bims-miptne 2026-06-21 papers

bims-miptne

Biomed News

on Mitochondrial permeability transition pore-dependent necrosis

Issue of 2026–06–21
eleven papers selected by
Oluwatobi Samuel Adegbite, University of Liverpool

An Evolutionarily Conserved TUSC2-OSCP Interface Suggests a Mitochondrial Ca2⁺-Sensing Mechanism for ATP Synthase Regulation.
Chronic hypoxia protects the mouse heart from oxidative stress via HIF-1α-mitochondria crosstalk.
Alzheimer's Disease and MERC Dysfunction: Integrating Mechanisms, Biomarkers, and Therapeutic Strategies.
Reverse engineering of BNIP3 identifies a mitochondrial protective peptide.
Mitochondrial protein OPA3 sustains cardiac function by regulating calcium handling in male mice.
SLC25A3 exports mitochondrial copper to metalate cytochrome c oxidase and prevent cuproptosis.
Replication origin firing capacity indicates ATR inhibitor sensitivity.
Selectively targeting inosine monophosphate dehydrogenase-2 impairs brain metastatic potential while preserving immune cell function.
NEDDylation maintains oocyte quality by stabilizing mitochondrial transcription.
3D EM uncovers mitochondrial network remodeling in residual triple negative breast cancer after conventional chemotherapy treatments.
15-LOX-catalytic bias towards ether-(alkenyl)-ETE-PEs oxidation bestows selectivity of PRO-ferroptotic cell death signaling.

J Mol Biol. 2026 Jun 18. pii: S0022-2836(26)00284-6. [Epub ahead of print] 169911

An Evolutionarily Conserved TUSC2-OSCP Interface Suggests a Mitochondrial Ca2⁺-Sensing Mechanism for ATP Synthase Regulation.

Sergey V Ivanov, Roman V Uzhachenko, Sergei P Budko, Anil Shanker, Sanika S Chirwa, Alla V Ivanova.

  Mitochondrial ATP synthase (mATPS) has the capacity to regulate the permeability transition pore (mPTP) during Ca2⁺ fluctuations. Dysregulation of this mechanism is implicated in neurodegenerative and other diseases; however, the endogenous mechanisms that couple calcium sensing to mATPS function remain poorly defined. We recently demonstrated that loss of TUSC2, a mitochondrial Ca2⁺-binding protein, leads to mitochondrial Ca2⁺ overload and sustained mPTP opening. The oligomycin sensitivity-conferring protein (OSCP), a regulatory subunit of mATPS, responds to Ca2⁺ and oxidative stress, positioning it as a potential integrator of bioenergetic and stress signals. With age, the ability of OSCP to maintain regulatory interactions and resist stress-induced conformational perturbations declines, contributing to multiple pathologies. Here, we combine AI-assisted structural modeling with phylogenetic analysis to nominate TUSC2 as a previously unrecognized candidate OSCP-interacting partner. Across evolution-from basal eukaryotes to higher metazoans-TUSC2 exhibits near-invariant conservation of its central Ca2⁺-binding motif (CBM), in contrast to pronounced divergence of its N-terminal region. AlphaFold3 modeling provides a structural framework for this conservation, predicting Ca2⁺-dependent engagement of the CBM with a conserved C-terminal region of OSCP with established regulatory function. The predicted interface is preserved across phylogenetically distant species, indicating co-conservation of interacting surfaces. The model further suggests coordinated engagement of Ca2⁺ and a second metal ion by TUSC2 and OSCP, as well as accommodation of a nucleotide. The deep conservation of these features across eukaryotes is consistent with a functionally constrained, Ca2⁺-sensing regulatory role for TUSC2 in mATPS function, with potential implications for mPTP regulation.

Keywords:  AlphaFold structural modeling; OSCP (ATP5PO); TUSC2 (FUS1); aging; calcium-binding motif; evolutionary conservation; metal ion coordination; mitochondrial ATP synthase; mitochondrial permeability transition pore (mPTP); oxidative stress

DOI:  https://doi.org/10.1016/j.jmb.2026.169911
Cell Mol Life Sci. 2026 Jun 18.

Chronic hypoxia protects the mouse heart from oxidative stress via HIF-1α-mitochondria crosstalk.

Barbora Opletalova, Lukas Alan, Miroslav Ferko, Natalia Andelova, David Janko, Adam Eckhardt, Kristyna Holzerova, Romana Bohuslavova, Gabriela Pavlinkova, Frantisek Kolar, Marketa Hlavackova, Petra Alanova.

  Adaptation to chronic hypoxia (CH) enhances myocardial tolerance to ischemia/reperfusion injury and is closely associated with stabilization of hypoxia-inducible factor-1 alpha (HIF-1α), a central transcription factor in hypoxic response. Given the central role of mitochondria in cardiac pathophysiology, we investigated the contribution of HIF-1α to cellular mechanisms underlying CH-induced cardioprotection, with a focus on proteomic remodeling, antioxidant defense, and regulation of the mitochondrial permeability transition pore (mPTP). Adult male wild-type and heterozygous Hif1a knockout mice were exposed to intermittent CH (7000 m, 8 h/day, 4 weeks) or kept under normoxia. Isolated perfused hearts treated with cyclosporine A, an inhibitor of mPTP opening, were subjected to global ischemia/reperfusion insult for infarct size determination. Quantitative label-free proteomics was conducted to assess HIF-1α-dependent changes. We evaluated oxidative stress, measured levels of proteins associated with antioxidant defense and mPTP regulation. In parallel, a proof-of-concept study was performed in transfected AC16 cardiomyocytes exposed to H2O2-induced oxidative stress. CH induced HIF-1α-dependent cardioprotection by limiting infarct size through regulation of mPTP opening. Moreover, CH attenuated oxidative stress and promoted the protective translocation of hexokinase-2 to mitochondria in an HIF-1α-dependent manner. Consistently, HIF-1α overexpression enhanced cardiomyocyte survival under oxidative stress, whereas HIF-1α inhibition by acriflavine reduced cell viability. These findings identify HIF-1α as a key mediator of CH-induced adaptive response and cardioprotection during I/R injury in the mouse heart, acting through mPTP regulation.

Keywords:  Cardioprotection; Chronic hypoxia; HIF-1α; Mitochondria; Oxidative stress; Permeability transition pore

DOI:  https://doi.org/10.1007/s00018-026-06299-7
Mol Neurobiol. 2026 Jun 18. pii: 701. [Epub ahead of print]63(1):

Alzheimer's Disease and MERC Dysfunction: Integrating Mechanisms, Biomarkers, and Therapeutic Strategies.

Mohd Kashif, Dhriti Majumder.

  Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder, characterized by progressive cognitive decline, memory loss, and neuronal dysfunction. The pathological hallmarks are characterized by extracellular amyloid-β (Aβ) plaques, intracellular tau tangles, neuroinflammation, and synaptic failure. However, these only partially explain disease onset and progression. Recent evidence highlights mitochondria-endoplasmic reticulum contact sites (MERCs) as crucial hubs of cellular homeostasis, integrating calcium exchange, lipid metabolism, redox balance, and autophagy regulation. Dysregulation of MERC signaling is emerging as a central contributor to AD pathogenesis. MERCs orchestrate processes that intersect with amyloidogenic processing, tau hyperphosphorylation, mitochondrial dysfunction, and impaired clearance of protein aggregates. Aberrant tethering protein expression, disrupted calcium transfer, and altered lipid trafficking at MERCs have been reported in both familial and sporadic AD models, underscoring their pathogenic relevance. Moreover, MERCs influence neuroinflammatory cascades and synaptic remodeling, bridging molecular alterations with clinical manifestations. This review synthesizes current knowledge on MERC biology in the context of AD, highlighting molecular mechanisms, disease-specific perturubations, and therapeutic opportunities. In this review, we discussed pharmacological and genetic interventions targeting MERCs, including small molecules, natural compounds, and nanotechnology-based approaches. Taken together, this review outlines open research questions and future directions, underscoring MERC signaling as a promising frontier for therapeutic innovation in AD.

Keywords:  Alzheimer’s disease; Calcium signaling; Interorganelle communication; Lipid metabolism; Mitochondria–endoplasmic reticulum contact sites (MERCs)

DOI:  https://doi.org/10.1007/s12035-026-06009-1
Nat Commun. 2026 06 17. pii: 5359. [Epub ahead of print]17(1):

Reverse engineering of BNIP3 identifies a mitochondrial protective peptide.

Ulrike B Hendgen-Cotta, Anna Roth, Christine Beuck, Daniel Messiha, Stephan Settelmeier, Shah Bahrullah Shah, Sebastian Korste, Kenny Bravo-Rodriguez, Mike Blueggel, Feyza Cansiz, Luiza Martins Nascentes Melo, Jonas Roesler, Sven W Meckelmann, Oliver J Schmitz, Farnusch Kaschani, Markus Kaiser, Sonja Esfeld, Omar El Bounkari, Jürgen Bernhagen, Sophie Brameyer, Kirsten Jung, Linda-Isabell Schmitt, Markus Leo, Tim Hagenacker, Matthias Totzeck, Thomas Minor, Michael Ehrmann, Alpaslan Tasdogan, Peter Bayer, Tienush Rassaf.

Recent advances in mitochondrial network dynamic and signalling highlight mitochondria as key therapeutic targets across diverse diseases. Yet, high drug development failure rates reflect an incomplete understanding of upstream molecular regulators of mitochondrial fate. Here, we address this gap by reverse engineering of the BH3-only protein BNIP3. Structural modelling and sequence-function analyses of its N-terminus identify a critical functional domain and amino acid hotspots that directly activate BCL-2 executioner proteins, triggering mitochondrial cell death. Leveraging these insights, we develop a BNIP3 antagonist peptide (B-017) that disrupts interactions between BNIP3 and BCL-2 executioner proteins, preserving mitochondrial integrity. B-017 demonstrates target specificity, a favourable safety profile, and robust suppression of cell death signalling in human cells. In clinically relevant animal models, it reduces tissue damage in the heart, brain, and liver. Together, these findings position B-017 as a promising therapeutic candidate targeting mitochondrial dysfunction.

DOI: https://doi.org/10.1038/s41467-026-73993-2
Nat Commun. 2026 Jun 17.

Mitochondrial protein OPA3 sustains cardiac function by regulating calcium handling in male mice.

Na Geng, Taiwei Chen, Hao Li, Shan Lu, Yuehong Wang, Ling Gao, Donald M Bers, Xiyuan Lu.

Heart failure (HF) is a growing global health burden characterized by impaired cardiac contractility and progressive remodeling, driven in part by disrupted Ca2+ handling and mitochondrial dysfunction. However, the molecular mechanisms coordinating these processes remain incompletely understood. Here we showed that OPA3 was decreased in both human and murine HF. Cardiomyocyte-specific deletion of Opa3 in male mice led to the progressive dilated cardiomyopathy (DCM), accompanied by impaired myocardial function, calcium cycling and mitochondria function. Mechanistically, OPA3 forms multimers that are required for its interaction with phospholamban (PLN), thereby maintaining sarcoplasmic reticulum (SR) Ca2+-ATPase (SERCA2a) activity and Ca2+ handling. OPA3 is localized to the mitochondrial outer membrane, and its absence impaired mitochondrial function. Cardiomyocyte-specific overexpression of Opa3 improved cardiac dysfunction in both pressure overload- and doxorubicin-induced HF models. Our data define a critical role of OPA3-PLN-SERCA2a axis that regulates both mitochondria and SR function, representing a potential therapeutic target for HF.

DOI: https://doi.org/10.1038/s41467-026-73991-4
Proc Natl Acad Sci U S A. 2026 Jun 23. 123(25): e2612098123

SLC25A3 exports mitochondrial copper to metalate cytochrome c oxidase and prevent cuproptosis.

Mohammad Zulkifli, Ifrah Farid, Laura E Oldfather, Vinit C Shanbhag, Scot C Leary, Michael J Petris, Paul A Cobine, Vishal M Gohil.

  Copper (Cu) is an essential cofactor for cytochrome c oxidase (CcO), a mitochondrial respiratory chain enzyme that is metalated in the intermembrane space (IMS) primarily using Cu derived from the mitochondrial matrix pool. While Cu import into the matrix depends on the inner membrane carrier SLC25A3, the route by which matrix Cu is exported to the IMS for insertion into CcO has remained a major, unresolved step in intramitochondrial Cu trafficking. Here, we leveraged our recent discovery that the Cu ionophore elesclomol (ES) releases Cu directly into the mitochondrial matrix to show that SLC25A3 is required for exporting Cu to the IMS for CcO metalation. Loss of SLC25A3 decreases mitochondrial Cu content and CcO activity as expected. Strikingly, bypassing the loss of SLC25A3 with ES-mediated Cu delivery to the matrix fails to restore CcO function; rather, it drives toxic Cu retention and triggers cuproptosis, revealing that SLC25A3-facilitated Cu export is the limiting determinant of CcO metalation. Heterologous expression in Lactococcus lactis confirms that SLC25A3 can mediate Cu export. These results suggest that SLC25A3 is the long-sought mitochondrial Cu exporter with a dual role in enabling CcO metalation and gating susceptibility to cuproptosis.

Keywords:  SLC25A3; copper; cuproptosis; cytochrome c oxidase; elesclomol

DOI:  https://doi.org/10.1073/pnas.2612098123
Nat Commun. 2026 Jun 19.

Replication origin firing capacity indicates ATR inhibitor sensitivity.

A Lumeau, P L Pfuderer, J A Scarth, E Maniati, M A Guscott, N Shaikh, F B Copley, H Gerdes, S De Angelis, E L Alard, J Wang, P R Cutillas, F K Mardakheh, M A Boemo, J V Forment, S E McClelland.

Inhibitors of ATR, a central kinase controlling DNA replication origin firing and cellular checkpoints, are undergoing clinical trials, yet mechanisms underpinning sensitivity to ATR inhibitors (ATRi) and patient stratification biomarkers are lacking. Here, we perform in parallel, proteomics, transcriptomics and functional analyses and demonstrate that sensitive cancer cell lines have higher expression of DNA replication initiation factors, and exhibit higher origin firing, increased pan-nuclear γH2AX signals and cell death upon ATRi treatment. ATRi sensitivity is causally associated with origin firing rates, since we could modulate ATRi sensitivity by either up- or down-regulating origin firing capacity using CDC7 inhibition, CDK2 inhibition or CDC45 overexpression in both breast and colorectal cancer cells. High expression of replication initiation factors predicts ATRi sensitivity across cell lines from multiple cancer types and acute myeloid leukemia patient samples. This study reveals a contribution of lethal origin firing capacity to ATR sensitivity, providing key steps towards developing a multimodal clinically applicable biomarker.

DOI: https://doi.org/10.1038/s41467-026-74588-7
Proc Natl Acad Sci U S A. 2026 Jun 23. 123(25): e2603440123

Selectively targeting inosine monophosphate dehydrogenase-2 impairs brain metastatic potential while preserving immune cell function.

Agata M Kieliszek, Erika Apel, Suky Zheng, Mathew Piotrowski, Danny Chui, Sébastien Alazet, Saeideh Shamsi, Daniel Mobilio, Jarrod W Johnson, Laura Escudero, Kurt Vandevoorde, Lin Mei, Mariana Acevedo, Juliette Sabbatani, Oliver A Kent, Fatemeh Dordahan, Arun Yadav, Bruce MacKay, Kevin Leguay, Kathleen J Berger, Petar Miletic, Kui Zhai, Patrick Ang, Ariana Huebner, Shawn C Chafe, Claudio Sturino, Janek Szychowski, Chitra Venugopal, Joseph Mancini, Amie L Phinney, Jakob Magolan, Sheila K Singh.

  Brain metastases (BM) occur in 26% of cancer patients and have a 90% mortality rate within 1 y of diagnosis, yet the current standard of care remains palliative. We have previously shown that de novo GTP synthesis is a druggable metabolic vulnerability in BM cells, through its rate-limiting enzyme, inosine monophosphate dehydrogenase (IMPDH). IMPDH inhibitors have progressed to phase-II oncology trials in the past, failing largely due to dose-limiting toxicities associated with off-target inhibition of IMPDH1, the constitutively expressed isoenzyme in normal human lymphocytes. Here, we determined that a single subtype (isoenzyme) of IMPDH, IMPDH2, is specifically upregulated in brain metastasis-initiating cells (BMICs), absent in normal brain tissue, and is sufficient to drive the formation of BM. Moreover, we show that genetic knockout of IMPDH2 stops the proliferation of BM cells in vitro and the onset of BM in vivo. We synthesized IMPDH2-selective compounds and showed that they maintain a potent antiproliferation effect on BMICs, but spare immune cell function compared to previously developed pan-IMPDH inhibitors. Furthermore, we introduce a positive correlation between compound selectivity for IMPDH2 and the ability to synergize with Osimertinib: the standard of care for EGFR-mutant non-small cell lung cancer. Overall, our results suggest that specifically blocking IMPDH2 is an effective therapeutic strategy for BM by overcoming the immune suppressive effects that have hindered the clinical development of pan-IMPDH inhibitors in the past. An IMPDH2 specific therapy could be coadministered with primary tumor standard of care treatments to provide a safe and interceptional approach for BM.

Keywords:  IMPDH2; brain metastases; preclinical; small molecule; xenografts

DOI:  https://doi.org/10.1073/pnas.2603440123
Sci Adv. 2026 Jun 19. 12(25): eaec3505

NEDDylation maintains oocyte quality by stabilizing mitochondrial transcription.

Avery A Ahmed, Tessa E Steenwinkel, Bethany K Patton, Peixin Jiang, Matthew D Meyer, Jaspreet K Rishi, Mei Leng, Alexander B Saltzman, Elizabeth S Anaya, Momal Sharif, Laurie J McKenzie, Laura Detti, Anna Malovannaya, Sean M Hartig, Stephanie A Pangas.

Age-related decline in oocyte quality increases the risk of infertility, miscarriage, and birth defects. Mitochondrial dysfunction is a key contributor to this decline. Here, we report that oocyte-specific deletion of Uba3, which encodes the catalytic subunit of the E1 NEDDylation-activating complex, causes sterility in mice. Fully grown, germinal vesicle-stage Uba3 conditional knockout oocytes exhibit mitochondrial dysfunction, including elevated reactive oxygen species, impaired oxidative phosphorylation, and depletion of mitochondrially encoded RNA transcripts. Proteomic analysis identified alterations in mitochondrial-associated proteins, including enrichment of mitochondrial matrix and respiratory chain components and reduced abundance of electron transport chain complexes. These defects were associated with reduced levels of the mitochondrial RNA polymerase, POLRMT [polymerase (RNA) mitochondrial DNA directed]. We further show that POLRMT is directly modified by NEDDylation, which alters its stability by antagonizing ubiquitylation and degradation. Notably, NEDD8 levels decline with age in both mouse and human oocytes. Together, these findings identify NEDDylation as a regulator of oocyte quality and connect this pathway to mitochondrial transcription in oocytes.

DOI: https://doi.org/10.1126/sciadv.aec3505
iScience. 2026 Jun 19. 29(6): 115865

3D EM uncovers mitochondrial network remodeling in residual triple negative breast cancer after conventional chemotherapy treatments.

Mariah J Berner, Heather K Beasley, Benjamin Rodriguez, Audra Lane, Steven W Wall, Andrea G Marshall, Zer Vue, Larry Vang, Mokryun L Baek, Mason Killion, Faben Zeleke, Bryanna Shao, Dominique Parker, Autumn Peterson, Julie Sterling Rhoades, Lacey E Dobrolecki, Amber Crabtree, Annet Kirabo, Sepiso K Masenga, Prasanna Katti, Prasanna Venkhatesh, Chandravanu Dash, Michael T Lewis, Antentor Hinton, Gloria V Echeverria.

  Mitochondria are hubs of metabolism and signaling. We previously demonstrated the importance of mitochondrial structure and function in chemotherapy-refractory triple-negative breast cancer (TNBC). Herein, we present the first 3D analysis of mitochondrial networks in human tumor tissues. Using serial block face scanning electron microscopy, we reconstructed 3,750 mitochondria and 800 lipid droplets (LDs) in naive and residual tumors persisting after conventional chemotherapies in two orthotopic patient-derived xenografts (PDX). Chemotherapies administered as monotherapy or in combination produced residual tumors that harbored mitochondria with significantly increased areas, volumes, and perimeters. We observed substantial reduction of mitochondrial intratumor heterogeneity following all treatments. Further, mitochondrial complexity was significantly elevated after single-agent treatments in one model, but was reduced in the other PDX model. Mitochondria-LD significantly increased contacts in residual tumors, congruent with our previous studies providing evidence for rewiring of lipid metabolism in residual TNBC. These results highlight the potential for structure-based monitoring of chemotherapy-induced metabolic rewiring in TNBC.

Keywords:  Biochemistry; Cell biology; Medical imaging; Oncology; Pathology; Pharmacology

DOI:  https://doi.org/10.1016/j.isci.2026.115865
Nat Commun. 2026 06 17. pii: 5360. [Epub ahead of print]17(1):

15-LOX-catalytic bias towards ether-(alkenyl)-ETE-PEs oxidation bestows selectivity of PRO-ferroptotic cell death signaling.

Yulia Y Tyurina, Karolina Mikulska-Ruminska, Vladimir A Tyurin, Brian A Kleiboeker, Alexander A Kapralov, Ayumi Hashimoto, Louis J Sparvero, Haider H Dar, Mert Akdogan, Kazuhiro Yamada, Jinming Zhao, Taha Kelestemur, Ecem Saritas, Sviatlana N Samovich, Theodore R Holman, Yuri L Bunimovich, Yulia Nefedova, Dmitry I Gabrilovich, Sally E Wenzel, Ivet Bahar, Valerian E Kagan, Hülya Bayır.

Ether (alkyl/alkenyl) phospholipids, particularly phosphatidylethanolamine (PE) and phosphatidylcholine (PC), are broadly represented in membranes, but their physiological functions are poorly characterized. The antioxidant role of plasmalogens realized via oxidation of sn-1 vinyl bond has been associated with anti-ferroptotic regulatory function. Alternatively, peroxidation of polyunsaturated fatty acid (PUFA) in sn-2-position of alkenyl-PEs can be pro-ferroptotic. Since 15-LOXs generate 15-HpETE-PEs as ferroptotic signals, we explored alkyl/alkenyl-ETE-PE as substrates of enzymatic peroxidation. Using redox lipidomics, biochemical, biophysical, genetic approaches, and molecular dynamics simulations, we established that both isoforms of 15-LOX (15-LOX-1 and 15-LOX-2) selectively oxidize alkyl/alkenyl-ETE-PE (but not alkyl/alkenyl-ETE-PC), forming 15-HpETE-PEs, triggering ferroptotic death, independently of the vinyl bond. We showed that LOX-catalyzed peroxidation rate of sn-1 vinyl bond is ~500-fold lower than sn-2-ETE-PE, thus excluding the antioxidant role of plasmalogens in ferroptosis. We showed 15-LOX-driven production of sn-1-alkenyl-sn-2-15-HpETE-PE acts as pathogenic factor in acute/chronic diseases: asthma, cancer, brain trauma, skin UVB-injury. Thus, 15-LOX-catalyzed bias towards oxidation of alkenyl-ETE-PE may represent a new therapeutic target.

DOI: https://doi.org/10.1038/s41467-026-71869-z