bims-miptne 2025-08-31 papers

bims-miptne

Biomed News

on Mitochondrial permeability transition pore-dependent necrosis

Issue of 2025–08–31
eight papers selected by
Oluwatobi Samuel Adegbite, University of Liverpool

The Mitochondrial Permeability Transition Pore in Platelets: Mechanisms, Physiological Roles, and Therapeutic Perspectives.
MRPL13 enhances mitochondrial function and promotes tumor progression in ovarian cancer by inhibiting mPTP opening via SLC25A6.
mTORC2/Akt axis promotes proteotoxic stress and mitochondrial Ca2+ overload during celastrol-induced paraptosis.
Allicin Attenuates Mitochondrial Calcium (Ca2+) Overload Induced by Acrylamide in Hepatocytes via the NAD+/SIRT3-FoxO3 Axis.
Inorganic Polyphosphate: An Emerging Regulator of Neuronal Bioenergetics and Its Implications in Neuroprotection.
Mitochondrial calcium uniporter promotes MSU crystal-induced inflammation through inducing mitochondrial Ca2+ overload and ubiquitination of SIRT5 protein.
The Multifaceted Role of Mitochondria in Angiogenesis.
A computational model of system dynamics of calcium and nitric oxide in pancreatic beta-cell.

Antioxidants (Basel). 2025 Jul 29. pii: 923. [Epub ahead of print]14(8):

The Mitochondrial Permeability Transition Pore in Platelets: Mechanisms, Physiological Roles, and Therapeutic Perspectives.

Chiara Lonobile, Alessia Di Nubila, Rosa Simone, Matilda Hushi, Silvia Stella Barbieri.

  Platelets have long been known to be critically involved in hemostasis and thrombosis. However, platelets are also recognized as metabolically active cells that require well-regulated mitochondrial function to support their multiple functions in hemostasis, thrombosis, and inflammation. Mitochondrial activity has also recently been shown to play a crucial role in determining platelet activation, survival, and pro-inflammatory potential. A key nexus in these processes is the mitochondrial permeability transition pore (mPTP), a high-conductance channel in the inner mitochondrial membrane. Sustained mPTP opening triggers mitochondrial depolarization, the cessation of ATP synthesis, osmotic swelling, and, finally, platelet dysfunction or clearance. However, its transient opening might play physiological signaling roles. This review summarizes the current understanding of the molecular components and regulatory factors governing the platelet mPTP, explores its physiological and pathological relevance, and evaluates its potential as a therapeutic target in cardiovascular disease, inflammation, cancer, and potentially neurodegenerative diseases. We also highlight the ongoing challenges and crucial future directions in deciphering the complexities of platelet mitochondrial dynamics and mPTP functions.

Keywords:  mitochondrial permeability transition pore; platelets; therapeutic targets

DOI:  https://doi.org/10.3390/antiox14080923
Cell Death Dis. 2025 Aug 21. 16(1): 634

MRPL13 enhances mitochondrial function and promotes tumor progression in ovarian cancer by inhibiting mPTP opening via SLC25A6.

Ouxuan Liu, Yuexin Hu, Shuang Wang, Xin Nie, Yuxuan Wang, Xiangcheng Fan, Kai Zeng, Xiao Li, Bingying Liu, Bei Lin.

Tumor cells typically exhibit dysregulation of mitochondrial energy metabolism and cell death. The role of mitochondrial function in ovarian cancer (OC) progression has garnered substantial attention, yet its precise molecular mechanisms remain elusive. Mitochondrial ribosomal protein L13 (MRPL13), involved in the translation of oxidative phosphorylation (OXPHOS) complex subunits, plays a critical role in regulating mitochondrial function. Our study demonstrated that MRPL13 is highly expressed in OC tissues and correlated with poor prognosis. Both in vitro and in vivo experiments confirmed that MRPL13 overexpression significantly promotes the malignant biological behavior of OC, while MRPL13 knockdown induces the opposite phenotype. Moreover, MRPL13 knockdown impairs mitochondrial function in OC cells, leading to decreased OXPHOS and ATP levels, increased reactive oxygen species (ROS) generation, mitochondrial depolarization, aberrant opening of the mitochondrial permeability transition pore (mPTP), and mitochondrial structural damage. Mechanistically, MRPL13 specifically interacts with SLC25A6 and facilitates its degradation via lysine (K)48-linked ubiquitination. MRPL13 inhibits mPTP opening by accelerating the degradation of SLC25A6, thereby preventing cytochrome c release into the cytoplasm, inhibiting cell death, and enhancing mitochondrial function. In conclusion, our study elucidates the mechanism by which the MRPL13-SLC25A6 axis enhances mitochondrial function and promotes tumor progression in OC by inhibiting mPTP opening, suggesting that MRPL13 holds significant potential for prognostic evaluation and targeted therapy in OC.

DOI: https://doi.org/10.1038/s41419-025-07953-x
Biochem Biophys Res Commun. 2025 Aug 11. pii: S0006-291X(25)01189-1. [Epub ahead of print]781 152474

mTORC2/Akt axis promotes proteotoxic stress and mitochondrial Ca2+ overload during celastrol-induced paraptosis.

Yeon Jung Park, Mi-Young Cho, In Young Kim, Dong Min Lee, Gyesoon Yoon, Kyeong Sook Choi.

  Celastrol, a triterpenoid with anticancer potential, induces paraptosis in breast cancer cells-a non-apoptotic form of cell death characterized by vacuolization of the endoplasmic reticulum (ER) and mitochondria. Although celastrol shows therapeutic promise, the signaling mechanisms mediating this pathway remain poorly defined. Here, we report that celastrol transiently activates both mTORC1 and mTORC2; however, only the mTORC2/Akt axis is essential for executing paraptotic cell death. Genetic or pharmacological inhibition of mTORC2 or Akt attenuated celastrol-induced cell death, reduced proteotoxic stress-evident from diminished polyubiquitinated protein accumulation and CHOP expression-and suppressed mitochondrial Ca2+ overload by downregulating the mitochondrial calcium uniporter (MCU) and MICU1. Knockdown of Raptor (mTORC1 component) did not affect these processes, indicating a specific role for mTORC2. These findings define mTORC2/Akt signaling as a pro-death regulator in paraptosis, highlighting its unexpected role in driving proteotoxic and mitochondrial stress.

Keywords:  Akt; Celastrol; Mitochondrial Ca(2+) overload; Paraptosis; Proteotoxic stress; mTORC2

DOI:  https://doi.org/10.1016/j.bbrc.2025.152474
J Agric Food Chem. 2025 Aug 27.

Allicin Attenuates Mitochondrial Calcium (Ca2+) Overload Induced by Acrylamide in Hepatocytes via the NAD+/SIRT3-FoxO3 Axis.

Lu Li, Ziyue Wang, Haiyang Yan, Ping Zhao, Yuan Yuan.

  Acrylamide (AA) is a byproduct of the Maillard reaction, with mitochondrial damage playing a pivotal role in mediating its hepatotoxicity. Allicin, a potent dietary phytochemical, has been used to mitigate the hepatotoxicity of AA. This study confirmed that allicin attenuated mitochondrial structural damage in AA-treated livers and AML-12 cells. Liver RNA-seq analysis identified that Ca2+ transport and nicotinamide adenine dinucleotide (NAD+) metabolism, which were associated with mitochondrial function, contributed to the hepatoprotective effects of allicin. Subsequent experiments demonstrated that allicin inhibited AA-caused excessive formation of the mitochondrial-associated endoplasmic reticulum membrane (MAM) and activation of the Ca2+ channel components. Additionally, allicin restored AA-suppressed NAD+ content and the expression of its dependent deacetylase SIRT3, thereby promoting FoxO3 deacetylation and protecting hepatocytes from mitochondrial Ca2+ overload. Deficiency of SIRT3 eliminated the protective effect of allicin, confirming that allicin antagonized AA-induced hepatotoxicity by regulating mitochondrial Ca2+ homeostasis through the NAD+/SIRT3-FoxO3 axis.

Keywords:  FoxO3; SIRT3; acrylamide (AA); allicin; mitochondrial calcium (Ca2+)

DOI:  https://doi.org/10.1021/acs.jafc.5c04431
Biomolecules. 2025 Jul 22. pii: 1060. [Epub ahead of print]15(8):

Inorganic Polyphosphate: An Emerging Regulator of Neuronal Bioenergetics and Its Implications in Neuroprotection.

Marcela Montilla, Norma Pavas-Escobar, Iveth Melissa Guatibonza-Arévalo, Alejandro Múnera, Renshen Eduardo Rivera-Melo, Felix A Ruiz.

  Inorganic polyphosphate (polyP) is an evolutionarily conserved polymer that has recently gained relevance in neuronal physiology and pathophysiology. Although its roles, such as mitochondrial bioenergetics, calcium homeostasis, and the oxidative stress response, for example, are increasingly recognized, its specific implications in neurological disorders remain underexplored. This review focuses on synthesizing the current knowledge of polyP in the context of central nervous system (CNS) diseases, highlighting how its involvement in key mitochondrial processes may influence neuronal survival and function. In particular, we examine recent evidence linking polyP to mechanisms relevant to neurodegeneration, such as the modulation of the mitochondrial permeability transition pore (mPTP), regulation of amyloid fibril formation, and oxidative stress responses. In addition, we analyze the emerging roles of polyP in inflammation and related cell signaling in CNS disorders. By organizing the existing data around the potential pathological and protective roles of polyP in the CNS, this review identifies it as a candidate of interest in the context of neurodegenerative disease mechanisms. We aim to clarify its relevance and stimulate future research on its molecular mechanisms and translational potential.

Keywords:  inorganic polyphosphate (polyP); mitochondrial bioenergetics; neurodegenerative diseases; neuroprotection; therapeutic target

DOI:  https://doi.org/10.3390/biom15081060
Arthritis Res Ther. 2025 Aug 22. 27(1): 168

Mitochondrial calcium uniporter promotes MSU crystal-induced inflammation through inducing mitochondrial Ca2+ overload and ubiquitination of SIRT5 protein.

Qingqing Yu, Renjie Li, Guizhao Yang, Yan Xiao, Xingyu Liu, Yaxin Deng, Xiongyan Luo, Qian Dai, Mei Zeng.

   BACKGROUND: The mitochondrial calcium uniporter (MCU) is the key channel regulating mitochondrial calcium (Ca²⁺) uptake. Growing evidence indicates that mitochondrial Ca²⁺ homeostasis plays a pivotal role in regulating immune cell function. However, how MCU contributes to MSU crystal-driven inflammation and its molecular mechanisms are unclear.
METHODS: Using bone marrow-derived macrophages (BMDMs), wild-type (WT, MCU⁺/⁺), and MCU knockout (MCU⁻/⁻) mice, we investigated the role of MCU in MSU crystal-induced inflammation. Co-immunoprecipitation assays were employed to examine interactions among MCU, SIRT5, and TRIM21.
RESULTS: MSU crystals stimulation up-regulated MCU expression and triggered mitochondrial Ca²⁺ overload in macrophages. MCU deficiency reduced mitochondrial Ca²⁺ accumulation, ameliorated mitochondrial dysfunction, and suppressed NLRP3 inflammasome activation in BMDMs treated with MSU crystals. Mechanistically, MCU promoted TRIM21 expression, leading to SIRT5 ubiquitination and degradation. Furthermore, MCU facilitated the interaction between TRIM21 and SIRT5, with MSU crystals enhancing this tripartite association. TRIM21 and SIRT5 were identified as key downstream effectors of MCU, mediating MSU crystal-induced inflammatory responses and oxidative stress. In vivo, MCU deficient mice exhibited diminished immune cell infiltration and IL-1β production in MSU crystal-induced peritonitis and arthritis models.
CONCLUSION: Our findings demonstrate that MCU drives mitochondrial Ca²⁺ overload in MSU crystal-induced inflammation and promotes SIRT5 degradation via the TRIM21-SIRT5 signaling axis. These insights highlight MCU as a potential therapeutic target in gouty inflammation.

Keywords:  MCU; MSU crystals; Mitochondrial Ca2+ ; SIRT5; TRIM21

DOI:  https://doi.org/10.1186/s13075-025-03627-3
Int J Mol Sci. 2025 Aug 18. pii: 7960. [Epub ahead of print]26(16):

The Multifaceted Role of Mitochondria in Angiogenesis.

Sara Cannito, Ida Giardino, Maria d'Apolito, Massimo Pettoello-Mantovani, Francesca Scaltrito, Domenica Mangieri, Annamaria Piscazzi.

  Angiogenesis, the formation of new blood vessels from pre-existing ones, is crucial for various physiological and pathological conditions, including embryonic development, wound healing, tissue regeneration and tumor progression. While traditionally attributed to the actions of growth factors and their receptors, emerging evidence highlights the crucial regulatory roles of mitochondria in angiogenesis. This narrative review explores the multifaceted functions of mitochondria in endothelial cells, which are central to blood vessel formation. Beyond their classical role in ATP production, mitochondria contribute to angiogenesis through redox signaling, calcium homeostasis, biosynthetic activity, and reactive oxygen species (ROS) generation. These organelles help regulate key endothelial behaviors such as proliferation, migration, and tube formation through mechanisms that include mitochondrial calcium signaling and ROS-mediated stabilization of hypoxia-inducible factor-1α (HIF-1α), leading to increased vascular endothelial growth factor (VEGF) expression. Additionally, mitochondrial dynamics, dysfunction, and genetic factors are discussed for their influence on angiogenic outcomes. Understanding these complex mitochondrial functions opens new therapeutic avenues for modulating angiogenesis in diseases such as cancer and cardiovascular disorders.

Keywords:  VEGFR2; angiogenesis; mitochondria; mitochondrial calcium transport; mtROS-HIF1a-VEGF axis

DOI:  https://doi.org/10.3390/ijms26167960
Comput Methods Biomech Biomed Engin. 2025 Aug 21. 1-16

A computational model of system dynamics of calcium and nitric oxide in pancreatic beta-cell.

Vaishali

  Calcium (Ca2+) and nitric oxide (NO) play a crucial role in chemical signaling, as regulators of various cellular functions, and as cytotoxic agents under different physiological and pathological settings. These two signaling systems have been investigated in the past as individual systems in pancreatic β-cells without considering their spatio-temporal relationships. These studies have generated limited insights, and thus, their role in regulatory and cytotoxic functions of pancreatic β-cells is poorly understood. Therefore, an effort has been put forth to create a mathematical model to explore spatio-temporal relationships of cytosolic calcium and NO in a β-cell based on the experimental and theoretical data. The model has been framed in terms of reaction-diffusion equation involving ER leak, SERCA pump, PMCA pump, VGCC,IP3 receptor, EGTA buffer, etc. The finite element and Crank-Nicolson methods have been used for numerical simulation. The impacts of various parameters involved in the regulation of Ca2+- NO dynamics for space and time have been identified from the numerical results. The regulatory and cytotoxic conditions for the β-cell have been assessed with the help of various parameters involved in the calcium and NO dynamics. The proposed model provides novel insights of the impacts of changes in various calcium signaling mechanism on NO dynamics in β-cell. The insights into spatio-temporal relationships of these two signaling systems can be helpful for developing various clinical applications.

Keywords:  FEM; NO; PMCA; SERCA; VGCC; calcium

DOI:  https://doi.org/10.1080/10255842.2025.2548571