bims-nenemi 2025-09-14 papers

bims-nenemi

Biomed News

on Neuroinflammation, neurodegeneration and mitochondria

Issue of 2025–09–14
nine papers selected by
Marco Tigano, Thomas Jefferson University

Mitochondrial DNA driven senescence-associated secretory phenotype facilitates the development of bronchopulmonary dysplasia.
Somatic mtDNA mutations at intermediate levels of heteroplasmy are a source of functional heterogeneity among primary leukemic cells.
Mammalian mitohormesis: from mitochondrial stressors to organismal benefits.
Structural insights into DdCBE in action enable high-precision mitochondrial DNA editing.
SEPTIN9 locally activates the RhoGEF ARHGEF18 to promote early stages of mitochondrial fission.
Structure and mechanism of the mitochondrial calcium transporter NCLX.
ADSL deficiency is a secondary mitochondrial disease affecting organelle homeostasis and ERK2/AKT signaling in a linear genotype-phenotype relation.
Mitochondria-associated condensates maintain mitochondrial homeostasis and promote lifespan.
Cellular pan-chain acyl-CoA profiling reveals SLC25A42/SLC25A16 in mitochondrial CoA import and metabolism.

Am J Physiol Cell Physiol. 2025 Sep 12.

Mitochondrial DNA driven senescence-associated secretory phenotype facilitates the development of bronchopulmonary dysplasia.

Yang Meng, Hui Shi, Hui Xu, Yazhou Sun, Xingyun Wang, Rui Wang, Yongjun Zhang.

  Bronchopulmonary dysplasia (BPD) is characterized by arrested alveolar development and disrupted vascular growth in preterm infants. While cellular senescence has been well established in age-related diseases, such as chronic lung diseases, its role in developmental lung diseases originating in the neonatal period remains largely unknown. Here, we investigated the role and underlying mechanisms of the senescence-associated secretory phenotype (SASP) in BPD using targeted inhibitor treatments and rescue strategies. Key SASP factors, including IL-6, IL-1β, MMP-12, and TGF-β1, were significantly elevated after hyperoxia exposure, indicating their involvement in BPD pathogenesis. Confocal imaging revealed that hyperoxia-induced partial mitochondrial outer membrane permeabilization triggered mitochondrial DNA (mtDNA) leakage, establishing mitochondrial dysfunction as a key driver of BPD progression. Further experiments demonstrated the role of the voltage-dependent anion channel 1 (VDAC1) oligomerization and the cGAS-STING pathway in mediating mtDNA release and SASP, respectively. Collectively, these findings define a molecular cascade where VDAC1 oligomerization causes mtDNA leakage, activating cGAS-STING to drive SASP during BPD progression. Targeting the cGAS-STING pathway holds therapeutic potential for alleviating the chronic impact of BPD.

Keywords:  Bronchopulmonary dysplasia; Incomplete mitochondrial outer membrane permeabilization; Lung development; Senescence-associated secretory phenotype

DOI:  https://doi.org/10.1152/ajpcell.00040.2025
Sci Adv. 2025 Sep 12. 11(37): eadt3873

Somatic mtDNA mutations at intermediate levels of heteroplasmy are a source of functional heterogeneity among primary leukemic cells.

Kelly McCastlain, Catherine Welsh, Yonghui Ni, Liang Ding, Ti-Cheng Chang, Robert J Autry, Besian I Sejdiu, Qingfei Pan, Melissa Franco, Wenan Chen, Huiyun Wu, Veronica Gonzalez-Pena, Patrick Schreiner, Sasi Arunachalam, Joung Hyuck Joo, Samuel Brady, Jinghui Zhang, Charles Gawad, William E Evans, M Madan Babu, Konstantin Khrapko, Jiyang Yu, Gang Wu, Stanley Pounds, Mondira Kundu.

Somatic mitochondrial DNA (mtDNA) mutations are frequently observed in tumors, yet their role in pediatric cancers remains poorly understood. The heteroplasmic nature of mtDNA-where mutant and wild-type mtDNA coexist-complicates efforts to define its contribution to disease progression. In this study, bulk whole-genome sequencing of 637 matched tumor-normal samples from the Pediatric Cancer Genome Project revealed an enrichment of functionally impactful mtDNA variants in specific pediatric leukemia subtypes. Collectively, the results from single-cell sequencing of five diagnostic leukemia samples demonstrated that somatic mtDNA mutations can arise early in leukemogenesis and undergo positive selection during disease progression, achieving intermediate heteroplasmy-a "sweet spot" that balances mitochondrial dysfunction with cellular fitness. Network-based systems biology analyses link specific heteroplasmic mtDNA mutations to metabolic reprogramming and therapy resistance. We reveal somatic mtDNA mutations as a potential source of functional heterogeneity and cellular diversity among leukemic cells, influencing their fitness and shaping disease progression.

DOI: https://doi.org/10.1126/sciadv.adt3873
EMBO J. 2025 Sep 08.

Mammalian mitohormesis: from mitochondrial stressors to organismal benefits.

Amanda L Gunawan, Irene Liparulo, Andreas Stahl.

  A variety of stressors, including environmental insults, pathological conditions, and transition states, constantly challenge cells that, in turn, activate adaptive responses to maintain homeostasis. Mitochondria have pivotal roles in orchestrating these responses that influence not only cellular energy production but also broader physiological processes. Mitochondria contribute to stress adaptation through mechanisms including induction of the mitochondrial unfolded protein response (UPRmt) and the integrated stress response (ISR). These responses are essential for managing mitochondrial proteostasis and restoring cellular function, with each being tailored to specific stressors and cellular milieus. While excessive stress can lead to maladaptive responses, mitohormesis refers to the beneficial effects of low-level mitochondrial stress. Initially studied in invertebrates and cell cultures, recent research has expanded to mammalian models of mitohormesis. In this literature review, we describe the current landscape of mammalian mitohormesis research and identify mechanistic patterns that result in local, systemic, or interorgan mitohormesis. These investigations reveal the potential for targeting mitohormesis for therapeutic benefit and can transform the treatment of diseases commonly associated with mitochondrial stress in humans.

Keywords:  Integrated Stress Response; Mammalian Models; Mitochondrial Retrograde Signaling; Mitochondrial Unfolded Protein Response (UPRmt); Mitohormesis

DOI:  https://doi.org/10.1038/s44318-025-00549-3
Mol Cell. 2025 Sep 03. pii: S1097-2765(25)00701-4. [Epub ahead of print]

Structural insights into DdCBE in action enable high-precision mitochondrial DNA editing.

Jiangchao Xiang, Wenchao Xu, Jing Wu, Yaxin Luo, Chengyu Liu, Yaofeng Hou, Jia Chen, Bei Yang.

  DddA-derived cytosine base editor (DdCBE) couples transcription activator-like effector (TALE) arrays and the double-stranded DNA (dsDNA)-specific cytidine deaminase DddA to target mitochondrial DNA (mtDNA) for editing. However, structures of DdCBE in action are unavailable, impeding its mechanistic-based optimization for high-precision-demanding therapeutic applications. Here, we determined the cryo-electron microscopy (cryo-EM) structures of DdCBE targeting two native mitochondrial gene loci and combined editing data from systematically designed spacers to develop WinPred, a model that can predict DdCBE's editing outcome and guide its design to achieve high-precision editing. Furthermore, structure-guided engineering of DddA narrowed the editing window of DdCBE to 2-3 nt while minimizing its off-target (OT) editing to near-background levels, thereby generating accurate DdCBE (aDdCBE). Using aDdCBE, we precisely introduced a Leber hereditary optic neuropathy (LHON)-disease-related mutation into mtDNA and faithfully recapitulated the pathogenic conditions without interference from unintended bystander or OT mutations. Our work provides a mechanistic understanding of DdCBE and establishes WinPred and aDdCBE as useful tools for faithfully modeling or correcting disease-related mtDNA mutations.

Keywords:  DdCBE; DddA engineering; cryo-EM structure; editing precision; editing window; mitochondrial DNA; mitochondrial disease modeling

DOI:  https://doi.org/10.1016/j.molcel.2025.08.016
J Cell Biol. 2025 Oct 06. pii: e202406017. [Epub ahead of print]224(10):

SEPTIN9 locally activates the RhoGEF ARHGEF18 to promote early stages of mitochondrial fission.

Rachel Shannon, Yadu Balachandran, Xindi Wang, Maxime Boutry, Hong Xie, Peter K Kim, William S Trimble.

Mitochondria continually undergo fission to maintain their network and health. Nascent fission sites are marked by the ER, which facilitates actin polymerization to drive calcium flux into the mitochondrion and constrict the inner mitochondrial membrane. Septins are a major eukaryotic cytoskeleton component that forms filaments that can both directly and indirectly modulate other cytoskeleton components, including actin. Septins have been implicated in mitochondrial fission; however, a connection between septins and the regulation of cytoskeletal machinery driving fission is not known. We find that SEPTIN9 is present at mitochondrial fission sites from its early stages with the ER and prior to the fission factor dynamin-related protein 1 (DRP1). SEPTIN9 has an isoform-specific role in fission, dependent on its N-terminal interaction to activate a Rho guanine nucleotide exchange factor, ARHGEF18. Without SEPTIN9, mitochondrial calcium influx is impaired, indicating SEPTIN9-containing octamers play a critical role in the early stages of fission.

DOI: https://doi.org/10.1083/jcb.202406017
Nature. 2025 Sep 10.

Structure and mechanism of the mitochondrial calcium transporter NCLX.

Minrui Fan, Chen-Wei Tsai, Jinru Zhang, Jianxiu Zhang, Aswini R Krishnan, Tsung-Yun Liu, Yu-Lun Huang, Deniz Aydin, Siyuan Du, Briana L Sobecks, Madison X Rodriguez, Andrew H Reiter, Carolyn R Bertozzi, Ron O Dror, Ming-Feng Tsai, Liang Feng.

As a key mitochondrial Ca2+ transporter, NCLX regulates intracellular Ca2+ signalling and vital mitochondrial processes1-3. The importance of NCLX in cardiac and nervous-system physiology is reflected by acute heart failure and neurodegenerative disorders caused by its malfunction4-9. Despite substantial advances in the field, the transport mechanisms of NCLX remain unclear. Here we report the cryo-electron microscopy structures of NCLX, revealing its architecture, assembly, major conformational states and a previously undescribed mechanism for alternating access. Functional analyses further reveal an unexpected transport function of NCLX as a H+/Ca2+ exchanger, rather than as a Na+/Ca2+ exchanger as widely believed1. These findings provide critical insights into mitochondrial Ca2+ homeostasis and signalling, offering clues for developing therapies to treat diseases related to abnormal mitochondrial Ca2+.

DOI: https://doi.org/10.1038/s41586-025-09491-0
Cell Rep. 2025 Sep 05. pii: S2211-1247(25)01001-0. [Epub ahead of print]44(9): 116230

ADSL deficiency is a secondary mitochondrial disease affecting organelle homeostasis and ERK2/AKT signaling in a linear genotype-phenotype relation.

Matteo Bordi, Beatrice Testa, Claudia Compagnucci, Fiorella Colasuonno, Francesca Cipressa, Elisabetta Betterini, Andrea Mancini, Claudia Carsetti, Illari Salvatori, Caterina Ferraina, Ming Yang, Rossella De Cegli, Eugenio Del Prete, Chiara Veroni, Salvatore Rizza, Sofia Mauri, Elena Ziviani, Marina Macchiaiolo, Davide Vecchio, Filippo Maria Panfili, Teresa Rizza, Gerrit Weber, Rosalba Carrozzo, Alberto Ferri, Silvia Campello, Andrea Ballabio, Christian Frezza, Gianluca Cestra, Marco Tartaglia, Andrea Bartuli, Francesco Cecconi.

  Adenylosuccinate lyase deficiency (ADSLd) is a rare autosomal recessive purine metabolism disorder with several clinical manifestations. While toxic substrate accumulation is a known hallmark, no additional molecular mechanisms have been established. Here, we show that ADSLd is associated with mitochondrial dysfunction, including increased fragmentation, impaired respiration, and reduced ATP production. The severity of mitochondrial impairment correlates with ADSLd pathology, especially in mitochondria-dependent tissues. We also identify defects in mitochondrial dynamics and transport linked to ERK2 and AKT suppression. Notably, overexpressing constitutively active ERK2 or supplementing purine intermediates partially rescues the mitochondrial phenotype. These findings suggest an alternative disease mechanism and highlight mitochondrial metabolism as a potential therapeutic target in ADSLd.

Keywords:  ADSL; CP: Metabolism; ERK; mitochondria; purine metabolism; rare genetic disease

DOI:  https://doi.org/10.1016/j.celrep.2025.116230
Nat Aging. 2025 Sep 10.

Mitochondria-associated condensates maintain mitochondrial homeostasis and promote lifespan.

Yan Bai, Tengfei Ma, Shan Zhao, Shalan Li, Xin Wang, Jingyang Li, Wenhao Sun, Yang Yang, Fenglian Liu, Qian Shan, Zizhen Qin, Nan Liu, Jie Zhang, Fei Tian, Mei Duan, Shunkai Chen, Fan Lai, Qingfeng Chen, Xuna Wu, Chonglin Yang.

Membraneless organelles assembled by liquid-liquid phase separation interact with diverse membranous organelles to regulate distinct cellular processes. It remains unknown how membraneless organelles are engaged in mitochondrial homeostasis. Here we demonstrate that mitochondria-associated translation organelles (MATOs) mediate local synthesis of proteins required for structural and functional maintenance of mitochondria. In Caenorhabditis elegans, the RNA-binding protein LARP-1 (La-related protein 1) orchestrates coalescence of translation machinery and multiple RNA-binding proteins via liquid-liquid phase separation into MATOs that associate with mitochondria in a translocase of the outer membrane complex-dependent manner. LARP-1 deficiency markedly reduces mitochondrial protein levels, impairing cristae organization and ATP production. Specifically, we show that the membrane-shaping MICOS subunit IMMT-1(MIC60) and the ATP synthase β subunit ATP-2, both being important for cristae organization, are synthesized in LARP-1 MATOs. During aging and starvation, LARP-1 MATOs dissociate from mitochondria; however, mitochondrion-persistent LARP-1 MATOs protect mitochondrial health and greatly extend lifespan. These findings suggest an important mitochondrion-regulating mechanism in aging and stress.

DOI: https://doi.org/10.1038/s43587-025-00942-x
Nat Metab. 2025 Sep 09.

Cellular pan-chain acyl-CoA profiling reveals SLC25A42/SLC25A16 in mitochondrial CoA import and metabolism.

Ran Liu, Zihan Zhang, Aye K Kyaw, Kariona A Grabińska, Hardik Shah, Hongying Shen.

The essential cofactor coenzyme A (CoASH) and its thioester derivatives (acyl-CoAs) have pivotal roles in cellular metabolism. However, the mechanism by which different acyl-CoAs are accurately partitioned into different subcellular compartments to support site-specific reactions, and the physiological impact of such compartmentalization, remain poorly understood. Here, we report an optimized liquid chromatography-mass spectrometry-based pan-chain acyl-CoA extraction and profiling method that enables a robust detection of 33 cellular and 23 mitochondrial acyl-CoAs from cultured human cells. We reveal that SLC25A16 and SLC25A42 are critical for mitochondrial import of free CoASH. This CoASH import process supports an enriched mitochondrial CoA pool and CoA-dependent pathways in the matrix, including the high-flux TCA cycle and fatty acid oxidation. Despite a small fraction of the mitochondria-localized CoA synthase COASY, de novo CoA biosynthesis is primarily cytosolic and supports cytosolic lipid anabolism. This mitochondrial acyl-CoA compartmentalization enables a spatial regulation of anabolic and energy-related catabolic processes, which promises to shed light on pathophysiology in the inborn errors of CoA metabolism.

DOI: https://doi.org/10.1038/s42255-025-01358-y