bims-nenemi 2025-05-11 papers

bims-nenemi

Biomed News

on Neuroinflammation, neurodegeneration and mitochondria

Issue of 2025–05–11
eighteen papers selected by
Marco Tigano, Thomas Jefferson University

Mitochondrial Respiratory Dysfunction Is Not Correlated With Mitochondrial Genotype in Premature Aging Mice.
Kinome screening identifies integrated stress response kinase EIF2AK1/HRI as a negative regulator of PINK1 mitophagy signaling.
Molecular basis of SIFI activity in the integrated stress response.
Sestrin2 is a central regulator of mitochondrial stress responses in disease and aging.
Annexin A5 controls VDAC1-dependent mitochondrial Ca2+ homeostasis and determines cellular susceptibility to apoptosis.
Hyperandrogenism triggers mtDNA release to participate in ovarian inflammation via mPTP/cGAS/STING in PCOS.
A nuclear-encoded endonuclease governs the paternal transmission of mitochondria in Cucumis plants.
Parkin mediates the mitochondrial dysfunction through mRpL18.
CINs of the cytoplasm: dissecting dsRNA signaling in chromosomal instability.
Mitochondrial GCN5L1 coordinates with YME1L and MICOS to remodel mitochondrial cristae in white adipocytes and modulate obesity.
Muscle metabolic resilience and enhanced exercise adaptation by Esr1-induced remodeling of mitochondrial cristae-nucleoid architecture in males.
SARM1 loss protects retinal ganglion cells in a mouse model of Autosomal Dominant Optic Atrophy.
A hidden cysteine in Fis1 targeted to prevent excessive mitochondrial fission and dysfunction under oxidative stress.
Tracing mitochondrial marks of neuronal aging in iPSCs-derived neurons and directly converted neurons.
Mitochondria and Endoplasmic Reticulum Contact Site as a Regulator of Proteostatic Stress Responses in Neurodegenerative Diseases.
A mitochondria-targeting and G-quadruplex structure-binding ligand inducing calcium overload and ferroptosis in human cancer cells.
Functional mitochondrial respiration is essential for glioblastoma tumour growth.
USP18 attenuates endoplasmic reticulum stress via the PERK-eIF2α-ATF4 axis to reduce apoptosis in hepatocellular carcinoma cells.

Aging Cell. 2025 May 02. e70085

Mitochondrial Respiratory Dysfunction Is Not Correlated With Mitochondrial Genotype in Premature Aging Mice.

Hiroaki Tamashiro, Kaori Ishikawa, Koichi Sadotomo, Emi Ogasawara, Kazuto Nakada.

  mtDNA mutator mice (Polgmut/mut mice) have reinforced the mitochondrial theory of aging. These mice accumulate multiple mutations in mtDNA with age due to a homozygous proofreading-deficient mutation in mtDNA polymerase gamma (Polg), resulting in mitochondrial respiratory dysfunction and premature aging phenotypes. However, whether the accumulation of multiple mutations in Polgmut/mut mice induces mitochondrial respiratory dysfunction remains unclear. Here, we determined the accurate mtDNA genotype, including the frequency of total mutations and the number of non-synonymous substitutions and pathogenic mutations, using next-generation sequencing in the progeny of all three genotypes obtained from the mating of heterozygous mtDNA mutator mice (Polg+/mut mice) and examined their correlation with mitochondrial respiratory activity. Although Polg+/mut mice showed equivalent mtDNA genotype to Polg+/+ (wild-type) mice, the mitochondrial respiratory activity in the Polg+/mut mice was mildly reduced. To further investigate the causal relationship between mtDNA genotype and mitochondrial respiratory activity, we experimentally varied the mtDNA genotype in Polg mice. However, mitochondrial respiratory activity was mildly reduced in Polg+/mut mice and severely reduced in Polgmut/mut mice, regardless of the mtDNA genotype. Moreover, by varying the mtDNA genotype, some Polg+/+ mice showed mtDNA genotype equivalent to those of Polgmut/mut mice, but mitochondrial respiratory activity in Polg+/+ mice was normal. These results indicate that the mitochondrial respiratory dysfunction observed in mice with proofreading-deficient mutation in Polg is correlated with the nuclear genotype of Polg rather than the mtDNA genotype. Thus, the mitochondrial theory of aging in Polgmut/mut mice needs further re-examination.

Keywords:  aging; mitochondria; mitochondrial DNA

DOI:  https://doi.org/10.1111/acel.70085
Sci Adv. 2025 May 09. 11(19): eadn2528

Kinome screening identifies integrated stress response kinase EIF2AK1/HRI as a negative regulator of PINK1 mitophagy signaling.

Pawan K Singh, Shalini Agarwal, Ilaria Volpi, Léa P Wilhelm, Giada Becchi, Andrew Keenlyside, Thomas Macartney, Rachel Toth, Adrien Rousseau, Glenn R Masson, Ian G Ganley, Miratul M K Muqit.

Loss-of-function mutations in the PINK1 kinase lead to early-onset Parkinson's disease (PD). PINK1 is activated by mitochondrial damage to phosphorylate ubiquitin and Parkin, triggering mitophagy. PINK1 also indirectly phosphorylates Rab GTPases, such as Rab8A. Using an siRNA library targeting human Ser/Thr kinases in HeLa cells, we identified EIF2AK1 [heme-regulated inhibitor (HRI) kinase], a branch of the integrated stress response (ISR), as a negative regulator of PINK1. EIF2AK1 knockdown enhances mitochondrial depolarization-induced PINK1 stabilization and phosphorylation of ubiquitin and Rab8A. These results were confirmed in SK-OV-3, U2OS, and ARPE-19 cells. Knockdown of DELE1, an activator of EIF2AK1, produced similar effects. Notably, the ISR inhibitor ISRIB also enhanced PINK1 activation. In human cells with mito-QC mitophagy reporters, EIF2AK1 knockdown or ISRIB treatment increased PINK1-dependent mitophagy without affecting deferiprone-induced mitophagy. These findings suggest that the DELE1-EIF2AK1 ISR pathway is a negative regulator of PINK1-dependent mitophagy. Further evaluation in PD-relevant models is needed to assess the therapeutic potential of targeting this pathway.

DOI: https://doi.org/10.1126/sciadv.adn2528
Nature. 2025 May 06.

Molecular basis of SIFI activity in the integrated stress response.

Zhi Yang, Diane L Haakonsen, Michael Heider, Samuel R Witus, Alex Zelter, Tobias Beschauner, Michael J MacCoss, Michael Rapé.

Chronic stress response activation impairs cell survival and causes devastating degenerative di-seases 1-3. Organisms accordingly deploy silencing factors, such as the E3 ubiquitin ligase SIFI, to terminate stress response signaling and ensure cellular homeostasis 4. How a silencing factor can sense stress across cellular scales to elicit timely stress response inactivation is poorly understood. Here, we combine cryo-electron microscopy of endogenous SIFI with AlphaFold modeling and biochemical analyses to report the structural and mechanistic basis of integrated stress response silencing. SIFI detects both stress-indicators and stress response components through flexible domains within an easily accessible scaffold, before building linkage-specific ubiquitin chains at separate, sterically restricted elongation modules. Ubiquitin handover by a ubiquitin-like domain couples versatile substrate modification to linkage-specific ubiquitin polymer formation. Stress response silencing therefore exploits a catalytic mechanism that is geared towards processing many diverse proteins and hence allows a single enzyme to monitor and, if needed, modulate a complex cellular state.

DOI: https://doi.org/10.1038/s41586-025-09074-z
Ageing Res Rev. 2025 May 02. pii: S1568-1637(25)00108-4. [Epub ahead of print]109 102762

Sestrin2 is a central regulator of mitochondrial stress responses in disease and aging.

Ivo F Machado, Carlos M Palmeira, Anabela P Rolo.

  Mitochondria supply most of the energy for cellular functions and coordinate numerous cellular pathways. Their dynamic nature allows them to adjust to stress and cellular metabolic demands, thus ensuring the preservation of cellular homeostasis. Loss of normal mitochondrial function compromises cell survival and has been implicated in the development of many diseases and in aging. Although exposure to continuous or severe stress has adverse effects on cells, mild mitochondrial stress enhances mitochondrial function and potentially extends health span through mitochondrial adaptive responses. Over the past few decades, sestrin2 (SESN2) has emerged as a pivotal regulator of stress responses. For instance, SESN2 responds to genotoxic, oxidative, and metabolic stress, promoting cellular defense against stress-associated damage. Here, we focus on recent findings that establish SESN2 as an orchestrator of mitochondrial stress adaptation, which is supported by its involvement in the integrated stress response, mitochondrial biogenesis, and mitophagy. Additionally, we discuss the integral role of SESN2 in mediating the health benefits of exercise as well as its impact on skeletal muscle, liver and heart injury, and aging.

Keywords:  Aging; Liver; Mitochondria; Mitohormesis; Muscle; Sestrin2

DOI:  https://doi.org/10.1016/j.arr.2025.102762
EMBO J. 2025 May 09.

Annexin A5 controls VDAC1-dependent mitochondrial Ca2+ homeostasis and determines cellular susceptibility to apoptosis.

Furkan E Oflaz, Alexander I Bondarenko, Michael Trenker, Markus Waldeck-Weiermair, Benjamin Gottschalk, Eva Bernhart, Zhanat Koshenov, Snježana Radulović, Rene Rost, Martin Hirtl, Johannes Pilic, Aditya Karunanithi Nivedita, Adlet Sagintayev, Gerd Leitinger, Bent Brachvogel, Susanne Summerauer, Varda Shoshan-Barmatz, Roland Malli, Wolfgang F Graier.

  Annexin A5 (AnxA5) is a Ca2+-dependent phospholipid-binding protein associated with the regulation of intracellular Ca2+ homeostasis. However, the precise role of AnxA5 in controlling mitochondrial Ca2+ signaling remains elusive. Here, we introduce a novel function of AnxA5 in regulating mitochondrial Ca2+ signaling. Our investigation revealed that AnxA5 localizes at and in the mitochondria and orchestrates intermembrane space Ca2+ signaling upon high Ca2+ elevations induced by ER Ca2+ release. Proximity ligation assays and co-immunoprecipitation revealed a close association but no direct contact of AnxA5 with the voltage-dependent anion channel (VDAC1) in the outer mitochondrial membrane (OMM). In single-cell mitochondrial Ca2+ measurements and electrophysiological recordings, AnxA5 was found to enhance Ca2+ flux through the OMM by promoting the Ca2+-permeable state of VDAC1. By modulating intermembrane space Ca2+ signaling, AnxA5 shapes mitochondrial ultrastructure and influences the dynamicity of the mitochondrial Ca2+ uniporter. Furthermore, by controlling VDAC1's oligomeric state, AnxA5 is protective against cisplatin and selenite-induced apoptotic cell death. Our study uncovers AnxA5 as an integral regulator of VDAC1 in physiological and pathological conditions.

Keywords:  Annexin-A5; Apoptotic Cell Death; Intermembrane Space Ca2⁺ Signaling; VDAC1 Ca2+ Permeability

DOI:  https://doi.org/10.1038/s44318-025-00454-9
iScience. 2025 May 16. 28(5): 112391

Hyperandrogenism triggers mtDNA release to participate in ovarian inflammation via mPTP/cGAS/STING in PCOS.

Jieyu Cai, Qi Zhu, Yu Xiang, Linglin Weng, Na Liang, Xiaoqi Hong, Mingrui Xue, Hongshan Ge.

  Hyperandrogenism induced ovarian inflammation is associated with the pathogenesis of polycystic ovary syndrome (PCOS), but the specific mechanism behind it remains unclear. The aim of this study was to elucidate the association between mitochondrial DNA-cGAS-STING pathway and PCOS inflammatory response. RNA sequencing analysis and other experiments showed that inflammatory pathways were activated, mitochondria were damaged, and mtDNA-cGAS-STING pathways were activated in PCOS women. In vitro, after stimulation of KGN cells with testosterone, the expression of pro-inflammatory factors was enhanced and the cGAS-STING pathway was activated. Stimulator of the interferon genes (STING) knockout can reduce testosterone-induced inflammatory response and improve follicular function. Cyclosporin A therapy reduces cytoplasmic mtDNA, blocks cGAS-STING pathway activation, alleviates inflammatory markers, and reverses abnormal follicular function. In vivo experiments have shown that inhibiting STING can reduce ovarian dysfunction and inflammation in PCOS patients. Hyperandrogenism in PCOS can trigger mitochondrial permeability transition pore (mPTP) overopening, leading to mtDNA release and cGAS-STING pathway activation, causing inflammation and follicle damage.

Keywords:  Endocrinology; Female reproductive endocrinology; Molecular biology

DOI:  https://doi.org/10.1016/j.isci.2025.112391
Nat Commun. 2025 May 08. 16(1): 4266

A nuclear-encoded endonuclease governs the paternal transmission of mitochondria in Cucumis plants.

Jia Shen, Xiaolong Lyu, Xinyang Xu, Zheng Wang, Yuejian Zhang, Chenhao Wang, Eduardo D Munaiz, Mingfang Zhang, Michael J Havey, Weisong Shou.

Non-Mendelian transmission of mitochondria has been well established across most eukaryotes, however the genetic mechanism that governs this uniparental inheritance remains unclear. Plants in the genus Cucumis, specifically melon and cucumber, exhibit paternal transmission of the mitochondrial (mt) DNA, making them excellent models for exploring the molecular mechanisms underlying mitochondrial transmission. Here, we develop a toolkit to screen for mutants in mitochondrial inheritance (mti), and use fine mapping to successfully identify a mitochondrially targeted endonuclease gene (MTI1) controlling mitochondrial transmission. Knockout of MTI1 results in a shift from paternal to bi-parental inheritance of the mtDNA, confirming the crucial role of MTI1 in uniparental inheritance of mitochondria. Moreover, we demonstrate that MTI1 exhibits robust endonuclease activity both in vitro and in vivo, specifically expresses in mitochondria of the fertilized ovule within 24 h of pollination. Collectively, this study reveals that a nuclear-encoded but mitochondria-targeted gene plays a causative role in governing the non-Mendelian mitochondrial inheritance, revolutionizing our knowledge about mitochondrial DNA transmission.

DOI: https://doi.org/10.1038/s41467-025-59568-7
J Biol Chem. 2025 May 07. pii: S0021-9258(25)02057-5. [Epub ahead of print] 110208

Parkin mediates the mitochondrial dysfunction through mRpL18.

Xiuxiu Ti, Hui Zuo, Guochun Zhao, Yuwei Li, Minghui Du, Liwen Xu, Shengnan Li, Zhaoliang Shan, Yuxue Gao, Guangming Gan, Yan Wang, Qing Zhang.

  Loss of function of parkin leads to the mitochondrial dysfunction, which is closely related to Parkinson's disease. However, the in vivo mechanism is far from clear. One of the dogmas is that impaired Parkin causes dysfunction of mitophagy mediated by Pink1-Parkin axis. The other is that impaired Parkin causes Mfn accumulation which leads to mitochondrial dysfunction. Surprisingly, in Drosophila muscles, as reported, the first dogma is not applicable; for the second dogma, our study suggests that Parkin mediates the mitochondrial dysfunction through modulating mitochondrial morphology, which is determined by synergy of both Marf and mitochondrial protein mRpL18 got from our genome-wide screen, whose RNAi rescues parkin RNAi phenotype. Mechanistically, we found that impaired Parkin upregulated both the transcription and protein levels of mRpL18 dependent on its E3 ligase activity, causing the mRpL18 accumulation outside mitochondria. Consequently, cytosolic accumulated mRpL18 competitively bound Drp1, leading to the reduction of the binding of Drp1 to its receptor Fis1, which finally inhibited the mitochondrial fission and tipped the balance to mitochondrial hyperfusion, thereby affected the mitochondrial function. Taken together, our study suggests that impaired Parkin causes mitochondrial hyperfusion due to two reasons: (1) Parkin defect impairs Pink1-Parkin axis-mediated Marf degradation, which promotes mitochondrial fusion; (2) Parkin defect causes mRpL18 accumulation, which inhibits Drp1/Fis1-mediated mitochondrial fission. These two ways function together to drive Parkin-mediated mitochondrial hyperfusion. Therefore, knockdown of either marf or mRpL18 can prevent mitochondrial hyperfusion, leading to the rescue of Parkin defect-triggered fly wing phenotypes. Overall, our study unveils a new facet of how Parkin regulates mitochondrial morphology to affect mitochondrial function, which provides new insights for the understanding and treatment of Parkinson's disease.

Keywords:  Drp1; Parkin; Parkinson's disease; mRpL18

DOI:  https://doi.org/10.1016/j.jbc.2025.110208
Mol Oncol. 2025 May 07.

CINs of the cytoplasm: dissecting dsRNA signaling in chromosomal instability.

Aglaia Skolariki, Rose L Jady-Clark, Eileen E Parkes.

  Chromosomal instability (CIN), a pervasive feature of cancer, promotes tumor evolution and inflammatory signaling, yet its influence on innate immune sensing remains incompletely understood. Ruptured micronuclei, a direct byproduct of CIN arising from missegregated chromosomes, expose out-of-context double-stranded DNA that engages the cGAS-STING pathway. In their recent study, Sasaki et al. show that micronuclei are also a source of immunogenic double-stranded RNA (dsRNA), triggering MAVS-dependent type I interferon responses independently of STING. The authors show that micronuclei undergo aberrant transcription, producing dsRNA from nonexonic, transcriptionally accessible loci, with many species localizing near interferon-stimulated genes. This work suggests a feedforward loop in which type I interferon signaling reinforces its own activation through transcriptional dysregulation. Using MPS1 inhibition to induce acute CIN, the authors show that MAVS signaling promotes MHC Class I expression and immune cell recruitment. These findings reposition CIN as a dual trigger of innate immunity through cytoplasmic DNA and RNA sensing. Future work should define how these pathways integrate in the context of chronic CIN and evaluate strategies to target DNA and RNA sensing in immune-edited tumors.

Keywords:  MAVS; RNA sensing; chromosomal instability; dsRNA; innate immunity; micronuclei

DOI:  https://doi.org/10.1002/1878-0261.70047
Cell Rep. 2025 May 07. pii: S2211-1247(25)00453-X. [Epub ahead of print]44(5): 115682

Mitochondrial GCN5L1 coordinates with YME1L and MICOS to remodel mitochondrial cristae in white adipocytes and modulate obesity.

Juan Xu, Qiqi Zhang, Xinyu Yang, Qiqi Tang, Yitong Han, Jiahui Meng, Jiaqi Zhang, Xin Lu, Danni Wang, Jing Liu, Bo Shan, Xue Bai, Kai Zhang, Longhao Sun, Lingdi Wang, Lu Zhu.

  The relationship between mitochondrial architecture and energy homeostasis in adipose tissues is not well understood. In this study, we utilized GCN5L1-knockout mice in white (AKO) and brown (BKO) adipose tissues to examine mitochondrial homeostasis in adipose tissues. GCN5L1, a regulator of mitochondrial metabolism and dynamics, influences resistance to high-fat-diet-induced obesity in AKO but not BKO mice. This resistance is mediated by an increase in mitochondrial cristae that stabilizes oxidative phosphorylation (OXPHOS) complexes and enhances energy expenditure. Our protein-interactome analysis reveals that GCN5L1 is associated with the mitochondrial crista complex MICOS (MIC13) and the protease YME1L, facilitating the degradation of MICOS and disassembly of cristae during obesity. This interaction results in decreased OXPHOS levels and subsequent adipocyte expansion. Accumulation of GCN5L1 in the mitochondrial intermembrane space is triggered by a high-fat diet. Our findings highlight a regulatory pathway involving YME1L/GCN5L1/MIC13 that remodels mitochondrial cristae in WAT in response to overnutrition-induced obesity.

Keywords:  CP: Cell biology; CP: Metabolism; MICOS; OXPHOS; YME1L; beige; mitochondria; mitochondrial crista remodeling; white adipose tissue

DOI:  https://doi.org/10.1016/j.celrep.2025.115682
Cell Rep Med. 2025 May 02. pii: S2666-3791(25)00189-2. [Epub ahead of print] 102116

Muscle metabolic resilience and enhanced exercise adaptation by Esr1-induced remodeling of mitochondrial cristae-nucleoid architecture in males.

Zhenqi Zhou, Timothy M Moore, Alexander R Strumwasser, Vicent Ribas, Hirotaka Iwasaki, Noelle Morrow, Alice Ma, Peter H Tran, Jonathan Wanagat, Thomas Q de Aguiar Vallim, Bethan Clifford, Zhengyi Zhang, Tamer Sallam, Brian W Parks, Karen Reue, Orian Shirihai, Rebeca Acin-Perez, Marco Morselli, Matteo Pellegrini, Sushil K Mahata, Frode Norheim, Mingqi Zhou, Marcus M Seldin, Aldons J Lusis, Cathy C Lee, Mark O Goodarzi, Jerome I Rotter, Joshua R Hansen, Ben Drucker, Tyler J Sagendorf, Joshua N Adkins, James A Sanford, Francesco J DeMayo, Sylvia C Hewitt, Kenneth S Korach, Andrea L Hevener.

  Reduced estrogen action is associated with obesity and insulin resistance. However, the cell and tissue-specific actions of estradiol in maintaining metabolic health remain inadequately understood, especially in men. We observed that skeletal muscle ESR1/Esr1 (encodes estrogen receptor α [ERα]) is positively correlated with insulin sensitivity and metabolic health in humans and mice. Because skeletal muscle is a primary tissue involved in oxidative metabolism and insulin sensitivity, we generated muscle-selective Esr1 loss- and gain-of-expression mouse models. We determined that Esr1 links mitochondrial DNA replication and cristae-nucleoid architecture with metabolic function and insulin action in the skeletal muscle of male mice. Overexpression of human ERα in muscle protected male mice from diet-induced disruption of metabolic health and enhanced mitochondrial adaptation to exercise training intervention. Our findings indicate that muscle expression of Esr1 is critical for the maintenance of mitochondrial function and metabolic health in males and that tissue-selective activation of ERα can be leveraged to combat metabolic-related diseases in both sexes.

Keywords:  estrogen action; exercise adaptation; insulin sensitivity; mitochondrial cristae architecture; mitochondrial function; mtDNA replication; oxidative metabolism

DOI:  https://doi.org/10.1016/j.xcrm.2025.102116
J Clin Invest. 2025 May 09. pii: e191315. [Epub ahead of print]

SARM1 loss protects retinal ganglion cells in a mouse model of Autosomal Dominant Optic Atrophy.

Chen Ding, Papa S Ndiaye, Sydney R Campbell, Michelle Y Fry, Jincheng Gong, Sophia R Wienbar, Whitney Gibbs, Philippe Morquette, Luke H Chao, Michael Tri H Do, Thomas Schwarz.

  Autosomal Dominant Optic Atrophy (ADOA), the most prevalent hereditary optic neuropathy, leads to retinal ganglion cell (RGC) degeneration and vision loss. ADOA is primarily caused by mutations in the OPA1 gene, which encodes a conserved GTPase important for mitochondrial inner membrane dynamics. To date, the disease mechanism remains unclear, and no therapies are available. We generated a mouse model carrying the pathogenic Opa1R290Q/+ allele that recapitulated key features of human ADOA, including mitochondrial defects, age-related RGC loss, optic nerve degeneration, and reduced RGC functions. We identified SARM1, a neurodegeneration switch, as a key driver of RGC degeneration in these mice. Sarm1 knockout nearly completely suppressed all the degeneration phenotypes without reversing mitochondrial fragmentation. Additionally, we showed that a portion of SARM1 localized within the mitochondrial intermembrane space (IMS). These findings indicated that SARM1 was activated downstream of mitochondrial dysfunction in ADOA, highlighting it as a promising therapeutic target.

Keywords:  Cell biology; Mitochondria; Neurodegeneration; Neuroscience; Therapeutics

DOI:  https://doi.org/10.1172/JCI191315
Nat Commun. 2025 May 06. 16(1): 4187

A hidden cysteine in Fis1 targeted to prevent excessive mitochondrial fission and dysfunction under oxidative stress.

Suman Pokhrel, Gwangbeom Heo, Irimpan Mathews, Shun Yokoi, Tsutomu Matsui, Ayori Mitsutake, Soichi Wakatsuki, Daria Mochly-Rosen.

Fis1-mediated mitochondrial localization of Drp1 and excessive mitochondrial fission occur in human pathologies associated with oxidative stress. However, it is not known how Fis1 detects oxidative stress and what structural changes in Fis1 enable mitochondrial recruitment of Drp1. We find that conformational change involving α1 helix in Fis1 exposes its only cysteine, Cys41. In the presence of oxidative stress, the exposed Cys41 in activated Fis1 forms a disulfide bridge and the Fis1 covalent homodimers cause increased mitochondrial fission through increased Drp1 recruitment to mitochondria. Our discovery of a small molecule, SP11, that binds only to activated Fis1 by engaging Cys41, and data from genetically engineered cell lines lacking Cys41 strongly suggest a role of Fis1 homodimerization in Drp1 recruitment to mitochondria and excessive mitochondrial fission. The structure of activated Fis1-SP11 complex further confirms these insights related to Cys41 being the sensor for oxidative stress. Importantly, SP11 preserves mitochondrial integrity and function in cells during oxidative stress and thus may serve as a candidate molecule for the development of treatment for diseases with underlying Fis1-mediated mitochondrial fragmentation and dysfunction.

DOI: https://doi.org/10.1038/s41467-025-59434-6
Commun Biol. 2025 May 10. 8(1): 723

Tracing mitochondrial marks of neuronal aging in iPSCs-derived neurons and directly converted neurons.

Nimmy Varghese, Leonora Szabo, M Zameel Cader, Imane Lejri, Amandine Grimm, Anne Eckert.

This study aims to determine if neurons derived from induced pluripotent stem cells (iPSCsNs) and directly converted neurons (iNs) from the same source cells exhibit changes in mitochondrial properties related to aging. This research addresses the uncertainty around whether aged iPSCsNs retain aging-associated mitochondrial impairments upon transitioning through pluripotency while direct conversion maintains these impairments. We observe that both aged models exhibit characteristics of aging, such as decreased ATP, mitochondrial membrane potential, respiration, NAD+/NADH ratio, and increased radicals and mitochondrial mass. In addition, both neuronal models show a fragmented mitochondrial network. However, aged iPSCsNs do not exhibit a metabolic shift towards glycolysis, unlike aged iNs. Furthermore, mRNA expression differed significantly between aged iPSCsNs and aged iNs. The study concludes that aged iPSCsNs may differ in transcriptomics and the aging-associated glycolytic shift but can be a valuable tool for studying specific feature of mitochondrial neuronal aging in vitro alongside aged iNs.

DOI: https://doi.org/10.1038/s42003-025-08152-2
Bioessays. 2025 May 04. e70016

Mitochondria and Endoplasmic Reticulum Contact Site as a Regulator of Proteostatic Stress Responses in Neurodegenerative Diseases.

Seiji Watanabe, Koji Yamanaka.

  Recent evidence indicates that the mitochondria-endoplasmic reticulum (ER) contact site is a novel microdomain essential for cellular homeostasis. Various proteins are accumulated at the mitochondria-associated membrane (MAM), an ER subcomponent closely associated with the mitochondria, contributing to Ca2+ transfer to the mitochondria, lipid synthesis, mitochondrial fission/fusion, and autophagy. These functions are disrupted in the diseases, particularly in neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and Alzheimer's disease. In this review, we summarize the disruption of protein homeostasis in various neurodegenerative diseases, present recent works on the mechanisms of MAM aberration, including ours mainly focused on ALS, and then discuss challenges and prospects for future MAM-targeted therapies in neurodegenerative diseases.

Keywords:  mitochondria‐associated membranes; neurodegenerative diseases; protein homeostasis

DOI:  https://doi.org/10.1002/bies.70016
Br J Pharmacol. 2025 May 09.

A mitochondria-targeting and G-quadruplex structure-binding ligand inducing calcium overload and ferroptosis in human cancer cells.

Bo-Xin Zheng, Wei Long, Yao-Xun Zeng, Meng-Ting She, Yingying Zheng, Wen-De Zheng, Ya-Kun Wang, Ka-Hin Chan, Alan Siu-Lun Leung, Chun-Ming Chan, Yu-Jing Lu, Wing-Leung Wong.

   BACKGROUND AND PURPOSE: Regulation of mitochondrial calcium overload and ferroptosis with mitochondria-targeting ligands is an attractive anticancer strategy but it remains a challenge. The aim of the present study was to demonstrate that a mitochondria-targeting and mtDNA G-quadruplex-binding ligand, BYB, induced mitochondrial calcium overload and ferroptosis in HeLa cells and showed potent in vitro and in vivo anticancer activity.
EXPERIMENTAL APPROACH: Cellular functions and molecular mechanism were studied using cell viability assay, live-cell imaging, western blotting, immunofluorescence, cell uptake, cell cycle arrest and apoptosis analysis, mitochondrial metabolism analysis, Comet assay, and wound-healing analysis. Pharmacokinetic studies were conducted in rat. In vivo antitumor activity was studied in a cervical cancer HeLa cell xenograft mouse model.
KEY RESULTS: Cellular results showed that BYB induced mitochondrial calcium overload, attributed to ligand-induced mitochondrial dysfunction via the mechanism of inhibiting mitochondrial DNA replication and transcription. The expression of respiratory chain complexes was markedly downregulated in BYB-treated HeLa cells. The respiratory chain function was also dysregulated. Mitophagy and mitochondrial calcium overload were induced in BYB-treated HeLa cells. Mitochondrial calcium overload markedly induced mtROS production. The induced mtDNA stress activated cGAS-STING pathway, leading to autophagy-dependent ferroptosis. The antitumour efficacy of BYB, evaluated in a HeLa tumour xenograft mouse model, achieved over 60% tumour weight reduction.
CONCLUSION AND IMPLICATIONS: BYB, via targeting mitochondria and mtDNA G-quadruplexes, induced mitochondrial calcium overload and ferroptosis, exhibited high in vivo antitumour efficacy and low toxicity. It shows high potential to be a mitochondria-targeting lead compound for chemical biology and drug discovery.

Keywords:  G‐quadruplex bindingligands; anticancer; calcium overload; ferroptosis; mitochondria‐targetingligands

DOI:  https://doi.org/10.1111/bph.70061
Oncogene. 2025 May 05.

Functional mitochondrial respiration is essential for glioblastoma tumour growth.

Petra Brisudova, Dana Stojanovic, Jaromir Novak, Zuzana Nahacka, Gabriela Lopes Oliveira, Ondrej Vanatko, Sarka Dvorakova, Berwini Endaya, Jaroslav Truksa, Monika Kubiskova, Alice Foltynova, Daniel Jirak, Natalia Jirat-Ziolkowska, Lukas Kucera, Karel Chalupsky, Krystof Klima, Jan Prochazka, Radislav Sedlacek, Francesco Mengarelli, Patrick Orlando, Luca Tiano, Paulo Oliveira, Carole Grasso, Michael V Berridge, Renata Zobalova, Miroslava Anderova, Jiri Neuzil.

Horizontal transfer of mitochondria from the tumour microenvironment to cancer cells to support proliferation and enhance tumour progression has been shown for various types of cancer in recent years. Glioblastoma, the most aggressive adult brain tumour, has proven to be no exception when it comes to dynamic intercellular mitochondrial movement, as shown in this study using an orthotopic tumour model of respiration-deficient glioblastoma cells. Although confirmed mitochondrial transfer was shown to facilitate tumour progression in glioblastoma, we decided to investigate whether the related electron transport chain recovery is necessary for tumour formation in the brain. Based on experiments using time-resolved analysis of tumour formation by glioblastoma cells depleted of their mitochondrial DNA, we conclude that functional mitochondrial respiration is essential for glioblastoma growth in vivo, because it is needed to support coenzyme Q redox cycling for de novo pyrimidine biosynthesis controlled by respiration-linked dihydroorotate dehydrogenase enzyme activity. We also demonstrate here that astrocytes are key mitochondrial donors in this model.

DOI: https://doi.org/10.1038/s41388-025-03429-6
Sci Rep. 2025 May 05. 15(1): 15659

USP18 attenuates endoplasmic reticulum stress via the PERK-eIF2α-ATF4 axis to reduce apoptosis in hepatocellular carcinoma cells.

Lin Li, Nana Liu, Pujuan Yang, Chunyan Rao, Lingna Kong, Yi Huang, Qingsong Lei, Huabao Liu.

  Ubiquitin-specific peptidase 18 (USP18) is a specific interferon-stimulated gene 15 demodifying enzyme that plays an important role in apoptosis. In this study, we investigated the role of USP18 in apoptosis in hepatocellular carcinoma cells, especially its ability to regulate apoptosis through endoplasmic reticulum (ER) stress. We found that protein levels of Bcl-2-associated protein x and cytochrome c were down-regulated by USP18, which suppressed the classical mitochondrial-mediated apoptosis pathway. USP18 also inhibited apoptosis through the unfolded protein response (UPR) pathway by inhibiting the phosphorylation of protein kinase RNA-like endoplasmic reticulum kinase (PERK) and the expression of CCAAT/enhance-binding protein homologous protein, which is a downstream marker molecule of ER stress. The UPR triggered by ER stress eventually led to the cleavage of downstream effecter proteases, including caspase-3, leading to apoptosis. Furthermore, USP18 combined with a PERK agonist regulated apoptosis through the PERK-eukaryotic initiation factor-2α-activating transcription factor 4 axis of the UPR. Our results show that USP18 participates in the regulation of hepatocellular carcinoma cell apoptosis through different pathways, especially the ER stress pathway, and that it plays a complex role in cell stress responses and apoptosis regulation.

Keywords:  Apoptosis; Endoplasmic reticulum stress; Hepatocellular carcinoma; Protein kinase RNA-like Endoplasmic reticulum kinase; Ubiquitin-specific peptidase 18

DOI:  https://doi.org/10.1038/s41598-025-00540-2