bims-nenemi Biomed News
on Neuroinflammation, neurodegeneration and mitochondria
Issue of 2025–08–31
eleven papers selected by
Marco Tigano, Thomas Jefferson University
  1. Putative PINK1/Parkin activators lower the threshold for mitophagy by sensitizing cells to mitochondrial stress.
  2. MAVS phosphorylation acts as a cellular stress sensor that modulates antiviral immunity.
  3. Intracristal space proteome mapping using super-resolution proximity labeling with isotope-coded probes.
  4. From mitochondria to heart: the role and challenges of mitochondrial antiviral signaling protein in cardiovascular disease.
  5. Single-molecule fluorescence reveals the DNA unwinding mechanism of mitochondrial helicase TWINKLE and its interplay with single-stranded DNA-binding proteins.
  6. Heme allocation in eukaryotic cells relies on mitochondrial heme export through FLVCR1b to cytosolic GAPDH.
  7. Genome-wide RNAi screening in C. elegans reveals OXPHOS and pyrimidine synthesis pathways as PKA regulators.
  8. The integrated stress response promotes macrophage inflammation and migration in autoimmune diabetes.
  9. Real-time monitoring of mitochondrial temperature and calcium spikes using fluorescent organic probes.
  10. Quality control at the powerhouse: mitochondrial proteostasis dysfunction and disease.
  11. The homoplasmic MT-TK m.8357T > C mtDNA variant as a cause of multiorgan mitochondrial disease.
  1. Sci Adv. 2025 Aug 29. 11(35): eady0240
    Putative PINK1/Parkin activators lower the threshold for mitophagy by sensitizing cells to mitochondrial stress.
    William M Rosencrans, Ryan W Lee, Logan McGraw, Ian Horsburgh, Ting-Yu Wang, Baiyi Quan, Diana Huynh, Jennifer A Johnston, David C Chan, Tsui-Fen Chou.
      The PINK1/Parkin pathway targets damaged mitochondria for degradation via mitophagy. Genetic evidence implicates impaired mitophagy in Parkinson's disease, making its pharmacological enhancement a promising therapeutic strategy. Here, we characterize two mitophagy activators: a novel Parkin activator, FB231, and the reported PINK1 activator MTK458. Both compounds lower the threshold for mitochondrial toxins to induce PINK1/Parkin-mediated mitophagy. However, global proteomics revealed that FB231 and MTK458 independently induce mild mitochondrial stress, resulting in impaired mitochondrial function and activation of the integrated stress response, effects that result from PINK1/Parkin-independent off-target activities. We find that these compounds impair mitochondria by distinct mechanisms and synergistically decrease mitochondrial function and cell viability in combination with classical mitochondrial toxins. Our findings support a model whereby weak or "silent" mitochondrial toxins potentiate other mitochondrial stressors, enhancing PINK1/Parkin-mediated mitophagy. These insights highlight important considerations for therapeutic strategies targeting mitophagy activation in Parkinson's disease.
    DOI:  https://doi.org/10.1126/sciadv.ady0240
  2. iScience. 2025 Sep 19. 28(9): 113256
    MAVS phosphorylation acts as a cellular stress sensor that modulates antiviral immunity.
    Dongyi Zhao, Nao Morimoto, Riho Saito, Juri Yamada, Shuntaro Abe, Hidetaka Kosako, Yukiko Gotoh, Tomohiko Okazaki.
      Upon viral infection, cytosolic RIG-I-like receptors recognize viral RNA and activate innate immune responses through the mitochondrial antiviral-signaling protein (MAVS), leading to type I interferon (IFN) production and apoptosis. Cellular stress influences immune activation, but its impact on MAVS signaling remains largely unclear. Here, we show that MAVS undergoes phosphorylation via p38 MAPK signaling, activated by the stress-activated MAPKKK ASK1. This modification enhances MAVS interaction with TRAF, a key downstream adaptor, thereby promoting type I IFN induction. Oxidative and endoplasmic reticulum stress significantly amplified type I IFN expression upon viral infection, but this effect was attenuated in cells expressing MAVS mutants lacking phosphorylation sites. These findings suggest MAVS phosphorylation as a key mechanism integrating cellular stress signals into antiviral immunity. By linking the MAPK pathway to MAVS-dependent IFN expression, we propose MAVS phosphorylation as a cellular stress sensor that modulates antiviral immunity in a context-dependent manner.
    Keywords:  Biochemistry; Cell biology; Immune response
    DOI:  https://doi.org/10.1016/j.isci.2025.113256
  3. Nat Commun. 2025 Aug 20. 16(1): 7757
    Intracristal space proteome mapping using super-resolution proximity labeling with isotope-coded probes.
    Myeong-Gyun Kang, Sanghee Shin, Dong-Gi Jang, Ohyeon Kwon, Song-Yi Lee, Pratyush Kumar Mishra, Minkyo Jung, Ji Young Mun, Jung-Min Kee, Jong-Seo Kim, Hyun-Woo Rhee.
      Proximity labeling with engineered ascorbate peroxidase (APEX) has been widely used to identify proteomes within various membrane-enclosed subcellular organelles. However, constructing protein distribution maps between two non-partitioned proximal spaces remains challenging with the current proximity labeling tools. Here, we introduce a proximity labeling approach using isotope-coded phenol probes for APEX labeling (ICAX) that enables the quantitative analysis of the spatial proteome at nanometer resolution between two distinctly localized APEX enzymes. Using this technique, we identify the spatial proteomic architecture of the mitochondrial intracristal space (ICS), which is not physically separated from the peripheral space. ICAX analysis further reveals unexpected dynamics of the mitochondrial spatiome under mitochondrial contact site and cristae organizing system (MICOS) complex inhibition and mitochondrial uncoupling, respectively. Overall, these findings highlight the importance of ICS for mitochondrial quality control under dynamic stress conditions.
    DOI:  https://doi.org/10.1038/s41467-025-62756-0
  4. Front Cardiovasc Med. 2025 ;12 1572559
    From mitochondria to heart: the role and challenges of mitochondrial antiviral signaling protein in cardiovascular disease.
    Mengting Jiang, Runze Huang, Wei Li.
      Mitochondrial Antiviral Signaling Protein (MAVS) is a pivotal adaptor protein in the innate immune response, mediating the activation of NF-κB and type I interferon signaling pathways during viral infections. As an integral component of the mitochondrial outer membrane, MAVS also plays critical roles in the regulation of apoptosis, cellular metabolism, and the activation of inflammasomes, including NLRP3 and caspase family members. Emerging evidence indicates that MAVS is not only essential in antiviral defense but also contributes significantly to the pathogenesis of various diseases, notably cardiovascular diseases. In this review, we provide a comprehensive overview of the molecular structure of MAVS and the regulatory mechanisms modulating its activity. We further highlight the involvement of MAVS in the development of cardiovascular diseases through its participation in innate immune signaling and mitochondrial dynamics. Particular attention is given to the regulation of MAVS by post-translational modifications-such as ubiquitination, methylation, and acetylation-as well as by microRNAs and other mitochondria-associated proteins. These insights aim to deepen the understanding of MAVS as a potential biomarker and therapeutic target, offering novel perspectives for the prevention, diagnosis, and immunotherapeutic intervention of cardiovascular diseases.
    Keywords:  cardiovascular diseases; inflammation; innate immunity; mitochondrial antiviral signaling protein (MAVS); mitochondrial homeostasis
    DOI:  https://doi.org/10.3389/fcvm.2025.1572559
  5. Nucleic Acids Res. 2025 Aug 27. pii: gkaf803. [Epub ahead of print]53(16):
    Single-molecule fluorescence reveals the DNA unwinding mechanism of mitochondrial helicase TWINKLE and its interplay with single-stranded DNA-binding proteins.
    Hsin-Yi Wang, Ying-Ying Lee, Po-Jung Chien, Wen-An Tsai, Pei-Jia Sun, Li-Ting Wang, Chyuan-Chuan Wu, Hsiu-Fang Fan.
      The mitochondrial DNA helicase TWINKLE, a hexameric ring-shaped helicase, plays a crucial role in maintaining mitochondrial DNA integrity. TWINKLE translocates along one DNA strand, unwinding the duplex by excluding the complementary strand through coordinated ATP hydrolysis. However, the precise mechanisms underlying this process remain incompletely understood. In this study, we utilized single-molecule Förster Resonance Energy Transfer (smFRET) to investigate the mechanisms of TWINKLE-mediated DNA unwinding. Our results reveal that TWINKLE occasionally pauses during unwinding, with the rate of unwinding and the duration of pausing strongly influenced by ATP concentration, but not by the presence of DNA mismatches or mitochondrial single-stranded DNA-binding protein (mtSSB). These findings suggest that the pausing events primarily arise from stochastic ATP hydrolysis within the helicase subunits. DNA mismatches exacerbate TWINKLE's pausing and dissociation from DNA, thereby impairing DNA unwinding. In contrast, mtSSB significantly mitigates helicase dissociation by stabilizing TWINKLE-DNA interactions. This study provides novel insights into the functional dynamics of TWINKLE, highlighting the role of ATP hydrolysis in orchestrating single-stranded DNA translocation, the detrimental effects of DNA mismatches on DNA unwinding, and the critical role of mtSSB in supporting helicase function.
    DOI:  https://doi.org/10.1093/nar/gkaf803
  6. Nat Commun. 2025 Aug 26. 16(1): 7972
    Heme allocation in eukaryotic cells relies on mitochondrial heme export through FLVCR1b to cytosolic GAPDH.
    Dhanya Thamaraparambil Jayaram, Pranav Sivaram, Pranjal Biswas, Yue Dai, Elizabeth A Sweeny, Dennis J Stuehr.
      Heme is an iron-containing cofactor generated in mitochondria that must leave this organelle to reach protein targets in other cell compartments. Because mitochondrial heme binding by cytosolic GAPDH enables its distribution in cells, we sought to uncover how heme reaches GAPDH. Experiments utilizing two human cell lines and a GAPDH reporter protein whose heme binding can be followed by fluorescence reveal that the mitochondrial protein FLVCR1b provides heme to GAPDH in concert with a rise and fall in their association. An absence of FLVCR1b diminishes GAPDH association with mitochondria and prevents GAPDH and cell hemeproteins from receiving heme. GAPDH heme procurement also requires the TANGO2 protein, which interacts with FLVCR1b to presumably support heme export. In isolated mitochondria, GAPDH associates with FLVCR1b to trigger heme release and delivery to client hemeproteins. Identifying FLVCR1b as the source of mitochondrial heme for GAPDH reveals a path by which this essential cofactor can reach multiple protein targets within eukaryotic cells.
    DOI:  https://doi.org/10.1038/s41467-025-62819-2
  7. Commun Biol. 2025 Aug 26. 8(1): 1280
    Genome-wide RNAi screening in C. elegans reveals OXPHOS and pyrimidine synthesis pathways as PKA regulators.
    Yanjie Li, Duo Duan, Shihao Zhu, Zicheng Liu, Qiang Zhang, Lianfeng Wu.
      Protein kinase A (PKA) plays a crucial and conserved role in various biological processes across species. Despite its significance, tissue-level regulatory networks controlling PKA activity remain incompletely characterized. In this study, we develop a live animal PKA sensor that can faithfully indicate changes in PKA activity in the intestines of Caenorhabditis elegans (C. elegans). Using complementary genome-wide and intestine-specific RNAi screens, we reveal both intestine-autonomous and non-autonomous regulators of intestinal PKA. Notably, we show that inhibiting mitochondrial oxidative phosphorylation, either through RNAi or chemical treatment, leads to a marked increase in intestinal PKA activity. Additionally, we demonstrate that the pyrimidine synthesis pathway serves as a critical autonomous regulator of PKA in the intestines of C. elegans, operating mechanistically in a cAMP-independent manner. Furthermore, this pathway holds a critical and conserved role in regulating PKA in cultured human cells. Overall, our study uncovers the first set of intestinal PKA regulators in C. elegans, with potential implications for PKA modulation under physiological or pathological conditions across species.
    DOI:  https://doi.org/10.1038/s42003-025-08718-0
  8. Cell Commun Signal. 2025 Aug 20. 23(1): 374
    The integrated stress response promotes macrophage inflammation and migration in autoimmune diabetes.
    Jiayi E Wang, Charanya Muralidharan, Armando A Puente, Titli Nargis, Jacob R Enriquez, Ryan M Anderson, Raghavendra G Mirmira, Sarah A Tersey.
      Type 1 diabetes (T1D) is an autoimmune disease characterized by the destruction of insulin-producing pancreatic β-cells. Macrophages infiltrate islets early in T1D pathogenesis, preceding the influx of T- and B-lymphocytes. The integrated stress response (ISR), a cellular pathway activated during stress, coordinates adaptive changes in gene expression to maintain cell function and survival. To study the ISR in macrophages, bone-marrow-derived macrophages were treated with a pharmacological inhibitor of the ISR (ISRIB) and polarized to a proinflammatory M1-like state. We observed a reduction in the number of proinflammatory macrophages, as well as a decrease in iNOS mRNA and protein levels, following ISRIB treatment. RNA-sequencing revealed a reduction in pathways related to stress responses, including ER stress, reactive oxygen species (ROS) regulation, and autophagy, as well as migration pathway genes. ISRIB treatment led to decreased macrophage migration after stimulation in vitro and reduced migration of macrophages to the site of injury after tailfin injury in zebrafish in vivo. Interestingly, ISRIB mediated reduction of M1-like macrophages and reduction of migration was recapitulated by the inhibition of PKR but not PERK, both upstream ISR kinases, highlighting PKR as a key mediator of the ISR in macrophages. Pre-diabetic female non-obese diabetic (NOD) mice administered ISRIB demonstrated an overall reduction in the macrophage numbers in the pancreatic islets. Additionally, the insulitic area of pancreata from ISRIB treated NOD mice had increased PD-L1 levels. PD-L1 protein but not mRNA levels were increased in M1-like macrophages after ISR and PKR inhibition. Our findings identify the ISR, particularly via PKR, as a critical regulator of macrophage driven inflammation and migration in T1D. Our study offers new insights into ISR signaling in macrophages, demonstrating that the ISR may serve as a potential target for intervention in macrophages during early T1D pathogenesis.
    Keywords:  Diabetes; Inflammation; Integrated stress response (ISR); Macrophages; Migration; Pancreatic islet; Unfolded protein response (UPR)
    DOI:  https://doi.org/10.1186/s12964-025-02372-z
  9. Biomater Sci. 2025 Aug 26.
    Real-time monitoring of mitochondrial temperature and calcium spikes using fluorescent organic probes.
    Mengnan Sun, Bo Chen, Aiguo Wu.
      Astrocytes, the abundant glial cells, maintain cerebral homeostasis and cognitive functions through calcium signalling - a regulatory pathway that is frequently altered in brain disease. Mitochondria serve as thermal hubs in living systems, generating metabolic heat during respiratory substrate oxidation and ATP synthesis. Crucially, mitochondrial temperature variations directly reflect metabolic status, as impaired ATP production induces thermodynamic shifts. Here, we utilized a fluorescent thermometer probe MTY for in vitro determination and visualization of intracellular mitochondrial temperatures at the single-cell level. Through precisely controlled thermal modulation of fixed, living, and laser-stimulated astrocytes, we established a platform extendable to MCF-7 and Panc02 cell lines. The methodology enabled real-time tracking of near-infrared-induced thermal perturbations and FCCP-mediated uncoupling effects. Spinning-disk confocal microscopy revealed synchronized mitochondrial thermogenesis and calcium transients, with thermal/laser stimulation inducing 2-4-fold greater calcium spiking versus controls. Mechanistic analysis suggested this response was likely mediated through TRPV4 channel-mediated extracellular Ca2+ influx and/or intracellular calcium release from mitochondrial and endoplasmic reticulum stores.
    DOI:  https://doi.org/10.1039/d5bm00691k
  10. Biochem Soc Trans. 2025 Aug 26. pii: BST20253044. [Epub ahead of print]
    Quality control at the powerhouse: mitochondrial proteostasis dysfunction and disease.
    Megan J Baker, Kai Qi Yek, Diana Stojanovski.
      Intrinsic protein quality control (QC) mechanisms are essential in maintaining mitochondrial health and function. These sophisticated molecular machineries govern protein trafficking and import, processing, folding, maturation and degradation, ensuring the organelle's health. Disruption in mitochondrial protein QC can lead to severe, multisystem disorders with variable age of onset and progression. In this review, we provide a snapshot of the intrinsic molecular protein QC machineries in mitochondria detailing their function, localisation and substrate specificity. We also highlight how dysfunction of these molecular machines contributes to mitochondrial disease. Ultimately, elucidating the consequences of proteostatic failure offers critical insights into the pathogenesis of complex mitochondrial disorders.
    Keywords:  AAA+; chaperone; disaggregase; extractase; mitochondria; mitochondrial disease; protease; protein quality control
    DOI:  https://doi.org/10.1042/BST20253044
  11. Mitochondrion. 2025 Aug 18. pii: S1567-7249(25)00077-7. [Epub ahead of print]85 102080
    The homoplasmic MT-TK m.8357T > C mtDNA variant as a cause of multiorgan mitochondrial disease.
    Luisa Zupin, Valeria Capaci, Maria Teresa Bonati, Eleonora Lamantea, Muhammad Suleman, Andrea Marsala, Fulvio Celsi, Beatrice Spedicati, Sergio Crovella, Giulia Gortani, Giorgia Girotto, Irene Bruno, Massimo Zeviani.
      The diagnosis of disorders associated with mitochondrial DNA (mtDNA) variants presents substantial complexity due to their genetic and clinical heterogeneity, which is largely influenced by mtDNA heteroplasmy. However, the level of heteroplasmy alone is often not sufficient to predict the clinical phenotype including its severity and progression. This study concerns the characterization of the m.8357T > C variant in the MT-TK gene, encoding for mt-tRNA-Lys found in two pediatric siblings. Both had symptoms suggestive of a mitochondrial disease, including severe hearing loss, easy fatigability, decreased activity of mitochondrial complex I in muscle samples, epilepsy, metabolic acidosis with hyperkalemia, and mild kidney impairment. The m.8357T > C mtDNA variant was homoplasmic in muscle, blood, urine and fibroblasts. Immortalized fibroblasts from the patients showed reduced activity of mitochondrial complexes I, III and IV, decreased mitochondrial respiration, and abnormal depolarization of the mitochondrial membrane potential. The mt-tRNA-Lys levels were reduced as compared to the mt-tRNA-Leu (UUR) or the snRNA encoded by RNU6B nuclear gene; the level of three mitochondrial DNA encoded proteins was decreased, altogether suggesting a defective translation machinery in cells carrying the variant. Consistently, fibroblasts from the mother, who had only mild hearing loss, despite high level of heteroplasmy, showed some biochemical abnormalities, however milder than in her daughter and son. Contrariwise, their maternal aunt, who showed intellectual disability, mild hearing loss, easy fatigability and weakness was also virtually homoplasmic for the m.8357T > C in blood and urinary sediment cells. These findings suggest the pathogenicity of the m.8357T > C variant but only in condition of homoplasmy.
    Keywords:  Heteroplasmy; Mitochondrial disease; mt-tRNA-Lys
    DOI:  https://doi.org/10.1016/j.mito.2025.102080
This page is being maintained by Thomas Krichel. It was last updated on 2025‒10‒13 at 14:29.