bims-miptne 2025-12-14 papers

bims-miptne

Biomed News

on Mitochondrial permeability transition pore-dependent necrosis

Issue of 2025–12–14
twelve papers selected by
Oluwatobi Samuel Adegbite, University of Liverpool

The Mitochondrial Permeability Transition Pore: Past, Present, and Future.
Spatiotemporal Ca2+ nanodomain remodeling at MERCS regulates mitochondrial proteostasis.
Rapid mitochondrial repolarization upon reperfusion after cardiac ischemia.
Stress at the gates: Mitochondrial import dysfunctions, response pathways, and therapeutic potential.
A direct role for a mitochondrial targeting sequence in signalling stress.
Copper ionophore elicits calpain-dependent paraptosis coincident with proteotoxic stress.
A metabolic cell death program downstream of SARM1 couples NAD+ depletion to BAX activation and APAF1 degradation.
Targeting mitochondria to protect the heart: a matter of balance?
Development of activators for SERCA2a for heart failure treatments.
Targeting mitochondrial phosphatidylethanolamine alters mitochondrial metabolism and proliferation in hepatocellular carcinoma.
Identification and validation of mitochondrial and programmed cell death-related prognostic markers in pediatric acute myeloid leukemia.
Mitochondria are absent from microglial processes performing surveillance, chemotaxis, and phagocytic engulfment.

Annu Rev Biophys. 2025 Dec 12.

The Mitochondrial Permeability Transition Pore: Past, Present, and Future.

Michela Carraro, Christoph Gerle, Paolo Bernardi.

The mitochondrial permeability transition (PT) is a Ca2+-dependent permeability increase of the inner mitochondrial membrane mediated by opening of a high-conductance channel, the PT pore. Its molecular nature has been the subject of intense research and the source of controversies, but a considerable consensus has been reached that the PT originates from specific conformations of the FOF1-ATP synthase and of the adenine nucleotide translocator. The ATP synthase forms high-conductance channels in mammals and yeast but not in the anoxia- and salt-tolerant brine shrimp Artemia franciscana, which is refractory to the PT; it forms low-conductance and Ca2+-selective channels in Drosophila melanogaster, which undergoes a process of Ca2+-induced Ca2+ release but not a PT. The structural definition of ATP synthases from several species may allow for some inferences to be made about the mechanism of channel formation, or lack thereof, and provides a testable framework for future research.

DOI: https://doi.org/10.1146/annurev-biophys-030722-020832
Protein Cell. 2025 Dec 08. pii: pwaf109. [Epub ahead of print]

Spatiotemporal Ca2+ nanodomain remodeling at MERCS regulates mitochondrial proteostasis.

Yanan Lv, Xuejing Zhao, Di Li, Zhaoqi Hao, Yue Zhao, Yuhang Zhou, Yujing Zhang, Han Chen, Zhongbing Lu, Dong Li, Yuting Guo.

  Mitochondrial calcium fluxes serve as pivotal regulators of optimal organellar function and cellular viability, yet the spatiotemporal regulation of nanodomain Ca2+ transients at mitochondria-ER contact sites (MERCS) and their integration into adaptive mitochondrial stress signaling remain unresolved. In this study, we employed custom-built high temporal-spatial resolution GI/3D-SIM imaging techniques to achieve nanoscale resolution of calcium transients. We identify that MERCS-localized calcium oscillations gate retrograde stress signaling. Mechanistically, we demonstrate that augmented mitochondria-associated ER membrane (MAMs) connectivity unexpectedly attenuated global mitochondrial Ca2+ efflux, which triggering ATF5 shuttling-mediated transcriptional licensing and calcium-sensitive epigenetic reprogramming that synergistically activating stress-resilience programs. Quantitative protein expression and transcriptome analyses confirm that CsA-mediated calcium retention mimics MAMs induction preserves mitochondrial integrity and protecting cells from apoptosis in Aβ1-42-challenged neurons through synchronized UPRmt activation. Our findings reveal a novel mechanism by which MERCS decode proteotoxic stress into transcriptional and epigenetic adaptations, offering therapeutic potential for neurodegenerative diseases.

Keywords:  Alzheimer’s disease; Mito-ER interaction; calcium transients; mitochondrial stress response; super-resolution microscopy

DOI:  https://doi.org/10.1093/procel/pwaf109
Nat Cardiovasc Res. 2025 Dec 11.

Rapid mitochondrial repolarization upon reperfusion after cardiac ischemia.

Abigail V Giles, Raul Covian, Hiran A Prag, Nils Burger, Bertrand Lucotte, Chak Shun Yu, Junhui Sun, Elizabeth Murphy, Thomas Krieg, Michael P Murphy, Robert S Balaban.

The mitochondrial membrane potential (ΔΨm) drives oxidative phosphorylation and alterations contribute to cardiac pathologies, but real-time assessment of ΔΨm has not been possible. Here we describe noninvasive measurements using mitochondrial heme bL and bH absorbances, which rapidly respond to ΔΨm. Multi-wavelength absorbance spectroscopy enabled their continuous monitoring in isolated mitochondria and the perfused heart. Calibration of heme b absorbance in isolated mitochondria revealed that reduced heme bL relative to total reduced heme b (fbL = bL/(bL + bH)) exhibits a sigmoidal relationship with ΔΨm. Extrapolating this relationship to the heart enabled estimation of ΔΨm as 166 ± 18 mV (n = 25, mean ± s.d.). We used this approach to assess how ΔΨm changes during ischemia-reperfusion injury, an unknown limiting the understanding of ischemia-reperfusion injury. In perfused hearts, ΔΨm declined during ischemia and rapidly reestablished upon reperfusion, supported by oxidation of the succinate accumulated during ischemia. These findings expand our understanding of ischemia-reperfusion injury.

DOI: https://doi.org/10.1038/s44161-025-00752-9
Mitochondrion. 2025 Dec 04. pii: S1567-7249(25)00104-7. [Epub ahead of print]87 102107

Stress at the gates: Mitochondrial import dysfunctions, response pathways, and therapeutic potential.

Hélène Calais, Giulia Bertolin.

  Mitochondrial protein import is necessary to ensure the proper functioning of the organelle of the cell as a whole. More than 1000 proteins are synthesized on cytosolic ribosomes and then imported into mitochondria through translocases such as TOMM and TIMM complexes. Upon entry, they can reach their final mitochondrial compartment, namely the outer mitochondrial membrane (OMM), the intermembrane space (IMS), the inner mitochondrial membrane (IMM), and the matrix. In this review, we will first explore the main mitochondrial protein import mechanisms. Then, we will focus on how import deficiencies may trigger stress paradigms. Stress response pathways are activated to restore correct cellular homeostasis. We will explore four interconnected pathways at the cellular or mitochondrial scale, which can compensate for import alterations. These are the DELE1-HRI axis combined with the ISR, the UPRam, the UPRmt, and mitophagy. Their activation depends on the extent of import alteration, with ISR and UPRmt pathways activated in conditions of low stress. If stress levels are too high, the elimination of dysfunctional mitochondria by mitophagy is triggered. Last, we will explore how mitochondrial import deficiencies are a feature common to multifaceted pathologies, such as neurodegenerative diseases and cancer. We will also present pharmacological compounds mimicking stress response mechanisms and that could be used as a therapeutic option in the near future to restore efficient mitochondrial protein import rates. Overall, this review highlights the critical role of mitochondrial protein import in cellular and mitochondrial stress response, and in disease pathogenesis. It also emphasizes the potential of mitochondrial protein import as a therapeutic target, despite the surprising absence of direct pharmacological treatments to date.

Keywords:  DELE1/HRI; ISR; Mitochondrial protein import; Pharmacological modulation; UPRam; UPRmt

DOI:  https://doi.org/10.1016/j.mito.2025.102107
Nature. 2025 Dec 10.

A direct role for a mitochondrial targeting sequence in signalling stress.

Zixuan Yuan, Megan Balzarini, Marina Volpe, Madeleine Goldstein, Tony Shengzhe Peng, Elizabeth Hui, Nancy Neng Fang, Waleed S Albihlal, Melika Hajimohammadi, Kevin Wei, Calvin K Yip, Folkert J van Werven, Thibault Mayor, Hilla Weidberg.

Mitochondrial protein import is required for maintaining organellar function1. Perturbations in this process are associated with various physiological and disease conditions2. Several stress responses, including the mitochondrial compromised protein import response (mitoCPR), combat damage caused by mitochondrial protein import defects2. However, how this defect is sensed remains largely unknown. Here we reveal that the conserved mitochondrial Hsp70 co-chaperone, Mge1, acts as a stress messenger in budding yeast. During mitochondrial stress, unimported Mge1 entered the nucleus and triggered the transcription of mitoCPR target genes. This was mediated by the interaction of Mge1 with the transcription factor Pdr3 on DNA regulatory elements. The mitochondrial targeting sequence of Mge1 was both sufficient and essential for mitoCPR induction, demonstrating that in addition to their roles in mitochondrial protein import, targeting sequences can also function as signalling molecules. As protein import defects are a common consequence of various types of mitochondrial damage3,4, these findings suggest a novel function for the targeting sequence of Mge1 as an indicator of mitochondrial health.

DOI: https://doi.org/10.1038/s41586-025-09834-x
Cell Commun Signal. 2025 Dec 12.

Copper ionophore elicits calpain-dependent paraptosis coincident with proteotoxic stress.

Apiwit Sae-Fung, Bengt Fadeel.

  Copper is essential to all living organisms. However, too much copper is deleterious, and cellular copper content is therefore subject to tight control. Excess copper was recently found to perturb a set of metabolic enzymes in mitochondria, leading to the aggregation of these proteins and the demise of the cell. However, our understanding of the mechanism of copper-dependent cell death remains incomplete. Here, we report that copper ionophore (elesclomol)-induced cell death is calpain-dependent, featuring dilation of the endoplasmic reticulum along with perinuclear clustering of mitochondria. Moreover, elesclomol evoked proteotoxic stress, manifested as a disruption of ubiquitin and proteasome homeostasis, coupled with a conserved heat shock response. Overall, these results have shown that elesclomol promotes calpain-dependent paraptosis with the involvement of both mitochondrial and extramitochondrial compartments of the cell.

Keywords:  Calpain; Cell death; Copper; Heat shock response; Proteasome; Proteomics

DOI:  https://doi.org/10.1186/s12964-025-02558-5
Proc Natl Acad Sci U S A. 2025 Dec 16. 122(50): e2522444122

A metabolic cell death program downstream of SARM1 couples NAD+ depletion to BAX activation and APAF1 degradation.

Weilong Pan, Dejia Guo, Daiyuan Liu, Xiaodong Wang.

  SARM1 is a neuronal Nicotinamide adenine dinucleotide (NAD+) hydrolase that drives axonal degeneration and neuronal death by depleting NAD+, yet how NAD+ loss triggers axon loss and cell death has remained unclear. Here, we define a nonapoptotic death program downstream of endogenous SARM1 activation and NAD+ loss using a genetically tractable nonneuronal eHAP cell model. Upon NAD+ depletion, BAX is activated but caspase activation is suppressed due to APAF1 degradation via the E3 ligase HERC4, effectively uncoupling mitochondrial outer membrane permeabilization from apoptosome formation. Mechanistically, NAD+ depletion inhibits mTOR/AKT signaling, destabilizing MCL1 and relieving BAX from repression. We further identified Neurofibromatosis type II, NF2, as a regulator that promotes SARM1 transcription through the Hippo-YAP/TAZ pathway. The SARM1-dependent BAX activation and the role of NF2 in axon degradation were validated in neuronal models of axon degeneration. Together, these findings reveal how SARM1-driven metabolic collapse rewires cell death execution, positioning BAX, MCL1, APAF1, NF2, and HERC4 as core effectors in a nonapoptotic degenerative pathway linking metabolic stress to neurodegeneration.

Keywords:  APAF1; Apoptosis; BAX; NAD+; SARM1

DOI:  https://doi.org/10.1073/pnas.2522444122
Clin Sci (Lond). 2025 Dec 08. pii: CS20258287. [Epub ahead of print]139(23):

Targeting mitochondria to protect the heart: a matter of balance?

Fouad A Zouein, George W Booz.

  Mitochondria are dynamic, undergoing both fission and fusion. Evidence indicates that a balance between these two processes is necessary to maintain a healthy state. With ischemia/reperfusion (I/R) of the heart, fission is enhanced and is associated with mitochondrial swelling, depolarization, and production of reactive oxygen species, as well as apoptosis. Accumulating evidence indicates that blocking fission is effective in reducing I/R-induced tissue damage and contractile dysfunction. In theory, enhancing fusion should also serve to prevent I/R-related heart damage. In this perspective article, we present evidence from preclinical studies over the last several years supporting the conclusion that targeting mitochondrial dynamics is a promising pharmacological strategy to protect the heart. Such an approach has great value in limiting heart damage from not only myocardial infarction but also medical interventional reperfusion, alcohol consumption, chemotherapy, and sepsis.

Keywords:  cardiac myocyte; ischemia-reperfusion injury; mitochondrial dynamics; mitochondrial fission; mitochondrial fusion; myocardial infarction

DOI:  https://doi.org/10.1042/CS20258287
Eur J Med Chem. 2025 Nov 29. pii: S0223-5234(25)01173-0. [Epub ahead of print]303 118408

Development of activators for SERCA2a for heart failure treatments.

Marzena Brinkmann, Tsung-Yun Kent Wong, Osha Roopnarine, Samantha L Yuen, Kaja Berg, Razvan L Cornea, Robyn T Rebbeck, David D Thomas, Courtney C Aldrich.

  The sarco/endoplasmic reticulum Ca2+-ATPase (SERCA2a) is a central regulator of cardiac Ca2+ handling and an emerging therapeutic target for heart failure. Here, we report a comprehensive structure-activity relationship (SAR) study around small-molecule activator compound 1, integrating Ca2+-ATPase and Ca2+-uptake assays, isoform selectivity profiling, and ADMET characterization across more than fifty analogues. Systematic modification of the left-hand aryl/heteroaryl region revealed a strong dependence of activity on aromaticity and lipophilicity, with CF3- and Br-substituted analogues providing substantial gains in potency. Optimization of the central amide linker established the importance of N-alkyl chain length, subtle hydrogen-bonding capacity, and a bent ligand geometry for productive SERCA2a engagement. Electronic tuning of the right-hand benzyl group further modulated efficacy, highlighting the essential contribution of an ortho-donor substituent. Functional evaluation across multiple Ca2+ concentrations identified several analogues with ATPase activation but inhibitory Ca2+-uptake effects, underscoring the need for dual-assay assessment to ensure bona fide activation. Among the series, compound 25 emerged as a balanced lead, displaying micromolar potency, robust concordant enhancement of ATPase and Ca2+-uptake activity, favorable solubility, and improved cytotoxicity relative to compound 1. Collectively, these findings define key structural determinants governing SERCA2a activation and provide a rational framework for developing next-generation, drug-like cardiac SERCA2a modulators.

Keywords:  ADMET; ATPase activity; Activators; Calcium uptake; Heart failure; SAR; SERCA2a

DOI:  https://doi.org/10.1016/j.ejmech.2025.118408
Oncogenesis. 2025 Dec 08.

Targeting mitochondrial phosphatidylethanolamine alters mitochondrial metabolism and proliferation in hepatocellular carcinoma.

Melina C Mancini, Cameron P McCall, Robert C Noland, Wagner S Dantas, Timothy D Heden.

Mitochondrial metabolism is crucial for hepatocellular carcinoma (HCC) to thrive. Although phospholipids modulate mitochondrial metabolism, their impact on metabolism in HCC remains unknown. Here we report that the mitochondrial phospholipidome is unaltered in HCC mitochondria, suggesting HCC maintain their mitochondrial phospholipidome to enable efficient metabolism and promote thriftiness. Consistent with this, silencing phosphatidylserine decarboxylase (PISD), the inner mitochondrial membrane protein that generates mitochondrial phosphatidylethanolamine (PE), in HEPA1-6 cells impairs mitochondrial metabolism of fatty acid and glucose-derived substrates and reduces electron transport chain I and IV abundance. Moreover, PISD deficiency increased mitochondrial superoxide generation and altered mitochondria dynamics by augmenting mitochondrial fission, mitophagy, and mitochondrial extracellular efflux. Despite compensatory increases in anaerobic glycolysis and peroxisome fat oxidation, mitochondrial PE deficiency reduced DNA synthesis and cell proliferation, effects associated with reduced mTOR signaling and peptide levels. We conclude that targeting mitochondrial PE synthesis may be a viable therapy to slow HCC progression.

DOI: https://doi.org/10.1038/s41389-025-00593-y
Front Immunol. 2025 ;16 1671230

Identification and validation of mitochondrial and programmed cell death-related prognostic markers in pediatric acute myeloid leukemia.

Xiaoyan Hu, Qiang Zhao, Wei Deng, Yonghuan Li, Bei Liu.

   Background: Pediatric acute myeloid leukemia (AML) is characterized by poor prognosis and low survival rates following recurrence. While mitochondria and programmed cell death (PCD) are implicated in various diseases, their role in pediatric AML remains poorly understood. Identifying prognostic genes associated with PCD and mitochondrial function could enhance therapeutic approaches.
Methods: Transcriptomic data and gene sets were sourced from public databases. Differentially expressed genes (DEGs) that intersected with PCD-related genes (PCD-RGs) and mitochondrial-related genes (mito-RGs) were selected as candidate genes. Regression analyses were performed to identify prognostic genes, which were then used to develop and validate a prognostic model. A nomogram was constructed, followed by functional analysis, immune microenvironment assessment, molecular regulatory network investigation, drug sensitivity profiling, and clinical validation through RT-qPCR.
Results: Twenty-six candidate genes were identified, with three-PDHA1, OGG1, and OPA1-confirmed as potential prognostic markers through regression analyses. The prognostic model demonstrated robustness in both internal and external validations, and the nomogram exhibited good predictive power. Pathway enrichment analysis highlighted the involvement of DNA replication and epithelial-mesenchymal transition, alongside 14 differentially abundant immune cells (p < 0.05). Molecular network analysis indicated that hsa-miR-199a-5p regulates PDHA1 and OGG1. Drug sensitivity profiling identified potential therapeutic agents, including SB505124_1194. RT-qPCR validation confirmed consistent expression patterns for the prognostic genes.
Conclusions: PDHA1, OGG1, and OPA1 were identified as potential prognostic markers for pediatric AML, providing valuable insights for the development of targeted therapeutic strategies. However, further validation in larger and more diverse clinical cohorts is still required to confirm its clinical applicability.

Keywords:  mitochondria; pediatric acute myeloid leukemia; prognosis genes; prognostic model; programmed cell death

DOI:  https://doi.org/10.3389/fimmu.2025.1671230
Nat Commun. 2025 Dec 12. 16(1): 11104

Mitochondria are absent from microglial processes performing surveillance, chemotaxis, and phagocytic engulfment.

Alicia N Pietramale, Xhoela Bame, Megan E Doty, Kiera E Schwarz, Robert A Hill.

Microglia continually surveil the brain allowing for rapid detection of tissue damage or infection. Microglial metabolism is linked to tissue homeostasis, yet how mitochondria are subcellularly partitioned in microglia and dynamically reorganize during surveillance, injury responses, and phagocytic engulfment in the intact brain are not known. Here, we performed intravital imaging and ultrastructural analyses of microglia mitochondria in mice and human tissue, revealing that microglial processes diverge in their mitochondrial content, with some containing multiple mitochondria while others are completely void. Microtubules and hexokinase 2 mirror this uneven mitochondrial distribution indicating that these cytoskeletal and metabolic components are linked to mitochondrial organization in microglia. Microglial processes that engage in minute-to-minute surveillance typically do not have mitochondria. Moreover, unlike process surveillance, mitochondrial motility does not change with animal anesthesia. Likewise, the processes that acutely chemoattract to a lesion site or initially engage with a neuron undergoing programmed cell death do not contain mitochondria. Rather, microglia mitochondria have a delayed arrival into the responding cell processes. Thus, there is subcellular heterogeneity of mitochondrial partitioning. Moreover, microglial processes that surveil and acutely respond to damage do not contain mitochondria.

DOI: https://doi.org/10.1038/s41467-025-66708-6