish a functional interplay between TMBIM5 and MICU1 in maintaining mitochondrial integrity, with implications for understanding calcium homeostasis mechanisms.

DOI: https://doi.org/10.1038/s42003-025-08839-6

Cell Signal. 2025 Sep 14. pii: S0898-6568(25)00552-2. [Epub ahead of print]136 112137

YAP regulates the hypertrophy and apoptosis of antler chondrocytes through maintaining calcium homeostasis and mitochondrial function.

Bai-Yu Li, Zhan-Qing Yang, Yin-Fei Xing, Qiao-Ling Zhang, Chen-Hao Wang, Zhan-Peng Yue, Bin Guo.

YAP is required for chondrogenesis and endochondral bone formation, but its effect on the hypertrophy and apoptosis of antler chondrocytes remains unclear. The present study revealed that YAP was abundantly expressed in antler chondrocytes. Inactivation of YAP restrained the hypertrophy of antler chondrocytes and facilitated chondrocyte apoptosis. Further analysis indicated that blockage of YAP induced the accumulation of cytosolic Ca2+ by enhancing the stability of IP3R1/2 mRNA dependent on YTHDF2, that had been identified as a direct downstream target of YAP/TEAD. Meanwhile, attenuation of YAP activated the cytosolic Ca2+-mediated PPP3R1/NFATC pathway and then brought about the elevation of mitochondrial Ca2+ via NFATC-targeted MCU. In antler chondrocytes, inactivation of YAP disrupted the mitochondrial morphology, diminished the ATP content and lowered the mitochondrial membrane potential, but these effects were neutralized by the blockage of MCU. Moreover, inhibition of YAP promoted the leakage of mtROS from dysfunctional mitochondria into the cytosol through opening the mitochondrial permeability transition pore, resulting in intracellular ROS accumulation and lipid peroxidation. Addition of ROS scavenger rescued the defective differentiation of antler chondrocytes and protected chondrocytes against apoptosis under the context of YAP inactivation. Collectively, YAP regulated the hypertrophy and apoptosis of antler chondrocytes through maintaining Ca2+ homeostasis and mitochondrial function.

Keywords: Antler chondrocytes; Ca(2+) homeostasis; Mitochondrion; YAP; mtROS leakage

DOI: https://doi.org/10.1016/j.cellsig.2025.112137