bims-miptne 2025-10-26 papers

bims-miptne

Biomed News

on Mitochondrial permeability transition pore-dependent necrosis

Issue of 2025–10–26
eight papers selected by
Oluwatobi Samuel Adegbite, University of Liverpool

Calcium dynamics unplugged: NCLX in disease and therapeutic frontiers.
Mitochondrial calcium overload is the trigger for carbon monoxide neurotoxicity.
Polydopamine as a biocompatible and precise mitochondrial targeted therapeutic platform for reversing myocardial ischemia-reperfusion injury.
Mitochondrial orchestration of PANoptosis: mechanisms, disease pathogenesis, and emerging therapeutic frontiers.
Emerging therapy strategies for energy metabolism in acute myocardial infarction.
Increased Intermembrane Space [Ca2+] Drives Mitochondrial Structural Damage in CPVT.
Mitochondrial homeostasis collapse to cardiac remodeling: From mechanisms to novel targeted therapeutic avenues.
Large transient assemblies of Apaf1 constitute the apoptosome in cells.

Mol Biol Rep. 2025 Oct 25. 53(1): 12

Calcium dynamics unplugged: NCLX in disease and therapeutic frontiers.

Dhriti Majumder.

  Mitochondrial ion channels and transporters are pivotal for cellular bioenergetics, signalling, and homeostasis, with the sodium-calcium-lithium exchanger (NCLX) emerging as a critical regulator of mitochondrial calcium dynamics. By extruding calcium in exchange for sodium or lithium ions, NCLX prevents calcium overload, a key contributor to mitochondrial dysfunction and cell death. While previous reviews have explored NCLX in the context of specific diseases or immune cell function, this article provides a comprehensive analysis of its role across multiple disease states, including cardiovascular, neurological, metabolic, and pregnancy-related conditions. Moreover, it highlights the potential of ethnobotanical compounds such as resveratrol and curcumin as therapeutic candidates targeting NCLX. By integrating insights from structural biology, disease mechanisms, and emerging therapeutic strategies, this review aims to advance our understanding of NCLX's role in pathophysiology and explore novel avenues for its targeted modulation in diseases characterized by disrupted mitochondrial calcium homeostasis.

Keywords:  Calcium exchange; Cardiovascular diseases; Mitochondria; NCLX; NCLX targeting therapeutics; Neurodegeneration

DOI:  https://doi.org/10.1007/s11033-025-11188-6
Cell Death Dis. 2025 Oct 21. 16(1): 747

Mitochondrial calcium overload is the trigger for carbon monoxide neurotoxicity.

Plamena R Angelova, Artyom Y Baev, Sergey O Bachurin, Isabella Myers, Andrey Y Abramov.

Carbon monoxide is an important gasotransmitter and regulator of cell function in different tissues, including the central nervous system. However, in large doses, it is a poisonous gas that causes mortality and morbidity. Moreover, the majority of survivors of high-dose exposures develop serious neurological conditions. Here, we studied the effect of toxic concentrations of carbon monoxide released from the compound CORM-401 and its removal (re-oxygenation) on calcium signalling in primary cortical neurons and astrocytes. We found that CO induces changes in intracellular Ca2+ concentration in both neurons and astrocytes. The mechanism of these signals was different-in neurons, it was activated by NMDA and AMPA receptors, while in astrocytes, CO-induced fusion of VNUT2-positive vesicles followed by activation of P2Y receptors. Calcium signal in neurons and astrocytes promotes mitochondrial calcium uptake, which dramatically increases after the removal of CO from the medium, which, in combination with higher rates of production of ROS, induces mitochondrial permeability transition and cell death. CO-induced death of neurons and astrocytes could be prevented with partial inhibition of mitochondrial calcium uptake by Tg2112x and/or inhibition of ROS production in the phase of re-oxygenation. Thus, the bidirectional interaction between mitochondrial calcium overload and production of reactive oxygen species is crucial for CO-induced death of neurons and astrocytes.

DOI: https://doi.org/10.1038/s41419-025-08012-1
Bioact Mater. 2025 Nov;53 908-931

Polydopamine as a biocompatible and precise mitochondrial targeted therapeutic platform for reversing myocardial ischemia-reperfusion injury.

Tianjiao Zhao, Yunying Huang, Wensheng Chen, Weimin Qi, Jue Wang, Yingci Xia, Jia Zhou, Xingyu Long, Yayun Nan, Qiong Huang, Kelong Ai.

  Targeting mitochondria offers a compelling strategy for treating a broad spectrum of major diseases. However, the development of specific and biocompatible mitochondrial delivery vectors remains a key obstacle. In this study, we identified polydopamine (PDA)-a highly biocompatible material with inherent reactive oxygen species (ROS)-scavenging capabilities-as a naturally mitochondria-targeting biomaterial. PDA exhibits strong binding affinity to several critical outer mitochondrial membrane proteins, including the voltage-dependent anion channel and translocases of the outer membrane, conferring it with intrinsic mitochondrial tropism. As a proof-of-concept, we constructed a special channel PDA nanocapsule (CP) to encapsulate the mitochondrial permeability transition pore (mPTP) inhibitor cyclosporine A (CsA), forming CPC. In a myocardial ischemia-reperfusion injury (MIRI) model, intravenously administered CPC selectively accumulated in infarcted myocardium and was highly enriched within cardiomyocyte mitochondria. CPC not only suppressed the mitochondrial ROS burst but also released CsA in a controlled manner via its specialized channels, inhibiting mPTP opening. This intervention prevented cardiomyocyte apoptosis and attenuated the subsequent inflammatory cascade by blocking the cGAS-STING pathway. Remarkably, CPC nearly reversed the pathological effects of MIRI, with efficacy surpassing that of CsA alone. This innovative mitochondrial-targeting approach offers a versatile platform for mitochondrial repair and presents new therapeutic avenues for a range of diseases associated with mitochondrial injury.

Keywords:  Mitochondrial targeting; Myocardial ischemia-reperfusion injury; Oxidative stress; cGAS-STING pathway; mPTP opening

DOI:  https://doi.org/10.1016/j.bioactmat.2025.07.037
Cell Death Discov. 2025 Oct 21. 11(1): 476

Mitochondrial orchestration of PANoptosis: mechanisms, disease pathogenesis, and emerging therapeutic frontiers.

Jiale Zhang, Xiaoya Fu, Feifan Jia, Yahao Jing, Jiameng Zhang, Aoxue Bai, Mengyuan Cui, Lei Zhang, Kunhou Yao.

Mitochondria, traditionally known as cellular powerhouses, are now recognized as central regulators of programmed cell death (PCD) and key players in disease pathogenesis. This review synthesizes current knowledge on mitochondrial mechanisms in PANoptosis-a convergent pathway integrating apoptosis, necroptosis, and pyroptosis-and their implications in diverse pathologies. Mitochondria govern intrinsic apoptosis via Bcl-2 family proteins and mitochondrial outer membrane permeabilization (MOMP), amplify necroptosis through RIPK1/RIPK3-driven ROS signaling, and indirectly regulate pyroptosis via inflammasome-mitochondria crosstalk. Dysfunctional mitochondria contribute to neurodegenerative diseases, cardiovascular disorders, cancer, and autoimmune/metabolic syndromes. Emerging therapies targeting mitochondrial pathways, such as Bcl-2 inhibitors, mPTP modulators, and ROS-inducing agents, demonstrate clinical promise in restoring cell death sensitivity and mitigating inflammation. By bridging molecular mechanisms with therapeutic innovations, this work underscores mitochondria as dynamic hubs of cellular fate and disease intervention.

DOI: https://doi.org/10.1038/s41420-025-02750-z
J Transl Med. 2025 Oct 21. 23(1): 1140

Emerging therapy strategies for energy metabolism in acute myocardial infarction.

Ruixin Ma, Dazhou Lu, Zeyu Yang, Xiaohang Ji, Rui Tian, Feng Xu, Yuguo Chen, Chuanbao Li.

  Acute myocardial infarction (AMI) is a life-threatening cardiovascular event caused by the sudden blockage of a coronary artery, usually triggered by thrombotic events. This leads to significant myocardial ischaemia and hypoxia, disrupting the heart's energy metabolism and ultimately resulting in irreversible injury to cardiomyocytes. Despite advancements in reperfusion therapies, ischaemia-reperfusion injury (IRI) remains a critical contributor to complications such as arrhythmias and heart failure. This review explores the pivotal role of myocardial energy metabolism in AMI pathogenesis, focusing on the dysregulation of fatty acid oxidation (FAO), glycolysis, and mitochondrial dysfunction during ischaemia-reperfusion. Key mechanisms, including the overproduction of reactive oxygen species (ROS), succinate accumulation, and the opening of the mitochondrial permeability transition pore (mPTP), are highlighted as drivers of cellular injury. Emerging therapeutic strategies targeting metabolic reprogramming, mitochondrial protection, and ischaemic conditioning are discussed, highlighting their potential to mitigate IRI. By integrating preclinical and clinical evidence, this review highlights the promise of metabolic modulation as a significant approach to enhancing outcomes in AMI patients.

Keywords:  Cardiac metabolism; Energy metabolism; Myocardial infarction

DOI:  https://doi.org/10.1186/s12967-025-07088-9
Circ Res. 2025 Oct 23.

Increased Intermembrane Space [Ca2+] Drives Mitochondrial Structural Damage in CPVT.

Shanna Hamilton, Radmila Terentyeva, Roland Veress, Fruzsina Perger, Zuzana Nichtova, Mark Bannister, Jinxi Wang, Sage Quiggle, Rachel Battershell, Matthew W Gorr, Sandor Györke, Bum-Rak Choi, Christopher H George, Andriy E Belevych, György Csordás, Dmitry Terentyev.

   BACKGROUND: Mitochondrial dysfunction caused by abnormally high RyR2 (ryanodine receptor) activity is a common finding in cardiovascular diseases. Mechanisms linking RyR2 gain of function with mitochondrial remodeling remain elusive. We hypothesized that RyR2 hyperactivity in cardiac disease increases [Ca2+] in the mitochondrial intermembrane space (IMS) and activates the Ca2+-sensitive protease calpain, driving remodeling of mitochondrial cristae architecture through cleavage of structural protein OPA1 (optic atrophy protein 1).
METHODS: We generated a highly arrhythmogenic rat model of catecholaminergic polymorphic ventricular tachycardia, induced by RyR2 gain-of-function mutation S2236L(±). We created a new biosensor to measure IMS-[Ca2+] in adult cardiomyocytes with intact Ca2+ cycling. We used ex vivo whole heart optical mapping, confocal and electron microscopy, as well as in vivo/in vitro gene editing techniques to test the effects of calpain in the IMS.
RESULTS: We found altered mitochondrial cristae structure, increased IMS-[Ca2+], reduced OPA1 expression, and augmented mito-reactive oxygen species emission in catecholaminergic polymorphic ventricular tachycardia myocytes. We show that calpain-mediated OPA1 cleavage led to disrupted cristae organization and, thereby, decreased electron transport chain supercomplex assembly, resulting in accelerated reactive oxygen species production. Genetic inhibition of calpain activity in IMS reversed mitochondria structural defects in catecholaminergic polymorphic ventricular tachycardia myocytes and reduced arrhythmic burden in ex vivo optically mapped hearts.
CONCLUSIONS: Our data suggest that RyR2 hyperactivity contributes to mitochondrial structural damage by promoting an increase in IMS-[Ca2+], sufficient to activate IMS-residing calpain. Calpain activation leads to proteolysis of OPA1 and cristae widening, thereby decreasing assembly of electron transport chain components into supercomplexes. Consequently, excessive mito-reactive oxygen species release critically contributes to RyR2 hyperactivation and ventricular tachyarrhythmia. Our new findings suggest that targeting IMS calpain may be beneficial in patients at risk for sudden cardiac death.

Keywords:  calcium; cardiovascular diseases; heart failure; mitochondrial proteins; sarcoplasmic reticulum

DOI:  https://doi.org/10.1161/CIRCRESAHA.125.326841
Cell Signal. 2025 Oct 17. pii: S0898-6568(25)00585-6. [Epub ahead of print]136 112170

Mitochondrial homeostasis collapse to cardiac remodeling: From mechanisms to novel targeted therapeutic avenues.

Qi-Yun Liu, Fan-Liang Meng, Jia-Min Du, Wen-Jing Li, Si-Yuan Zhou, Ying Li.

  Myocardial remodeling is a common pathological process in various cardiovascular diseases (CVDs) and represents the heart's adaptive response to pressure or volume overload. However, prolonged myocardial remodeling often leads to a progressive decline in cardiac function, ultimately resulting in heart failure (HF). This process is primarily characterized by myocardial hypertrophy and fibrosis, both of which are closely linked to mitochondrial dysfunction. Emerging research uncovers a pivotal orchestrator of this lethal transition: mitochondrial homeostasis. As the powerhouse of cardiomyocytes, dysfunctional mitochondria ignite a catastrophic cascade-energy bankruptcy, oxidative tsunamis, and apoptotic avalanches-propelling pathological hypertrophy and fibrosis. Although extensive research has explored mitochondrial homeostasis in cardiovascular diseases, a comprehensive summary of the specific mechanisms and effects of mitochondrial dysfunction in myocardial remodeling remains lacking. This review focuses on pathological myocardial remodeling associated with mitochondrial abnormalities and examines four critical factors: mitochondrial Ca2+ signaling, metabolism, dynamics, and mitophagy. Bridging molecular mechanisms to next-generation therapeutics, we systematically evaluates their roles in disease progression and discusses potential mitochondrial-targeted therapeutic strategies, offering new insights into research and treatment approaches for related conditions.

Keywords:  Ca(2+); Dynamics; Metabolism; Mitochondrial homeostasis; Mitophagy; Myocardial remodeling

DOI:  https://doi.org/10.1016/j.cellsig.2025.112170
Nat Commun. 2025 Oct 24. 16(1): 9429

Large transient assemblies of Apaf1 constitute the apoptosome in cells.

Alicia C Borgeaud, Iva Ganeva, Calvin Klein, Amandine Stooss, Daniela Ross-Kaschitza, Liyang Wu, Joel S Riley, Stephen W G Tait, Thomas Lemmin, Thomas Kaufmann, Wanda Kukulski.

Upon cell death signals, the apoptotic protease-activating factor Apaf1 and cytochrome c interact to form the apoptosome complex. The apoptosome is crucial for mitochondrial apoptosis, as it activates caspases that dismantle the cell. However, the in vivo assembly mechanism and appearance of the apoptosome remain unclear. We show that upon onset of apoptosis, Apaf1 molecules accumulate into multiple foci per cell. Disassembly of the foci correlates with cell survival. Structurally, Apaf1 foci resemble organelle-sized, cloud-like assemblies. They form through specific interactions with cytochrome c, contain caspase-9, and depend on procaspase-9 expression for their formation. We propose that Apaf1 foci correspond to the apoptosome in cells. Transientness and ultrastructure of Apaf1 foci suggest that the dynamic spatiotemporal organisation of apoptosome components regulates progression of apoptosis.

DOI: https://doi.org/10.1038/s41467-025-64478-9