bims-nenemi Biomed News
on Neuroinflammation, neurodegeneration and mitochondria
Issue of 2025–09–07
25 papers selected by
Marco Tigano, Thomas Jefferson University
  1. Replication competition drives the selective mtDNA inheritance in Drosophila ovary.
  2. Peri-mitochondrial actin filaments inhibit Parkin assembly by disrupting ER-mitochondria contacts.
  3. PPA2 activates MTFP1-DNM1L fission signaling to govern mitochondrial proliferation and mitophagy.
  4. Accumulation of pathogenic mitochondrial DNA mutations in the kidney.
  5. Innate immune sensing of Z-nucleic acids by ZBP1-RIPK1 axis drives neuroinflammation in Alzheimer's disease.
  6. Mitochondrial DNA Deletion Mutations: A Molecular Cause of Age-Induced Skeletal Muscle Fiber Dysfunction and Fiber Death Contributing to Sarcopenia.
  7. MitoTraP: mitochondrial protection for cellular proteostasis.
  8. Dnm1 Is Required for the Focal Clustering of Fis1 on the Mitochondrial Outer Membrane.
  9. Proximity-specific ribosome profiling reveals the logic of localized mitochondrial translation.
  10. Mitochondrial protein import stress augments α-synuclein aggregation and neural damage independent of bioenergetics.
  11. Mitochondria power the nucleus under pressure.
  12. MitoCOMON: whole mitochondrial DNA sequencing by primer design and long overlapping amplicon assembly.
  13. TP53 mutations drive therapy resistance via post-mitochondrial caspase blockade.
  14. Reversible compromise of physiological resilience by accumulation of heteroplasmic mtDNA mutations.
  15. MPTP controls the release of mtDNA and induces endothelial cell PANoptosis in trichloroethylene-induced immune kidney injury.
  16. Mitochondria structurally remodel near synapses to fuel the sustained energy demands of plasticity.
  17. Mitochondria-ER contact site components regulate the formation and localization of specialized high-capacity mitochondria in the C. elegans anchor cell.
  18. Genetically encoded tool for manipulation of ATP/ADP ratio in human cells.
  19. Evidence that mitochondria in macrophages are destroyed by microautophagy.
  20. Mitochondrial fission controls astrocyte morphogenesis and organization in the cortex.
  21. Mitophagy Activation by N-Acetylcysteine Protects against Mic60 Deficiency-Induced Auditory Neuropathy.
  22. LRRK2 kinase activity restricts NRF2-dependent mitochondrial protection in microglia.
  23. Abnormal mitochondrial structure and function in brown adipose tissue of SLC35A4-MP knockout mice.
  24. Quiescent OXPHOS-high triple-negative breast cancer cells that persist after chemotherapy depend on BCL-XL for survival.
  25. Restoring mitochondrial quantity and quality to reverse the Warburg effect and drive neuroblastoma differentiation.
  1. Cell Rep. 2025 Sep 04. pii: S2211-1247(25)00992-1. [Epub ahead of print]44(9): 116221
    Replication competition drives the selective mtDNA inheritance in Drosophila ovary.
    Cheng Zhang, Zhe Chen, Hansong Ma, Hong Xu.
      Purifying selection that limits the transmission of harmful mitochondrial DNA (mtDNA) mutations has been observed in both human and animal models. Yet, the precise mechanism underlying this process remains undefined. Here, we present a highly specific and efficient in situ imaging method capable of visualizing mtDNA variants that differ by only a few nucleotides at single-molecule resolution in Drosophila ovaries. Using this method, we revealed that selection primarily occurs within a narrow developmental window during germline cyst differentiation. At this stage, the proportion of the deleterious mtDNA variant decreases without a reduction in its absolute copy number. Instead, the healthier mtDNA variant replicates more frequently, thereby outcompeting the co-existing deleterious variant. These findings provide direct evidence that mtDNA selection is driven by replication competition rather than by active elimination processes, shedding light on a fundamental yet previously unresolved mechanism governing mitochondrial genome transmission.
    Keywords:  CP: Molecular biology; germline; mitochondria; mitophagy; mtDNA inheritance; mtDNA mutation; mtDNA replication; oogenesis; purifying selection; rolling circle amplification; single-molecule imaging
    DOI:  https://doi.org/10.1016/j.celrep.2025.116221
  2. EMBO Rep. 2025 Aug 29.
    Peri-mitochondrial actin filaments inhibit Parkin assembly by disrupting ER-mitochondria contacts.
    Tak Shun Fung, Amrapali Ghosh, Maite R Zavala, Zuzana Nichtova, Dhavalkumar Shukal, Marco Tigano, Gyorgy Csordas, Henry N Higgs, Rajarshi Chakrabarti.
      Mitochondrial damage represents a dramatic change in cellular homeostasis, necessitating metabolic adaptation and clearance of the damaged organelle. One rapid response to mitochondrial damage is peri-mitochondrial actin polymerization within 2 min, which we term ADA (Acute Damage-induced Actin). ADA is vital for a metabolic shift from oxidative phosphorylation to glycolysis upon mitochondrial dysfunction. In the current study, we investigated the effect of ADA on Pink1/Parkin mediated mitochondrial quality control. We show that inhibition of proteins involved in the ADA pathway significantly accelerates Parkin recruitment onto depolarized mitochondria. Addressing the mechanism by which ADA resists Parkin recruitment onto depolarized mitochondria, we found that ADA disrupts ER-mitochondria contacts in an Arp2/3 complex-dependent manner. Interestingly, overexpression of ER-mitochondria tethers overrides the effect of ADA, allowing rapid recruitment of not only Parkin but also LC3 after mitochondrial depolarization. During chronic mitochondrial dysfunction, Parkin and LC3 recruitment are completely blocked, which is reversed rapidly by inhibiting ADA. Taken together we show that ADA acts as a protective mechanism, delaying mitophagy following acute damage, and blocking mitophagy during chronic mitochondrial damage.
    Keywords:  Actin; Arp2/3 Complex; ER; LC3; Parkin
    DOI:  https://doi.org/10.1038/s44319-025-00561-y
  3. Autophagy. 2025 Aug 27.
    PPA2 activates MTFP1-DNM1L fission signaling to govern mitochondrial proliferation and mitophagy.
    Soumya Ranjan Mishra, Priyadarshni Mishra, Kewal Kumar Mahapatra, Bishnu Prasad Behera, Gajanan Kendre, Moureq Rashed Alotaibi, Vijay Pandey, Birija Sankar Patro, Daniel J Klionsky, Sujit Kumar Bhutia.
      The inorganic pyrophosphatase PPA2, a matrix-localized protein, maintains mitochondrial function. Here, we identified the role of PPA2 in activating mitochondrial fission signaling. We found that PPA2 overexpression promotes mitochondrial fission by upregulating the mitochondrial translocation of phosphorylated DNM1L S616. Moreover, PPA2 interacts with MTFP1, a mitochondrial inner membrane protein, to induce fission signaling; cells knocked down for MTFP1 and overexpressing PPA2 failed to induce DNM1L activation and subsequent mitochondrial fission. Furthermore, in physiological conditions, PPA2 directed mitochondrial fission at the midzone through MFF-DNM1L, leading to mitochondrial proliferation. Interestingly, during mitochondrial stress following CCCP treatment, PPA2 triggers peripheral fission through FIS1 and DNM1L to segregate parts of damaged mitochondria, which is essential for mitophagy. In addition, PPA2 utilized the C-terminal LC3-interacting region (LIR) of MTFP1 for mitophagy-mediated clearance of damaged mitochondria. In conclusion, PPA2 activates mitochondrial fission signaling through MTFP1-DNM1L and is essential in defining the site of mitochondrial fission, leading to mitochondrial proliferation or mitophagy for maintaining mitochondrial homeostasis.
    Keywords:  MTFP1; Mitochondria; PPA2; mitochondrial fission; mitophagy
    DOI:  https://doi.org/10.1080/15548627.2025.2552900
  4. Nat Rev Nephrol. 2025 Aug 29.
    Accumulation of pathogenic mitochondrial DNA mutations in the kidney.
    Ellen F Carney.
      
    DOI:  https://doi.org/10.1038/s41581-025-01002-8
  5. Immunity. 2025 Aug 25. pii: S1074-7613(25)00333-4. [Epub ahead of print]
    Innate immune sensing of Z-nucleic acids by ZBP1-RIPK1 axis drives neuroinflammation in Alzheimer's disease.
    Ziwen Song, Xingxing Xie, Yulu Chen, Boxin Zhang, Xingyan Li, Yuanxin Yang, Wei Mo, Jian Zhang, Daichao Xu.
      Neuroinflammation drives Alzheimer's disease (AD) pathogenesis. Z-DNA, a non-canonical left-handed DNA structure, activates innate immune signaling through Z-DNA-binding protein 1 (ZBP1). However, the functional significance of ZBP1-mediated Z-DNA detection in AD remains undefined. Here, we found that ZBP1 is amplified in AD microglia, driving innate immune responses and neuroinflammation through sensing Z-form mitochondrial DNA (mtDNA). We show that oxidized mtDNA, generated by amyloid-β (Aβ)-induced oxidative stress, was fragmented and released into the cytoplasm, forming Z-DNA. Z-DNA-activated ZBP1 engaged receptor-interacting protein kinase 1 (RIPK1), promoting its kinase activation and inducing transcription of pro-inflammatory molecules and inflammatory signaling mediators. Genetic deletion of Zbp1 or inhibition of RIPK1 attenuated neuroinflammation, Aβ pathology, and behavioral deficits in an AD mouse model. Our findings reveal that oxidation induces the Z conformer in mtDNA and establish the ZBP1-RIPK1 axis as a key driver of AD neuroinflammation, providing insights into the immune mechanisms underlying AD pathogenesis and identifying a potential therapeutic target.
    Keywords:  8-oxoguanine; Alzheimer's disease; DNA fragmentation; RIPK1; Z-DNA; ZBP1; amyloid-β; mitochondrial DNA; neuroinflammation; oxidative stress
    DOI:  https://doi.org/10.1016/j.immuni.2025.07.024
  6. Adv Exp Med Biol. 2025 ;1478 343-363
    Mitochondrial DNA Deletion Mutations: A Molecular Cause of Age-Induced Skeletal Muscle Fiber Dysfunction and Fiber Death Contributing to Sarcopenia.
    Jonathan Wanagat, Robert Musci, Allen Herbst, Judd M Aiken.
      This chapter describes a molecular basis for age-induced muscle fiber loss involving the mammalian mitochondrial genome (mtDNA). Early studies of human mitochondrial myopathies, which display many phenotypes associated with muscle aging, led to the search for and subsequent discovery of similar genetic and histopathological changes in aging skeletal muscle. A diverse spectrum of mtDNA deletion mutations increase in abundance with age and clonally accumulate to high abundance within individual cells. Deletion accumulation results in a focal loss of electron transport and oxidative phosphorylation. These metabolic derangements activate apoptosis, leading to necrosis, fiber splitting, and eventual fiber loss. We have identified a number of interventions that are capable of modulating mtDNA deletion mutation frequency and the abundance of electron transport chain deficient fibers. Interestingly, in each case, the genetic and histological measures of mtDNA quality predict the lifespan effects of these interventions. We highlight the value of incorporating a geroscience view into the study of sarcopenia. The sequence of events from the deletion mutation of a single mtDNA molecule to muscle fiber death is not limited to skeletal muscle and has been observed in most other aging tissues, where these events likely contribute to cell loss.
    Keywords:  Mitochondria; Mitochondrial DNA; Mutations; Sarcopenia
    DOI:  https://doi.org/10.1007/978-3-031-88361-3_14
  7. Trends Biochem Sci. 2025 Aug 27. pii: S0968-0004(25)00193-8. [Epub ahead of print]
    MitoTraP: mitochondrial protection for cellular proteostasis.
    Michaela Oborská-Oplová, Michael A Ruoss, Vikram G Panse.
      Cells depend on the efficient import of thousands of nuclear-encoded mitochondrial proteins to maintain mitochondrial function. A new study by Flohr et al. reveals a quality control strategy that traps a subset of mitochondrial precursors in the intermembrane space during energy stress, preventing their toxic accumulation in the cytosol or nucleus.
    Keywords:  mitochondrial import; mitochondrial intermembrane space; mitochondrial quality control; mitochondrial ribosomal proteins (MRPs); mitochondrial stress; proteotoxic stress
    DOI:  https://doi.org/10.1016/j.tibs.2025.08.004
  8. MicroPubl Biol. 2025 ;2025
    Dnm1 Is Required for the Focal Clustering of Fis1 on the Mitochondrial Outer Membrane.
    Miyu Sasahara, Shunsuke Matsumoto, Yasushi Tamura.
      In yeast, mitochondrial fission is mediated by the dynamin-like GTPase Dnm1, which is recruited to the mitochondrial outer membrane by its receptor, Fis1. To investigate the spatial distribution of Fis1, we used the CRISPR-Cas9 system to insert the gene fragment encoding mNeonGreen into the FIS1 gene for its N-terminal tagging. Fluorescence microscopy revealed that mNeonGreen-Fis1 appeared as discrete puncta on mitochondria, in addition to a diffuse signal. Here, we show that the focal clustering of Fis1 is dependent on Dnm1. Our findings provide insight into the spatial organization of membrane proteins, highlighting a mechanism by which a downstream effector can influence the distribution of its upstream receptor.
    DOI:  https://doi.org/10.17912/micropub.biology.001780
  9. Cell. 2025 Aug 25. pii: S0092-8674(25)00916-X. [Epub ahead of print]
    Proximity-specific ribosome profiling reveals the logic of localized mitochondrial translation.
    Jingchuan Luo, Stuti Khandwala, Jingjie Hu, Song-Yi Lee, Kelsey L Hickey, Zebulon G Levine, J Wade Harper, Alice Y Ting, Jonathan S Weissman.
      Localized translation broadly enables spatiotemporal control of gene expression. Here, we present LOV-domain-controlled ligase for translation localization (LOCL-TL), an optogenetic approach for monitoring translation with codon resolution at any defined subcellular location under physiological conditions. Application of LOCL-TL to mitochondrially localized translation revealed that ∼20% of human nuclear-encoded mitochondrial genes are translated on the outer mitochondrial membrane (OMM). Mitochondrially translated messages form two classes distinguished by encoded protein length, recruitment mechanism, and cellular function. An evolutionarily ancient mechanism allows nascent chains to drive cotranslational recruitment of long proteins via an unanticipated bipartite targeting signal. Conversely, mRNAs of short proteins, especially eukaryotic-origin electron transport chain (ETC) components, are specifically recruited by the OMM protein A-kinase anchoring protein 1 (AKAP1) in a translation-independent manner that depends on mRNA splicing. AKAP1 loss lowers ETC levels. LOCL-TL thus reveals a hierarchical strategy that enables preferential translation of a subset of proteins on the OMM.
    Keywords:  AKAP1; OXPHOS; cis-element analysis; cotranslational targeting; localized translation; mitochondrial bipartite targeting signal; outer mitochondrial membrane; oxidative phosphorylation; translation-independent mRNA targeting
    DOI:  https://doi.org/10.1016/j.cell.2025.08.002
  10. Res Sq. 2025 Aug 18. pii: rs.3.rs-3136613. [Epub ahead of print]
    Mitochondrial protein import stress augments α-synuclein aggregation and neural damage independent of bioenergetics.
    Xin Jie Chen, Liam Coyne, Arnav Rana, Xiaowen Wang, Sanaea Bhagwagar, Yumiko Umino, Eduardo Solessio, Frank Middleton.
      Genetic and environmental factors are known to converge on mitochondria to cause Parkinson's disease (PD). However, the mechanisms by which mitochondrial dysfunction contributes to neurodegeneration remain incompletely understood. Non-bioenergetic pathways of the mitochondria are increasingly appreciated, but confounding bioenergetic defects are a major barrier to experimental validation. Here, we show that mild mitochondrial protein import stress augments neural damage independent of bioenergetics. We induce protein import stress in a mouse model of PD expressing α-synuclein(A53T). The double mutant mice demonstrate increased size of α-synuclein aggregates, increased aggregation of mitochondrial preproteins, heightened neuroinflammation and worsened motor defect relative to α-synuclein(A53T) single mutants. Importantly, we found no evidence of bioenergetic defects in any of the mutant mice. These data suggest that mitochondrial protein import stress, which can be induced by many types of mitochondrial injuries, can contribute to neural damage through cytosolic proteostatic stress and possible co-aggregation of mitochondrial and neuropathogenic proteins independent of bioenergetics.
    DOI:  https://doi.org/10.21203/rs.3.rs-3136613/v1
  11. Mechanobiol Med. 2025 Sep;3(3): 100146
    Mitochondria power the nucleus under pressure.
    Meng Yao, Yao Zong, Junjie Gao.
      Mechanical confinement of cells, as occurs during processes like tumor cell invasion or immune cell trafficking, poses a pressure that can threaten nuclear integrity and cell viability. Recent findings illuminate a rapid adaptive mechanism by which cells under acute compressive stress rearrange their internal architecture to preserve nuclear functions. Upon confinement, mitochondria swiftly relocate to cluster around the nucleus (forming nuclear-associated mitochondria, NAM), entrapped by a web of endoplasmic reticulum (ER) and actin filaments. This proximity provides a localized surge of ATP within the nucleus, fueling energy-intensive nuclear processes, notably maintaining an open chromatin state and facilitating efficient DNA damage repair. This targeted energy delivery maintains nuclear chromatin accessibility, supports DNA repair mechanisms, and ensures sustained cell proliferation despite physical constraints. Here we provide a commentary on these findings, discussing the biological significance of mitochondria-nucleus repositioning, the role of nuclear ATP in safeguarding chromatin, and the broader implications for cellular fitness in development and disease.
    Keywords:  Mechanical confinement; Mitochondrial dynamics; Nuclear ATP
    DOI:  https://doi.org/10.1016/j.mbm.2025.100146
  12. BMC Genomics. 2025 Aug 30. 26(1): 787
    MitoCOMON: whole mitochondrial DNA sequencing by primer design and long overlapping amplicon assembly.
    Yoshikazu Furuta, Manami Kakita, Hidenori Tanaka.
       BACKGROUND: Mitochondrial DNA sequences are used for inter- and intra-specific comparison analysis in ecological studies. Instead of using short regions as marker sequences, analyzing longer regions, such as whole mitochondrial DNA sequences, can improve the accuracy of such studies by increasing the likelihood of detecting species or specific sequences. However, current methods for sequencing whole mitochondrial DNA require primer design for each target species or long fragments of genomic DNA as a PCR template. We developed a method and accompanying tool for PCR-based long-read sequencing of whole mitochondrial DNA, named MitoCOMON, which is applicable to wide-target taxonomic clades and partially digested template DNA.
    RESULTS: PCR amplification of whole mitochondrial DNA as four fragments facilitates the successful assembly of the whole mitochondrial DNA sequence, even when a sample is a mixture of multiple species or partially degraded. The tool that we developed consists of two modules that can design a primer set for species in a target taxonomic clade and assemble the whole mitochondrial DNA sequence from amplicons which were amplified using the designed primer set. Primer sets were designed for mammal and bird species, which showed a high success rate for whole mitochondrial DNA sequencing with high sequence accuracy. Multiple whole mitochondrial DNA sequences were also assembled from samples mixed with the genomic DNA of several species without forming chimeric sequences. In addition to the accuracy, some assembled sequences also retained a long duplication at the D-loop region, suggesting that the method addresses large rearrangements. Compared with a method that amplifies the whole mitochondrial DNA as a single amplicon, our method was effective for partially degraded samples.
    CONCLUSIONS: Our method and accompanying tool, named MitoCOMON, enables an easier acquisition of whole mitochondrial DNA sequences from samples with some DNA degradation without designing species-specific primers. This approach can enhance the accessibility of mitochondrial genomic data and is expected to improve the resolution of ecological analyses, including accurate species identification and individual-level discrimination.
    Keywords:   De Novo assembly; Long reads; Structural variation; Whole mitochondrial DNA sequencing
    DOI:  https://doi.org/10.1186/s12864-025-12010-0
  13. bioRxiv. 2025 Aug 31. pii: 2025.08.28.672283. [Epub ahead of print]
    TP53 mutations drive therapy resistance via post-mitochondrial caspase blockade.
    Ahmed M Mamdouh, Elyse A Olesinski, Fang Qi Lim, Shaista Jasdanwala, Yang Mi, Nicole Si En Lin, Daniel Tan En Liang, Nishtha Chitkara, Leah Hogdal, R Coleman Lindsley, Anthony Letai, Koji Itahana, Shruti Bhatt.
      Acute myeloid leukemia (AML) is a heterogeneous disease characterized by a broad spectrum of molecular alterations that influence clinical outcomes. TP53 mutations define one of the most lethal subtypes of acute myeloid leukemia (AML), driving resistance to nearly all available treatment modalities, including venetoclax plus azacitidine (VenAza). Yet, the molecular basis of this resistance, beyond affecting transactivation of BCL-2 family genes, has remained elusive. Here, we demonstrate that VenAza treatment leads to reduced transcriptional upregulation of the p53 signaling pathway in TP53 mutant/deficient AML compared to wild-type AML. Functionally, TP53 mutant/deficient AML exhibits selective failure in apoptosis induction rather than impaired G1 arrest or senescence. Despite inhibition of pro-apoptotic BAX and selective enrichment for MCL-1 in TP53 mutant isogenic AML cells, compensatory upregulation of BIM preserved functional mitochondrial outer membrane permeabilization (MOMP). TP53 mutant primary AML tumors at baseline also had retained capacity for MOMP. Instead, TP53 mutant AML exhibited disruption in caspase-3/7 activation to evade apoptosis after VenAza therapy, decoupling the mitochondrial and executioner phases of apoptosis. Importantly, this (post-MOMP brake) is not a bystander effect but itself a driver of VenAza and chemotherapy resistance in TP53 mutant/deficient AML. This previously unrecognized mechanistic insight shifts the focus from mitochondrial priming to terminal caspase blockade in TP53 mutant AML and opens the door for urgently needed therapeutic strategies that reignite apoptosis at its execution point.
    DOI:  https://doi.org/10.1101/2025.08.28.672283
  14. Science. 2025 Sep 04. eadk7978
    Reversible compromise of physiological resilience by accumulation of heteroplasmic mtDNA mutations.
    Huihui Huang, Yi Wang, Zsuzsanna K Zsengeller, Joshua M Gorham, Vamsidhara Vemireddy, Amanda J Clark, Hui Pan, Jonathan M Dreyfuss, Vasantha Jotwani, Michael G Shlipak, Mark J Sarnak, Chirag R Parikh, Heather Thiessen-Philbrook, Ronit Katz, Sushrut S Waikar, Nicole J Lake, Monkol Lek, Wen Shi, Daniela Puiu, Yun Soo Hong, Jonathan G Seidman, Dan E Arking, Samir M Parikh.
      Somatically acquired mitochondrial DNA mutations accumulate with age, but the mechanisms and consequences are poorly understood. Here we show that transient injuries induce a burst of persistent mtDNA mutations that impair resilience to future injuries. mtDNA mutations suppressed energy-intensive nucleotide metabolism. Repletion of adenosine, but not other nucleotides, restored ATP generation, which required a nuclear-encoded purine biosynthetic enzyme, adenylate kinase 4 (AK4). Analysis of 369,912 UK Biobank participants revealed a graded association between mutation burden and chronic kidney disease severity as well as an independent increase in the risk of future acute kidney injury events (p < 10-7). Heteroplasmic mtDNA mutations may therefore reflect the cumulative effect of acute injuries to metabolically active cells, impairing major functions in a fashion amenable to nuclear-controlled purine biosynthesis.
    DOI:  https://doi.org/10.1126/science.adk7978
  15. Eur J Pharmacol. 2025 Sep 03. pii: S0014-2999(25)00872-6. [Epub ahead of print] 178118
    MPTP controls the release of mtDNA and induces endothelial cell PANoptosis in trichloroethylene-induced immune kidney injury.
    Haibo Xie, Jingyi Zhao, Jian Chen, Rui Li, Hui Li, Qifeng Wu, Chen You, Jiaxiang Zhang, Bo Liang, Qixing Zhu.
      Vascular endothelial cells (ECs) damage is closely related to kidney injury. Our previous research revealed the involvement of interferon regulatory factor 1 (IRF1)-mediated PANoptosis of renal ECs in trichloroethylene (TCE)-induced immune kidney injury. However, how IRF1 regulates ECs PANoptosis remains unclear. In this study, we explored the mechanism of PANoptosis in renal ECs by introducing TCE-sensitized mice model, in vitro experiments and population studies. We found that serum tumour necrosis factor alpha (TNF-α) and interferon gamma (IFN-γ) were associated with kidney and ECs injury in patients with occupational medicamentose-like dermatitis due to trichloroethylene (OMDT). The combination of TNF-α and IFN-γ influences the opening of the mitochondrial permeability transition pore (mPTP) in human umbilical vein endothelial cells (HUVECs), thereby promoting the release of mitochondrial reactive oxygen species (mtROS) and mitochondrial DNA (mtDNA). The inhibition of mPTP opening through the application of cyclosporin A (CsA) led to a decrease in the cytoplasmic release of mtDNA and a subsequent reduction in cellular PANoptosis. CsA administration not only mitigated renal damage but also inhibited PANoptosis in renal ECs and suppressed the expression of IRF1 and Z-nucleic acid-binding protein 1 (ZBP1). IRF1 suppression alleviated cellular PANoptosis, whereas concurrent ZBP1 overexpression rescued it. In summary, TNF-α combined with IFN-γ induced mitochondrial mPTP opening and facilitated mtDNA release. The presence of mtDNA enhances the intranuclear transcription of IRF1, which in turn upregulates ZBP1 expression. ZBP1 recognizes mtDNA and contributes to cellular PANoptosis.
    Keywords:  Endothelial cell; Mitochondrial DNA; Mitochondrial permeability transition pore; PANoptosis; Trichloroethylene
    DOI:  https://doi.org/10.1016/j.ejphar.2025.178118
  16. bioRxiv. 2025 Aug 27. pii: 2025.08.27.672715. [Epub ahead of print]
    Mitochondria structurally remodel near synapses to fuel the sustained energy demands of plasticity.
    Monil Shah, Ilika Ghosh, Luca Pishos, Valentina Villani, Tristano Pancani, Ryohei Yasuda, Chao Sun, Naomi Kamasawa, Vidhya Rangaraju.
      The brain is a metabolically demanding organ as it orchestrates and stabilizes neuronal network activity through plasticity. This mechanism imposes enormous and prolonged energetic demands at synapses, yet it is unclear how these needs are met in a sustained manner. Mitochondria serve as a local energy supply for dendritic spines, providing instant and sustained energy during synaptic plasticity. However, it remains unclear whether dendritic mitochondria restructure their energy production unit to meet the sustained energy demands. We developed a correlative light and electron microscopy pipeline with deep-learning-based segmentations and 3D reconstructions to quantify mitochondrial remodeling at 2 nm pixel resolution during homeostatic plasticity. Using light microscopy, we observe global increases in dendritic mitochondrial length, as well as local increases in mitochondrial area near spines. Examining the mitochondria near spines using electron microscopy, we reveal increases in mitochondrial cristae surface area, cristae curvature, endoplasmic reticulum contacts, and ribosomal cluster recruitment, accompanied by increased ATP synthase clustering within mitochondria using single-molecule localization microscopy. Using mitochondria- and spine-targeted ATP reporters, we demonstrate that the local structural remodeling of mitochondria corresponds to increased mitochondrial ATP production and spine ATP levels. These findings suggest that mitochondrial structural remodeling is a key underlying mechanism for meeting the energy requirements of synaptic and network function.
    DOI:  https://doi.org/10.1101/2025.08.27.672715
  17. MicroPubl Biol. 2025 ;2025
    Mitochondria-ER contact site components regulate the formation and localization of specialized high-capacity mitochondria in the C. elegans anchor cell.
    Isabel W Kenny-Ganzert, David R Sherwood.
      Mitochondria-endoplasmic reticulum contact sites (MERCS) play crucial roles in mediating calcium signaling and lipid metabolism, and regulate mitochondrial morphology, function, and quality control. Recent studies have found that the C. elegans anchor cell (AC) harbors a specialized pool of high-capacity mitochondria that localize to the invasive front and are enriched with electron transport chain proteins to generate high ATP levels to fuel invasion. We conducted an RNAi screen of 59 MERCS-encoding components and identified over 30 required for high-capacity mitochondria formation. Our results suggest that MERCS may play a key role in the formation of specialized high-capacity mitochondria.
    DOI:  https://doi.org/10.17912/micropub.biology.001679
  18. bioRxiv. 2025 Aug 23. pii: 2025.08.12.670003. [Epub ahead of print]
    Genetically encoded tool for manipulation of ATP/ADP ratio in human cells.
    Alex E Ekvik, Megan M Kober, Denis V Titov.
      The ability of cells to power energy-demanding processes depends on maintaining the ATP hydrolysis reaction a billion-fold away from equilibrium. Cells respond to changes in energy state by sensing changes in ATP, ADP, AMP, and inorganic phosphate. A key barrier to a better understanding of the maintenance of energy homeostasis is a lack of tools for direct manipulation of energy state in living cells. Here, we report the development of ATPGobble-a genetically encoded tool for controlling cellular ATP hydrolysis rate. We validated ATPGobble by showing that it doubles the energy demand, decreases [ATP]/[ADP] and [ATP]/[AMP] ratios, and activates AMPK activity in human cells. We then used ATPGobble to systematically characterize the proteome and phosphoproteome changes caused by direct manipulation of the energy state. Our results establish ATPGobble as a powerful approach for dissecting the regulatory roles of energy state in human cells, opening new opportunities to study how cellular energy state governs physiology, stress responses, and disease processes.
    DOI:  https://doi.org/10.1101/2025.08.12.670003
  19. Nat Commun. 2025 Aug 30. 16(1): 8123
    Evidence that mitochondria in macrophages are destroyed by microautophagy.
    Shiou-Ling Lu, Siyu Chen, Kazuya Noda, Yangjie Li, Chao-Yuan Tsai, Hiroko Omori, Yumiko Kato, Zidi Zhang, Bohan Chen, Kanako Tokuda, Tongxin Zheng, Masahiro Wakita, Eiji Hara, Mitsunori Fukuda, Yoh Wada, Eiji Morita, Narikazu Uzawa, Shinya Murakami, Takeshi Noda.
      Microautophagy is an intracellular degradation process in which degradatory organelles, such as the lysosome, directly take up substrates by invagination and/or protrusion of their membranes. Here, we provide evidence that Rab32-positive, lysosome-related organelles in macrophages incorporate various other organelles, including endosomes and mitochondria. Our data indicates that, upon exposure to a mitochondria-damaging reagent, mitochondria can be directly engulfed by the lysosome-like organelles independently of macroautophagy or ESCRT machinery. Rab32 GTPase, phosphatidylinositol 3,5-bisphosphates, ubiquitination, and p62/SQSTM1 are crucial for this degradation. Furthermore, the degree of M1 polarization of macrophages, which is facilitated by metabolic reprogramming into increased glycolysis via mitochondrial elimination, is significantly reduced in Rab32/38 double-knockout macrophages. Thus, microautophagy plays a role in the physiological regulation of macrophages.
    DOI:  https://doi.org/10.1038/s41467-025-63531-x
  20. J Cell Biol. 2025 Oct 06. pii: e202410130. [Epub ahead of print]224(10):
    Mitochondrial fission controls astrocyte morphogenesis and organization in the cortex.
    Maria Pia Rodriguez Salazar, Sprihaa Kolanukuduru, Valentina Ramirez, Boyu Lyu, Gracie Manigault, Gabrielle Sejourne, Hiromi Sesaki, Guoqiang Yu, Cagla Eroglu.
      Dysfunctional mitochondrial dynamics are a hallmark of devastating neurodevelopmental disorders such as childhood refractory epilepsy. However, the role of glial mitochondria in proper brain development is not well understood. We show that astrocyte mitochondria undergo extensive fission while populating astrocyte distal branches during postnatal cortical development. Loss of mitochondrial fission regulator, dynamin-related protein 1 (Drp1), decreases mitochondrial localization to distal astrocyte processes, and this mitochondrial mislocalization reduces astrocyte morphological complexity. Functionally, astrocyte-specific conditional deletion of Drp1 induces astrocyte reactivity and disrupts astrocyte organization in the cortex. These morphological and organizational deficits are accompanied by loss of perisynaptic astrocyte process (PAP) proteins such as gap junction protein connexin 43. These findings uncover a crucial role for mitochondrial fission in coordinating astrocytic morphogenesis and organization, revealing the regulation of astrocytic mitochondrial dynamics as a critical step in neurodevelopment.
    DOI:  https://doi.org/10.1083/jcb.202410130
  21. Neurosci Bull. 2025 Aug 30.
    Mitophagy Activation by N-Acetylcysteine Protects against Mic60 Deficiency-Induced Auditory Neuropathy.
    Yilin Sun, Chunying Liu, Yakun Liang, An Lv, Wang Nie, Shuyue Bao, Xiaoyi Li, Jing Zhou, Weimin Tong, Yong Tao, Xueling Wang, Tingting Dong.
      Auditory neuropathy (AN) is a sensorineural hearing loss that impairs speech perception, but its mechanisms and treatments remain limited. Mic60, essential for the mitochondrial contact site and cristae organizing system, is linked to neurological disorders, yet its role in the auditory system remains unclear. We demonstrate that Mic60+/- mice develop progressive hearing loss from 6 months of age, with reduced auditory brainstem response amplitudes despite preserved outer hair cell function, consistent with AN. Mitochondrial abnormalities in spiral ganglion neurons (SGNs) emerge by 3 months, followed by mitochondrial loss and SGN degeneration, indicating progressive auditory neuron dysfunction. In vitro, Mic60 deficiency disrupts mitochondrial respiration, reversible by N-acetylcysteine (NAC). NAC treatment preserves mitochondrial integrity and rescues hearing by enhancing mitophagy. Our findings establish Mic60+/- mice as an AN animal model, highlight the role of Mic60 in the mitochondria of primary auditory neurons, and identify NAC as a potential AN treatment.
    Keywords:  Antioxidant; Auditory neuropathy; Mic60; Mitochondria; Mitophagy; N-acetylcysteine
    DOI:  https://doi.org/10.1007/s12264-025-01485-2
  22. J Immunol. 2025 Sep 04. pii: vkaf215. [Epub ahead of print]
    LRRK2 kinase activity restricts NRF2-dependent mitochondrial protection in microglia.
    Chi G Weindel, Aja K Coleman, Lily M Ellzey, Sandeep Kumar, Sara L Chaisson, Jacob R Davis, Kristin L Patrick, Robert O Watson.
      Mounting evidence supports a critical role for central nervous system (CNS) glial cells in neuroinflammation and neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's Disease (PD), Multiple Sclerosis (MS), as well as neurovascular ischemic stroke. Previously, we found that loss of the PD-associated gene leucine-rich repeat kinase 2 (Lrrk2) in macrophages, peripheral innate immune cells, induced mitochondrial stress and elevated basal expression of type I interferon (IFN) stimulated genes (ISGs) due to chronic mitochondrial DNA engagement with the cGAS/STING DNA sensing pathway. Here we report that loss of LRRK2 results in a paradoxical response in microglial cells, a CNS-specific macrophage population. In primary murine microglia and microglial cell lines, loss of Lrrk2 reduces tonic IFN signaling leading to a reduction in ISG expression. Consistent with reduced type I IFN, mitochondria from Lrrk2 KO microglia are protected from stress and have elevated metabolism. These protective phenotypes involve upregulation of NRF2, an important transcription factor in the response to oxidative stress and are restricted by LRRK2 kinase activity. Collectively, these findings illustrate a dichotomous role for LRRK2 within different immune cell populations and give insight into the fundamental differences between immune regulation in the CNS and the periphery.
    Keywords:  LRRK2 kinase inhibitors; NRF2; mitochondria; tissue-specific macrophages; type I IFN
    DOI:  https://doi.org/10.1093/jimmun/vkaf215
  23. Sci Adv. 2025 Aug 29. 11(35): eads7381
    Abnormal mitochondrial structure and function in brown adipose tissue of SLC35A4-MP knockout mice.
    Andréa L Rocha, Christian Schmedt, Guy Perkins, Antonio Pinto, Jolene K Diedrich, Huanqi Shan, Kaja Plucińska, Eduardo Vieira de Souza, Joan M Vaughan, Mark Foster, Srinath C Sampath, Srihari C Sampath, Paul Cohen, Mark H Ellisman, Alan Saghatelian.
      Uncovering the role of upstream open reading frames (uORFs) challenges conventional views of one protein per messenger RNA and reveals the capacity of some uORFs to encode microproteins that contribute to cellular biology and physiology. This study explores the functional role of a recently identified mitochondrial microprotein, SLC35A4-MP, in the brown adipose tissue of mice. Our findings reveal dynamic regulation of SLC35A4-MP expression during primary brown adipocyte differentiation in vitro and during cold exposure or high-fat diet (HFD)-induced obesity in mice. Using a knockout mouse model, we show that loss of SLC35A4-MP disrupts mitochondrial lipid composition, decreasing cardiolipins and phosphatidylethanolamine in brown adipose tissue from HFD-fed mice. SLC35A4-MP deficiency also impairs mitochondrial activity, alters mitochondrial number and morphology, and promotes inflammation. Knockout mice accumulate acylcarnitines during cold exposure, indicating defective fatty acid oxidation. These findings reveal SLC35A4-MP as a previously unrecognized microprotein in regulating mitochondrial function and tissue lipid metabolism, adding to the growing list of functional endogenous microproteins.
    DOI:  https://doi.org/10.1126/sciadv.ads7381
  24. bioRxiv. 2025 Aug 25. pii: 2025.08.21.671546. [Epub ahead of print]
    Quiescent OXPHOS-high triple-negative breast cancer cells that persist after chemotherapy depend on BCL-XL for survival.
    Slawomir Andrzejewski, Marie Winter, Leandro Encarnacao Garcia, Olusiji Akinrinmade, Francisco D M Marques, Emmanouil Zacharioudakis, Anna Skwarska, Julio Aguirre-Ghiso, Marina Konopleva, Guangrong Zheng, Susan Fineberg, Daohong Zhou, Evripidis Gavathiotis, Tao Wang, Eugen Dhimolea.
      The persistent residual tumor cells that survive after chemotherapy are a major cause of treatment failure, but their survival mechanisms remain largely elusive. These cancer cells are typically characterized by a quiescent state with suppressed activity of MYC and MTOR. We observed that the MYC-suppressed persistent triple-negative breast cancer (TNBC) cells are metabolically flexible and can upregulate mitochondrial oxidative phosphorylation (OXPHOS) genes and respiratory function ("OXPHOS-high" cell state) in response to DNA-damaging anthracyclines such as doxorubicin, but not to taxanes. The elevated biomass and respiratory function of mitochondria in OXPHOS-high persistent cancer cells were associated with mitochondrial elongation and remodeling suggestive of increased mitochondrial fusion. A genome-wide CRISPR editing screen in doxorubicin-persistent OXPHOS-high TNBC cells revealed BCL-XL gene as the top survival dependency in these quiescent tumor cells, but not in their untreated proliferating counterparts. Quiescent OXPHOS-high TNBC cells were highly sensitive to BCL-XL inhibitors, but not to inhibitors of BCL2 and MCL1. Interestingly, inhibition of BCL-XL in doxorubicin-persistent OXPHOS-high TNBC cells rapidly abrogated mitochondrial elongation and respiratory function, followed by caspase 3/7 activation and cell death. The platelet-sparing proteolysis targeted chimera (PROTAC) BCL-XL degrader DT2216 enhanced the efficacy of doxorubicin against TNBC xenografts in vivo without induction of thrombocytopenia that is often observed with the first-generation BCL-XL inhibitors, supporting the development of this combinatorial treatment strategy for eliminating dormant tumor cells that persist after treatment with anthracycline-based chemotherapy.
    DOI:  https://doi.org/10.1101/2025.08.21.671546
  25. Proc Natl Acad Sci U S A. 2025 Sep 09. 122(36): e2502483122
    Restoring mitochondrial quantity and quality to reverse the Warburg effect and drive neuroblastoma differentiation.
    Haowen Jiang, Sarah Jane Tiche, Clifford Jiajun He, Junyan Liu, Fuyun Bian, Mohamed Jedoui, Balint Forgo, Md Tauhidul Islam, Meng Zhao, Pamela Emengo, Bo He, Yang Li, Albert M Li, Anh T Truong, Jestine Ho, Cathyrin Simmermaker, Yanan Yang, Meng-Ning Zhou, Zhen Hu, Katrin J Svensson, Daniel J Cuthbertson, Florette K Hazard, Lei Xing, Hiroyuki Shimada, Bill Chiu, Jiangbin Ye.
      Reduced mitochondrial quality and quantity in tumors is associated with dedifferentiation and increased malignancy. However, it remains unclear how to restore mitochondrial quantity and quality in tumors and whether mitochondrial restoration can drive tumor differentiation. Our study shows that restoring mitochondrial function using retinoic acid (RA) to boost mitochondrial biogenesis and a mitochondrial uncoupler to enhance respiration synergistically drives neuroblastoma differentiation and inhibits proliferation. U-13C-glucose/glutamine isotope tracing revealed a metabolic shift from the pentose phosphate pathway to oxidative phosphorylation, accelerating the tricarboxylic acid cycle and switching substrate preference from glutamine to glucose. These effects were abolished by electron transport chain (ETC) inhibitors or in ρ0 cells lacking mitochondrial DNA, emphasizing the necessity of mitochondrial function for differentiation. Dietary RA and uncoupler treatment promoted tumor differentiation in an orthotopic neuroblastoma xenograft model, evidenced by neuropil production and Schwann cell recruitment. Single-cell RNA sequencing of xenografts revealed that this strategy effectively eliminated the stem cell population, promoted differentiation, and increased mitochondrial gene signatures along the differentiation trajectory, potentially improving patient outcomes. Collectively, our findings establish a mitochondria-centric therapeutic strategy for inducing tumor differentiation, suggesting that maintaining/driving differentiation in tumor requires not only ATP production but also continuous ATP consumption and sustained ETC activity.
    Keywords:  differentiation; mitochondria; neuroblastoma; retinoic acid; uncoupler
    DOI:  https://doi.org/10.1073/pnas.2502483122
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