bims-nenemi Biomed News
on Neuroinflammation, neurodegeneration and mitochondria
Issue of 2025–08–03
28 papers selected by
Marco Tigano, Thomas Jefferson University
  1. Human mitochondrial RNA polymerase structures reveal transcription start site and slippage mechanism.
  2. VDAC2 brake release: unleashing inflammation via IFNγ.
  3. Alterations in Lipid Saturation Trigger Remodeling of the Outer Mitochondrial Membrane.
  4. Mitochondrial glutathione import enables breast cancer metastasis via integrated stress response signaling.
  5. Oligomer-based functions of mitochondrial porin.
  6. Tom40 functions as a channel for protein retrotranslocation in the mitochondria-associated degradation (MAD) pathway.
  7. Proteasomal dysfunction in the mouse forebrain induces mitochondrial DNA release, cGAS-STING signaling activation, and necroptosis.
  8. ANKZF1 helps to eliminate stress-damaged mitochondria by LC3-mediated mitophagy.
  9. A Membrane-Disruptive Action of VBIT-4 Challenges Its Role as a Widely Used VDAC Oligomerization Inhibitor.
  10. Structural basis for promoter recognition and transcription factor binding and release in human mitochondria.
  11. Inhibition of HDAC6 alters fumarate hydratase activity and mitochondrial structure.
  12. An updated inventory of genes essential for oxidative phosphorylation identifies a mitochondrial origin in familial Ménière's disease.
  13. Mitochondria-derived nuclear ATP surge protects against confinement-induced proliferation defects.
  14. In situ cryo-ET visualization of mitochondrial depolarization and mitophagic engulfment.
  15. Mitochondrial dysfunction mediated by ER-calcium dysregulation in neurons derived from Alzheimer's disease patients.
  16. Retraction Note: Parkin and PINK1 mitigate STING-induced inflammation.
  17. 2-hydroxyglutarate mediates whitening of brown adipocytes coupled to nuclear softening upon mitochondrial dysfunction.
  18. Opantimirs: A class of antagonizing microRNAs that upregulate Opa1 and improve mitochondrial and disuse myopathies.
  19. Mitochondrial protein aggregates recruit key chaperones and are sequestered in a fission/fusion-dependent process.
  20. Senescence-associated lysosomal dysfunction impairs cystine deprivation-induced lipid peroxidation and ferroptosis.
  21. Disrupting tRNA modifications to target mitochondrial vulnerabilities in drug-resistant leukemia cells.
  22. mRNA trafficking directs cell-size-scaling of mitochondria distribution and function.
  23. PA28γ promotes the malignant progression of tumor by elevating mitochondrial function via C1QBP.
  24. Targeting SLC25A33 Suppresses Vascular Smooth Muscle Cell Proliferation and Migration by Reducing Cytosolic mtDNA Levels: Implications for Occlusive Vascular Diseases.
  25. Rab14 promotes Parkin mediated mitophagy.
  26. CUMS stress facilitates hippocampal neural mitophagy through FIS1/MFF-mediated mitochondrial fragmentation.
  27. Atrazine-induced hippocampal neurotoxicity: Involvement of Drp1-mediated mitochondrial fission.
  28. The impact of ERUPR on mitochondrial integrity mediated by PDK4.
  1. Mol Cell. 2025 Jul 22. pii: S1097-2765(25)00581-7. [Epub ahead of print]
    Human mitochondrial RNA polymerase structures reveal transcription start site and slippage mechanism.
    Jiayu Shen, Quinten Goovaerts, Yogeeshwar Ajjugal, Brent De Wijngaert, Kalyan Das, Smita S Patel.
      Transcription of the human mitochondrial DNA is initiated by POLRMT and initiation factors mitochondrial transcription factor A (TFAM) and mitochondrial transcription factor B2 (TFB2M). We present cryo-electron microscopy (cryo-EM) structures of three transcription initiation intermediates (pre-catalytic IC3 [pre-IC3], slipped-IC3, and slipped pre-IC4) catalyzing RNA synthesis by normal and slippage pathways with fully resolved transcription bubbles and RNA transcripts starting from the +1 or -1 position. The structural and biochemical studies reveal mechanisms of promoter melting, start site selection, and slippage synthesis. Promoter melting begins at -4 with base-specific interactions of template -4 and -3 guanines with POLRMT and non-template -1 adenine with TFB2M. The NT-stabilizing loop (K153LDPRSGGVIKPP165) and Y209 of TFB2M and W1026 of POLRMT interact with the non-template strand to guide initiation from the +1 start site. The -1 position is not an alternative start site but supports slippage initiation by base-pairing with a slipped or rebound 2-nt RNA. Cryo-EM resolved additional apo and dimeric complexes whose populations may regulate transcription initiation.
    Keywords:  POLRMT; TFAM; TFB2M; abortive synthesis; cryo-EM structure; light strand promoter; promoter melting; slippage synthesis; start site selection; transcription initiation
    DOI:  https://doi.org/10.1016/j.molcel.2025.07.002
  2. Trends Pharmacol Sci. 2025 Jul 29. pii: S0165-6147(25)00144-0. [Epub ahead of print]
    VDAC2 brake release: unleashing inflammation via IFNγ.
    Swapneel J Patel, Zhijian J Chen.
      Identification of therapeutic vulnerabilities in cancer remains a high priority for cancer research. A recent CRISPR/Cas9 screen identified that VDAC2 deletion in tumors enhanced their sensitivity to interferon-γ (IFNγ) through the release of mitochondrial DNA (mtDNA) and activation of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway. These data suggest that VDAC2 inhibition could enhance antitumor therapies.
    Keywords:  STING; VDAC; cGAS; cancer; inflammation
    DOI:  https://doi.org/10.1016/j.tips.2025.07.001
  3. Mol Biol Cell. 2025 Jul 30. mbcE25010033
    Alterations in Lipid Saturation Trigger Remodeling of the Outer Mitochondrial Membrane.
    Sara Wong, Katherine R Bertram, Sai Sangeetha Balasubramaniam, Nidhi Raghuram, Thomas Knight, J Alan Maschek, James E Cox, Adam L Hughes.
      Lipid saturation is a key determinant of membrane function and organelle health, with changes in saturation triggering adaptive quality control mechanisms to maintain membrane integrity. Among cellular membranes, the mitochondrial outer membrane (OMM) is an important interface for many cellular functions, but how lipid saturation impacts OMM function remains unclear. Here, we show that increased intracellular unsaturated fatty acids (UFAs) remodel the OMM by promoting the formation of multilamellar mitochondrial-derived compartments (MDCs), which sequester proteins and lipids from the OMM. These effects depend on the incorporation of UFAs into membrane phospholipids, suggesting that changes in membrane bilayer composition mediate this process. Furthermore, elevated UFAs impair the assembly of the OMM protein translocase (TOM) complex, with unassembled TOM components captured into MDCs. Collectively, these findings suggest that alterations in phospholipid saturation may destabilize OMM protein complexes and trigger an adaptive response to sequester excess membrane proteins through MDC formation.
    DOI:  https://doi.org/10.1091/mbc.E25-01-0033
  4. Cancer Discov. 2025 Jul 31.
    Mitochondrial glutathione import enables breast cancer metastasis via integrated stress response signaling.
    Hsi-Wen Yeh, Nicole Lauren DelGaudio, Beste Uygur, Alon Millet, Artem Khan, Gokhan Unlu, Michael Xiao, Rebecca C Timson, Caifan Li, Kerem Ozcan, Karl W Smith, Luiza Martins Nascentes Melo, Gabriele Allies, Olca Basturk, Albert Sickmann, Erol C Bayraktar, Richard Possemato, Alpaslan Tasdogan, Kivanc Birsoy.
      Cancer cells require substantial metabolic adaptations to metastasize to distant organs, but the metabolites essential for successful colonization remain poorly defined. Here, we used a mitochondrial metabolomics approach to compare primary and metastatic breast cancer cells. This analysis revealed accumulation of mitochondrial glutathione (GSH) during lung metastasis, driven by elevated expression of SLC25A39, a mitochondrial GSH transporter. Loss of SLC25A39 impairs metastatic colonization in genetic screens, cell line models, and patient-derived xenografts, without affecting primary tumor growth. Mitochondrial GSH import is specifically required during early colonization and functions independently of its canonical antioxidant role. CRISPR activation screens identified ATF4, a stress-induced transcription factor, as a bypass mechanism that restores metastatic potential in SLC25A39-deficient cells. Mechanistically, SLC25A39 is required for optimal ATF4 activation during metastasis and under hypoxia, linking mitochondrial GSH availability to integrated stress response signaling. These findings identify mitochondrial GSH as a necessary and limiting metabolite for metastatic progression.
    DOI:  https://doi.org/10.1158/2159-8290.CD-24-1556
  5. Nat Commun. 2025 Jul 25. 16(1): 6854
    Oligomer-based functions of mitochondrial porin.
    Hironori Takeda, Saori Shinoda, Chiho Goto, Akihisa Tsutsumi, Haruka Sakaue, Chunming Zhang, Takashi Hirashima, Yuta Konishi, Haruka Ono, Yu Yamamori, Kentaro Tomii, Hiroya Shiino, Yasushi Tamura, Solène Zuttion, Bruno Senger, Sylvie Friant, Hubert D Becker, Yuhei Araiso, Nanako Kobayashi, Noriyuki Kodera, Masahide Kikkawa, Toshiya Endo.
      Porin, or the voltage-dependent anion channel (VDAC), is a primary β-barrel channel in the mitochondrial outer membrane. It transports small metabolites and ions through its β-barrel pore and plays key roles in apoptosis and inflammatory response. Here we report the cryo-electron microscopy structure of yeast porin (Por1) in its hexameric form at 3.2 Å resolution. This structure allows us to introduce various mutations at the protomer interfaces, uncovering three critical functions of Por1 assembly beyond transport. Por1 binds unassembled Tom22, a subunit of the mitochondrial protein import gate (the TOM complex), to facilitate protein import into the intermembrane space, maintains proper mitochondrial lipid composition in the outer membrane through lipid scramblase activity, and contributes to the retention and regulated loss of mitochondrial DNA, in cooperation with nucleases identified through screening enabled by the obtained Por1 mutant.
    DOI:  https://doi.org/10.1038/s41467-025-62021-4
  6. Commun Biol. 2025 Jul 29. 8(1): 1122
    Tom40 functions as a channel for protein retrotranslocation in the mitochondria-associated degradation (MAD) pathway.
    Pin-Chao Liao, Tzu-Ying Lin, Catherine A Tsang, Chen-Jing Huang, Katherine Filpo, Istvan Boldogh, Liza A Pon.
      The mitochondria-associated degradation pathway (MAD) mediates removal and elimination of damaged, unfolded mitochondrial proteins by the ubiquitin-proteasome system (UPS). Previous studies revealed that MAD is critical for mitochondrial protein quality control and that MAD function extends beyond mitochondrial outer membrane (MOM) to proteins within the organelle. Here, we reconstitute retrotranslocation of MAD substrates from the mitochondrial matrix across mitochondrial inner and outer membranes in cell-free systems. This retrotranslocation is ATP-dependent but membrane potential-independent. We also identify a role for the TOM complex, the protein import channel in the MOM, in this process. Inhibition of protein translocation across the Tom40p channel reduces the retrotranslocation of MAD substrates. Our studies support the model that the TOM complex is a bidirectional protein channel in the MOM: it mediates retrotranslocation of damaged mitochondrial proteins across the MOM in the MAD pathway for mitochondrial protein quality control in addition to its function in import of proteins into the organelle.
    DOI:  https://doi.org/10.1038/s42003-025-08549-z
  7. J Neuropathol Exp Neurol. 2025 Aug 01. pii: nlaf093. [Epub ahead of print]
    Proteasomal dysfunction in the mouse forebrain induces mitochondrial DNA release, cGAS-STING signaling activation, and necroptosis.
    Abena Dwamena, Yasin Asadi, Erin Gilstrap, Hongmin Wang.
      Impaired proteasome function is associated with various neurodegenerative disorders that are hallmarked by neuroinflammation and neurodegeneration, including Alzheimer disease (AD); however, the relationships between these phenomena remain unclear. By utilizing a neuron-specific Psmc1 conditional knockout (cKO) mouse model in which one of the 19S proteasome is disrupted, we studied the effect of impaired proteasome function on neuroinflammation and neuronal death in the brain. We discovered that disrupting the 19S proteasome led to increased release of mitochondrial double-stranded DNA into the cytosol, upregulated levels of cyclic GMP-AMP synthase (cGAS), stimulator of interferon gene (STING), phosphorylated TBK1, and IRF3, and the downstream pro-inflammatory mediators, including STAT1, NF-κB, IL-1β, IL-6, and TNFα in the cKO mouse brains as compared to control brains. Importantly, we also observed reduced brain weight and elevation in levels of factors involved in necroptosis, ie the mixed lineage kinase domain-like (MLKL) protein, phosphorylated MLKL, and receptor-interacting protein kinases (RIPK) 1 and 3 in the cKO mouse brains. Together, our data suggest that proteasome dysfunction activates the cGAS-STING pathway and induces neuroinflammation and necroptotic neuronal death.
    Keywords:  cGAS-STING; necroptosis; neurodegenerative disease; neuroinflammation; proteasome; proteasome dysfunction
    DOI:  https://doi.org/10.1093/jnen/nlaf093
  8. Cell Death Discov. 2025 Jul 29. 11(1): 349
    ANKZF1 helps to eliminate stress-damaged mitochondria by LC3-mediated mitophagy.
    Mudassar Ali, Anjali, Koyeli Mapa.
      Mitochondria, the double membrane-bound organelles of endosymbiotic origin, are crucial centers for cellular energy production and several essential metabolic pathways. Recent studies reveal that mitochondria become dysfunctional following numerous cellular stresses, and during pathologies, demanding an extensive investigation of mitochondrial turnover mechanisms. Apart from the specific response pathways to tackle different stresses, mitophagy, or degradation of mitochondria by autophagy, is a critical quality control mechanism that clears irreversibly damaged mitochondria. Mitophagy is majorly executed either by receptor-mediated or PINK1-Parkin-dependent pathways. Here, we show that the human orthologue of yeast Vms1, ANKZF1, participates in PINK1-Parkin-mediated mitophagy. We show that ANKZF1 is extensively recruited to damaged mitochondria along with Parkin during mitochondrial proteotoxic stress induced by the expression of a single misfolded/aggregated protein or during uncoupler-induced membrane depolarization. Importantly, ANKZF1 recruitment to damaged mitochondria is significantly enhanced in the presence of Parkin, and ANKZF1 physically interacts with Parkin and LC3 during mitochondrial proteotoxic or depolarization stress. ANKZF1 harbors six putative LC3-interacting regions (LIRs), LIR4 present at residues 333-336, is particularly important for ANKZF1-LC3 interaction. Furthermore, we show that ANKZF1 knockout cells are compromised in clearing stress-damaged mitochondria by mitophagy, indicating an important role of ANKZF1 in mitochondrial turnover during stress. In summary, we show a new role of ANKZF1 in eliminating the stress-damaged mitochondria, reiterating the mito-protective role of Vms1/ANKZF1 during mitochondrial stresses. PINK1/Parkin signaling leads to polyubiquitination of outer mitochondrial membrane (OMM) proteins on stressed mitochondria. ANKZF1 functions as an adaptor protein, binding to polyubiquitinated OMM proteins via UBA domain and autophagosome receptor LC3 via LIR motif.
    DOI:  https://doi.org/10.1038/s41420-025-02638-y
  9. bioRxiv. 2025 Jul 03. pii: 2025.06.30.661942. [Epub ahead of print]
    A Membrane-Disruptive Action of VBIT-4 Challenges Its Role as a Widely Used VDAC Oligomerization Inhibitor.
    Varun Ravishankar, Luis Borges-Araujo, Elodie Lafargue, Deborah Byrne, Nicolas Buzhinsky, Mya Wolfe, Nina Bautista, Bethel Beyene, Motahareh Larimi, Jean-Pierre Duneau, James Sturgis, Megha Rajendran, Sergey Bezrukov, Ignacio Casuso, Tatiana K Rostovtseva, Lucie Bergdoll.
      VDAC, the most abundant protein in the outer mitochondrial membrane, plays a central role in mitochondrial physiology. Its oligomerization has been contemplated to be involved in critical processes such as mtDNA release and apoptosis, yet the underlying molecular mechanisms remain poorly defined. VBIT-4, a small molecule widely used as a VDAC1 oligomerization inhibitor, has seen extensive applications over the past five years without proper mechanistic characterization. Using high-speed atomic force microscopy, we directly visualized VDAC1 oligomerization in planar lipid membranes and examined the effects of VBIT-4. Unexpectedly, VBIT-4 partitioned into lipid bilayers at micromolar concentrations and disrupted membrane structure even in the absence of VDAC1. Complementary approaches, including single-channel electrophysiology, microscale thermophoresis, and coarse-grained molecular dynamics, confirmed the membrane partitioning and destabilizing effects of VBIT-4. The compound also induced VDAC1-independent cytotoxicity in HeLa cells at concentrations above 10 microM. Our findings demonstrate that VBIT-4 disrupts membrane integrity by partitioning into lipids and inducing membrane defects rather than specifically inhibiting VDAC1 oligomerization, highlighting the need for caution when interpreting results and the importance of revisiting conclusions drawn from its prior use.
    DOI:  https://doi.org/10.1101/2025.06.30.661942
  10. Mol Cell. 2025 Jul 22. pii: S1097-2765(25)00545-3. [Epub ahead of print]
    Structural basis for promoter recognition and transcription factor binding and release in human mitochondria.
    Karl Herbine, Ashok R Nayak, Angelica Zamudio-Ochoa, Dmitry Temiakov.
      Transcription in human mitochondria is driven by a core apparatus consisting of a Pol A family RNA polymerase (mtRNAP), the initiation factors TFAM and TFB2M, and the elongation factor TEFM. While earlier structures of initiation and elongation complexes provided valuable snapshots, they represent isolated stages of a highly dynamic and multistep process. Critical aspects of mitochondrial transcription-such as DNA recognition and melting, promoter escape, and the release of initiation factors-remain poorly understood. Here, we present a series of cryoelectron microscopy (cryo-EM) structures that capture the transcription complex as it transitions from the initial open promoter complex to the processive elongation complex through intermediate stages. Our data reveal new, previously unidentified determinants of promoter specificity: the sequential disengagement of mtRNAP from TFAM and the promoter, the release of TFB2M, and the recruitment of TEFM. Together, these findings provide a detailed molecular mechanism underlying transcription in human mitochondria.
    Keywords:  POLRMT; RNA polymerase; TEFM; TFAM; TFB2M; mitochondrial transcription; mtRNAP; promoter; transcription-replication switch
    DOI:  https://doi.org/10.1016/j.molcel.2025.06.016
  11. Nat Commun. 2025 Jul 28. 16(1): 6923
    Inhibition of HDAC6 alters fumarate hydratase activity and mitochondrial structure.
    Andrew Roe, Catríona M Dowling, Cian D'Arcy, Daniel Alencar Rodrigues, Yu Wang, Matthew Hiller, Carl Keogh, Kate E R Hollinshead, Massimiliano Garre, Brenton Cavanagh, Kieran Wynne, Tianyan Liu, Zhixing Chen, Emma Kerr, Marie McIlroy, Jochen H M Prehn, Ingmar Schoen, Tríona Ní Chonghaile.
      Fumarate hydratase (FH), a key node of mitochondrial metabolism, is also a tumour suppressor. Despite its prominent roles in tumourigenesis and inflammation, its regulation remains poorly understood. Herein, we show that histone deacetylase 6 (HDAC6) regulates FH activity. In triple-negative breast cancer cells, HDAC6 inhibition or knockdown results in alterations to mitochondrial cristae structure, as detected by live-cell super-resolution STED nanoscopy and electron microscopy, along with the release of mitochondrial DNA. Mass-spectrometry immunoprecipitation reveals multiple mitochondrial HDAC6-interactors, with FH emerging as a top hit. Super-resolution 3D-STORM shows HDAC6 interactions with FH in mitochondrial networks, which increases after perturbation of HDAC6 activity with BAS-2. Treatment with BAS-2 leads to fumarate accumulation by 13C glucose labelling, along with downstream succination of proteins and cell death. Together, these results identify HDAC6 inhibition as a regulator of endogenous FH activity in tumour cells, and highlight it as a promising candidate for indirectly targeting tumour metabolism.
    DOI:  https://doi.org/10.1038/s41467-025-61897-6
  12. Cell Rep. 2025 Jul 25. pii: S2211-1247(25)00840-X. [Epub ahead of print]44(8): 116069
    An updated inventory of genes essential for oxidative phosphorylation identifies a mitochondrial origin in familial Ménière's disease.
    Marcell Harhai, Mads M Foged, Christine Zarges, Juan C Landoni, Sylvain Chollet, Michele Simonelli, Emeline Recazens, Miriam Lisci, Nora Laban, Suliana Manley, Jan Riemer, Jose Antonio Lopez-Escamez, Anna Lysakowski, Alexis A Jourdain.
      Mitochondrial disorders (MDs) are among the most common inborn errors of metabolism, and dysfunction in oxidative phosphorylation (OXPHOS) is a hallmark. Their complex mode of inheritance and diverse clinical presentations render the diagnosis of MDs challenging, and, to date, most lack a cure. Here, we build on previous efforts to identify genes necessary for OXPHOS and report a highly complementary galactose-sensitized CRISPR-Cas9 "growth" screen, presenting an updated inventory of 481 OXPHOS genes, including 157 linked to MDs. We further focus on FAM136A, a gene associated with Ménière's disease, and demonstrate that it supports intermembrane space protein homeostasis and OXPHOS in cell lines, mice, and patients. Our study identifies a mitochondrial basis in familial Ménière's disease, provides a comprehensive resource of OXPHOS-related genes, and sheds light on the pathways involved in MDs, with the potential to guide future diagnostics and treatments for MDs.
    Keywords:  CLPB; CP: Metabolism; FAM136A; HAX1; Ménière; OXPHOS; functional genomics; intermembrane space; mitochondria; mitochondrial disease; proteostasis
    DOI:  https://doi.org/10.1016/j.celrep.2025.116069
  13. Nat Commun. 2025 Jul 30. 16(1): 6613
    Mitochondria-derived nuclear ATP surge protects against confinement-induced proliferation defects.
    Ritobrata Ghose, Fabio Pezzano, Rémi Badia, Savvas Kourtis, Ilir Sheraj, Shubhamay Das, Antoni Gañez Zapater, Upamanyu Ghose, Sara Musa-Afaneh, Lorena Espinar, Albert Coll-Manzano, Katja Parapatics, Saška Ivanova, Paula Sànchez-Fernàndez-de-Landa, Dragana Radivojevikj, Valeria Venturini, Stefan Wieser, Antonio Zorzano, André C Müller, Verena Ruprecht, Sara Sdelci.
      The physical tissue microenvironment regulates cell state and behaviour. How mechanical confinement rewires the subcellular localisation of organelles and affects cellular metabolism is largely unknown. In this study, proteomics analysis revealed that cellular confinement induced a strong enrichment of mitochondrial proteins in the nuclear fraction. Quantitative live cell microscopy confirmed that mechanical cell confinement leads to a rapid re-localisation of mitochondria to the nuclear periphery in vitro, reflecting a physiologically relevant phenomenon in patient-derived tumours. This nucleus-mitochondria proximity is mediated by an endoplasmic reticulum-based net that entraps the mitochondria in an actin-dependent manner. Functionally, the nucleus-mitochondria proximity results in a nuclear ATP surge, which can be regulated by the genetic and pharmacological modulation of mitochondrial ATP production or via alterations of the actin cytoskeleton. The confinement-induced nuclear ATP surge has physiologically significant long-term effects on cell fitness, driven by changes in chromatin state, enhanced DNA damage repair, and cell cycle progression during mechanical cell deformation. Together, our data describe a confinement-induced metabolic adaptation that is required to enable prompt DNA damage repair and cell proliferation under mechanical confinement stress by facilitating chromatin state transitions.
    DOI:  https://doi.org/10.1038/s41467-025-61787-x
  14. Proc Natl Acad Sci U S A. 2025 Aug 05. 122(31): e2511890122
    In situ cryo-ET visualization of mitochondrial depolarization and mitophagic engulfment.
    Kevin Rose, Eric Herrmann, Eve Kakudji, Javier Lizarrondo, A Yasemin Celebi, Florian Wilfling, Samantha C Lewis, James H Hurley.
      Defective mitochondrial quality control in response to loss of mitochondrial membrane polarization is implicated in Parkinson's disease by mutations in PINK1 and PRKN. Parkin-expressing U2 osteosarcoma (U2OS) cells were treated with the depolarizing agents oligomycin and antimycin A (OA) and subjected to cryo-focused ion beam milling and in situ cryo-electron tomography. Mitochondria were fragmented and devoid of matrix calcium phosphate crystals. Phagophores were visualized, with bridge-like lipid transporter densities connected to mitophagic phagophores. A subpopulation of ATP synthases relocalized from cristae to the inner boundary membrane. The structure of the dome-shaped prohibitin complex, a dodecamer of PHB1-PHB2 dimers, was determined in situ by subtomogram averaging in untreated and treated cells and found to exist in open and closed conformations, with the closed conformation being enriched by OA treatment. These findings provide a set of native snapshots of the manifold nano-structural consequences of mitochondrial depolarization and provide a baseline for future in situ dissection of Parkin-dependent mitophagy.
    Keywords:  autophagy; cryo-ET; mitochondria; mitophagy; prohibitin
    DOI:  https://doi.org/10.1073/pnas.2511890122
  15. Acta Neuropathol Commun. 2025 Jul 29. 13(1): 165
    Mitochondrial dysfunction mediated by ER-calcium dysregulation in neurons derived from Alzheimer's disease patients.
    Sarah Mustaly-Kalimi, Wacey Gallegos, Daniel Steinbrenner, Smriti Gupta, Aiden J Houcek, David A Bennett, Robert A Marr, Daniel A Peterson, Israel Sekler, Grace E Stutzmann.
      Tight regulation of mitochondrial Ca2+ is essential for neuronal bioenergetics and cellular metabolism. Ca2+ transfer from ER-localized ryanodine receptors (RyR) and inositol triphosphate receptors (IP3R) to the mitochondria maintains a steady Ca2+ source that fuels oxidative phosphorylation and ATP production. In Alzheimer's disease (AD), RyR-evoked Ca2+ release is markedly increased, contributing to synaptic deficits, protein mishandling, and memory impairment. Here, we demonstrate dysregulated RyR-Ca2+ release in neurons from familial and sporadic AD patients, and this directly compromises mitochondrial activity and contributes to AD cellular pathology. We measured an array of mitochondrial functions using fluorescent biosensors and optical imaging in RyR2-expressing HEK cells and neurons derived from AD and nonAD individuals. In neurons from AD patients, resting mitochondrial Ca2+ levels were elevated alongside increased free radical production and higher caspase-3 activity relative to nonAD neurons. RyR-evoked Ca2+ release further potentiated pathogenic mitochondrial responses in AD neurons, with increased Ca2+ uptake and exaggerated mitochondrial membrane depolarization. Additionally, clearance of damaged mitochondria was impaired in AD neurons, demonstrating consequences from dysfunctional lysosomes. Notably, impairments to mitochondria in AD neurons were largely prevented with the RyR negative allosteric modulator, Ryanodex. These findings highlight how excess RyR-Ca2+ release broadly contributes to early cellular pathology in AD which includes a cascade of ER, lysosomal, and mitochondrial deficits culminating in neuronal decline and degeneration. Additionally, pharmacological suppression of RyR-Ca2+ release preserves mitochondrial, ER and lysosomal function, thus providing a novel and effective therapeutic strategy.
    Keywords:  Alzheimer’s disease; Calcium dysregulation; Mitochondria; Ryanodine receptor; iPSC-derived neurons
    DOI:  https://doi.org/10.1186/s40478-025-02023-x
  16. Nature. 2025 Jul 30.
    Retraction Note: Parkin and PINK1 mitigate STING-induced inflammation.
    Danielle A Sliter, Jennifer Martinez, Ling Hao, Xi Chen, Nuo Sun, Tara D Fischer, Jonathon L Burman, Yan Li, Zhe Zhang, Derek P Narendra, Huaibin Cai, Max Borsche, Christine Klein, Richard J Youle.
      
    DOI:  https://doi.org/10.1038/s41586-025-09346-8
  17. Nat Metab. 2025 Aug 01.
    2-hydroxyglutarate mediates whitening of brown adipocytes coupled to nuclear softening upon mitochondrial dysfunction.
    Harshita Kaul, Lea Isermann, Katharina Senft, Milica Popovic, Theodoros Georgomanolis, Linda Baumann, Pujyanathan Sivanesan, Andromachi Pouikli, Hendrik Nolte, Bojana Lucic, Ximena Hildebrandt, Katrin Seidel, Thorsten Gnad, Felix Gaedke, Ulrike Göbel, Franziska Peters, Maksym Cherevatenko, Joo Hyun Park, Astrid Schauss, Nieves Peltzer, Jens Claus Brüning, Jan-Wilhelm Kornfeld, Alexander Pfeifer, Thomas Langer, Marina Lusic, Sara A Wickström, Christian Frezza, Aleksandra Trifunovic.
      Mitochondria have a crucial role in regulating cellular homeostasis in response to intrinsic and extrinsic cues by changing cellular metabolism to meet these challenges. However, the molecular underpinnings of this regulation and the complete spectrum of these physiological outcomes remain largely unexplored. In this study, we elucidate the mechanisms driving the whitening phenotype in brown adipose tissue (BAT) deficient in the mitochondrial matrix protease CLPP. Here we show that CLPP-deficient BAT shows aberrant accumulation of lipid droplets, which occurs independently of defects in oxygen consumption and fatty acid oxidation. Our results indicate that mitochondrial dysfunction due to CLPP deficiency leads to the build-up of the oncometabolite D-2-hydroxyglutarate (D-2HG), which in turn promotes lipid droplet enlargement. We further demonstrate that D-2HG influences gene expression and decreases nuclear stiffness by modifying epigenetic signatures. We propose that lipid accumulation and altered nuclear stiffness regulated through 2HG are stress responses to mitochondrial dysfunction in BAT.
    DOI:  https://doi.org/10.1038/s42255-025-01332-8
  18. Cell Rep Med. 2025 Jul 16. pii: S2666-3791(25)00321-0. [Epub ahead of print] 102248
    Opantimirs: A class of antagonizing microRNAs that upregulate Opa1 and improve mitochondrial and disuse myopathies.
    Andre Djalalvandi, Keisuke Takeda, Francesca Grespi, Hualin Fan, Tiago Branco Fonseca, Leonardo Nogara, Saman Sharifi, Carlotta Barison, Martina Semenzato, Akiko Omori, Raffaele Cerutti, Davide Steffan, Lorenza Tsansizi, Valeria Balmaceda, Lukas Alan, Camilla Bean, Bert Blaauw, Carlo Viscomi, Luca Scorrano.
      Alterations in mitochondrial ultrastructure and reduced levels of the crista-shaping protein Opa1 are key features of mitochondrial myopathies and aging. We identify and characterize a biological therapy that improves mitochondrial and disuse myopathy models by boosting Opa1 levels. In silico analysis identifies microRNAs (miRNAs) 128-3p and 148/152-3p family as conserved modulators of OPA1 transcription and elevated in various muscle disorders. These miRNAs target the 3' UTR of murine and human OPA1, reducing its mRNA and protein levels, causing mitochondrial fragmentation and crista disorganization. Genetic experiments confirm that their mitochondrial effects rely on 3' UTR binding. In mitochondrial disease patient cells and murine models, elevated OPA1-specific miRNA levels are reduced by antagonistic miRNAs (Opantimirs), which restore mitochondrial ultrastructure, morphology, and function. In vivo, Opantimirs correct mitochondrial ultrastructure and fiber size in muscles of denervated and Cox15-ablated mice, improving strength in the latter. Thus, biopharmacological correction of the mitochondrial ultrastructure can ameliorate mitochondrial myopathies.
    Keywords:  OPA1; antimiRs; cristae remodeling; disuse myopathies; miR-128-3p; miR-148/152-3p family; microRNAs; mitochondrial myopathies; mitochondrial ultrastructure
    DOI:  https://doi.org/10.1016/j.xcrm.2025.102248
  19. J Cell Sci. 2025 Jul 30. pii: jcs.263680. [Epub ahead of print]
    Mitochondrial protein aggregates recruit key chaperones and are sequestered in a fission/fusion-dependent process.
    Laura Ruland, Marc Sylvester, Lydia Maus, Hannes Beckert, Wolfgang Voos.
      The potential proteotoxicity of mitochondrial aggregates in yeast cells is reduced by a sequestration of affected polypeptides into a mitochondrial protein quality control compartment (IMiQ). Based on the expression of an aggregation-prone protein in the mitochondrial matrix, we determined the effect of organelle dynamics on aggregate sequestration. Fusion deficient cells were unable to accumulate the aggregates in the IMiQ, resulting in a stress-sensitive phenotype. In contrast, fission deficient cells could not separate the aggregate from the mitochondrial network. In these mitochondria, the aggregates were neutralized by the formation of a shell formed by mitochondrial chaperones. We also performed quantitative mass spectrometry to analyse the mitochondrial proteome and the extent of co-aggregation of mitochondrial proteins. While only minor changes of the total proteome were detected in response to aggregate accumulation, we found a recruitment of proteins of the respiratory chain complexes and of the protein quality control system (PQC). In particular members of the Hsp70 chaperone family were prominently associated with the aggregate. We conclude that this chaperone-dependent neutralization prevents a major co-aggregation of endogenous mitochondrial proteins.
    Keywords:  Cell biology; Chaperone; Hsp70; Mitochondria; Protein aggregation; Proteostasis; Yeast
    DOI:  https://doi.org/10.1242/jcs.263680
  20. Nat Commun. 2025 Jul 29. 16(1): 6617
    Senescence-associated lysosomal dysfunction impairs cystine deprivation-induced lipid peroxidation and ferroptosis.
    Tze Mun Loo, Xiangyu Zhou, Yoko Tanaka, Sho Sugawara, Shota Yamauchi, Hiroko Kawasaki, Yuta Matsuoka, Yuki Sugiura, Shinya Sakuma, Yoko Yamanishi, Satoshi Yotsumoto, Kosuke Dodo, Yoshitaka Shirasaki, Takashi Kamatani, Akiko Takahashi.
      Senescent cells, characterized by irreversible cell cycle arrest and inflammatory factor secretion, promote various age-related pathologies. Senescent cells exhibit resistance to ferroptosis, a form of iron-dependent cell death; however, the underlying mechanisms remain unclear. Here, we discovered that lysosomal acidity was crucial for lipid peroxidation and ferroptosis induction by cystine deprivation. In senescent cells, lysosomal alkalinization causes the aberrant retention of ferrous iron in lysosomes, resulting in resistance to ferroptosis. Treatment with the V-ATPase activator EN6 restored lysosomal acidity and ferroptosis sensitivity in senescent cells. A similar ferroptosis resistance mechanism involving lysosomal alkalinization was observed in pancreatic cancer cell lines. EN6 treatment prevented pancreatic cancer development in xenograft and Kras mutant mouse models. Our findings reveal a link between lysosomal dysfunction and the regulation of ferroptosis, suggesting a therapeutic strategy for the treatment of age-related diseases.
    DOI:  https://doi.org/10.1038/s41467-025-61894-9
  21. Blood. 2025 Aug 01. pii: blood.2024027822. [Epub ahead of print]
    Disrupting tRNA modifications to target mitochondrial vulnerabilities in drug-resistant leukemia cells.
    Cornelius Pauli, Michael Kienhöfer, Maximilian Felix Blank, Oguzhan Begik, Christian Rohde, Sarah Mn Zimmermann, Laura Werner, Daniel Heid, Fu Xu, Katharina Weidenauer, Sylvain Delaunay, Nadja Krall, Katrin Trunk, Duoduo Zhao, Fengbiao Zhou, Laia Llovera, Ollivier Alexane, Anke Heit-Mondrzyk, Uwe Platzbecker, Claudia D Baldus, Hubert Serve, Martin Bornhäuser, Cathrine B Vågbø, Salvador Aznar Benitah, Jeroen Krijgsveld, Eva Maria Novoa, Carsten Müller-Tidow, Michaela Frye.
      Dysregulated RNA modifications contribute to cancer progression and therapy resistance, yet the underlying mechanism often remains unknown. Here, we perform CRISPR-based synthetic lethality screens to systematically explore the role of RNA modifications in mediating resistance to anti-leukaemic drugs. We identify the TRMT5-mediated formation of N1-methylguanosine (m1G) in the tRNA anticodon loop as essential for mediating drug tolerance to cytarabine and venetoclax in acute myeloid leukemia (AML). TRMT5 methylates nearly all mitochondrial and nuclear tRNAs with a guanosine at position 37, but its role in promoting drug tolerance specifically depends on its mitochondrial function. TRMT5 is essential for the dynamic upregulation of mitochondrial mRNA translation and oxidative phosphorylation (OXPHOS), which are critical for sustaining drug tolerance in leukemia cells. This mitochondrial dependency correlates with therapy outcomes in leukemia patients: lower expression of electron transport chain genes is linked to poorer outcomes in a cohort of nearly 100 AML patients undergoing first induction therapy. Finally, we demonstrate that targeted depletion of TRMT5 protein using a conditional degron, in conjunction with cytarabine and venetoclax treatment, synergistically induces cell death in drug-tolerant AML cells. Thus, our study reveals TRMT5 as promising drug target for therapy-resistant leukemia.
    DOI:  https://doi.org/10.1182/blood.2024027822
  22. Nat Commun. 2025 Jul 31. 16(1): 7029
    mRNA trafficking directs cell-size-scaling of mitochondria distribution and function.
    Joshua J Bradbury, Georgia E Hulmes, Ranjith Viswanathan, Guilherme Costa, Holly E Lovegrove, Shane P Herbert.
      The subcellular positioning of organelles is critical to their function and is dynamically adapted to changes in cell morphology. Yet, how cells sense shifts in their dimensions and redistribute organelles accordingly remains unclear. Here we reveal that cell-size-scaling of mitochondria distribution and function is directed by polarised trafficking of mRNAs. We identify a 29 bp 3'UTR motif in mRNA encoding TRAK2, a key determinant of mitochondria retrograde transport, that promotes cell-size-dependent targeting of TRAK2 mRNA to distal sites of cell protrusions. Cell-size-scaled mRNA polarisation in turn scales mitochondria distribution by defining the precise site of TRAK2-MIRO1 retrograde transport complex assembly. Consequently, 3'UTR motif excision perturbs size-regulated transport and eradicates scaling of mitochondria positioning, triggering distal accumulation of mitochondria and progressive hypermotility as cells increase size. Together, our results reveal an RNA-driven mechanistic basis for the cell-size-scaling of organelle distribution and function that is critical to homeostatic control of motile cell behaviour.
    DOI:  https://doi.org/10.1038/s41467-025-61940-6
  23. Elife. 2025 Jul 30. pii: RP101244. [Epub ahead of print]13
    PA28γ promotes the malignant progression of tumor by elevating mitochondrial function via C1QBP.
    Jiongke Wang, Yujie Shi, Ying Wang, Yingqiang Shen, Huan Liu, Silu Sun, Yimei Wang, Xikun Zhou, Yu Zhou, Xin Zeng, Jing Li, Qianming Chen.
      Proteasome activator 28γ (PA28γ) plays a critical role in malignant progression of various tumors, however, its role and regulation are not well understood. Here, using oral squamous cell carcinoma (OSCC) as the main research model, and combining co-immunoprecipitation (Co-IP), proximity ligation assays (PLA), AlphaFold 3-based molecular docking, and truncation constructs, we discovered that PA28γ interacted with complement 1q binding protein (C1QBP). This interaction is dependent on the C1QBP N-terminus (aa 1-167) rather than the known functional domain. Point mutation in C1QBP (T76A/G78N) disrupting predicted hydrogen bonding with PA28γ-D177 significantly reduced their binding. Notably, we found that PA28γ enhances C1QBP protein stability in OSCC. Functionally, PA28γ and C1QBP co-localized in mitochondria, promoting fusion (via upregulation of OPA1, MFN1/2), respiratory complex expression, oxidative phosphorylation (OXPHOS), ATP production, and ROS generation. Crucially, PA28γ-enhanced OSCC cell migration, invasion, and proliferation in vitro were dependent on C1QBP. In vivo, orthotopic OSCC models showed Pa28γ overexpression increased tumor growth and elevated C1qbp levels, correlating with elevated ATP and ROS. Using transgenic Psme3-/- mice and subcutaneous tumor grafts, we confirmed that silencing of Pa28γ suppresses tumor growth, reduces C1qbp levels, and dampens mitochondrial metabolism-specifically in knockout hosts. Clinically, PA28γ and C1QBP expression were positively correlated during oral carcinogenesis and in metastatic OSCC tissues across cohorts. High co-expression predicted poor prognosis in OSCC patients. Thus, PA28γ stabilizes C1QBP via N-terminal interaction to drive mitochondrial OXPHOS and tumor progression, highlighting its potential as a therapeutic target.
    Keywords:  C1QBP; PA28γ; cancer biology; human; mitochondria; mouse; oral squamous cell carcinoma; oxidative phosphorylation; protein‒protein interactions
    DOI:  https://doi.org/10.7554/eLife.101244
  24. Diabetes Metab J. 2025 Jul 30.
    Targeting SLC25A33 Suppresses Vascular Smooth Muscle Cell Proliferation and Migration by Reducing Cytosolic mtDNA Levels: Implications for Occlusive Vascular Diseases.
    Daehoon Kim, Jieun Shin, Yeon-Kyung Choi, You Mie Lee, Keun-Gyu Park, Hyang Sook Kim, Jun-Kyu Byun.
       Background: Vascular smooth muscle cells (VSMCs) play a crucial role in the development of occlusive vascular diseases through abnormal proliferation and migration. This pathological behavior is closely associated with mitochondrial reactive oxygen species (ROS)-mediated mitochondrial DNA (mtDNA) damage. The mitochondrial carrier protein solute carrier family 25 member 33 (SLC25A33), essential for nucleoside transport, is integral to mtDNA production. This study aimed to investigate the effects of SLC25A33 inhibition on the proliferation and migration of VSMCs, as well as its impact on neointima formation.
    Methods: VSMCs were isolated from the thoracic aorta of 4-week-old Sprague-Dawley rats. The effects of small interfering RNAinduced silencing of SLC25A33 mRNA on platelet-derived growth factor (PDGF)-induced proliferation and migration of VSMCs were analyzed. The in vivo effects of targeting the SLC25A33 gene on neointima formation were evaluated using a murine carotid artery ligation model by perivascularly applying Lenti-shSLC25A33 with Pluronic F-127 gel.
    Results: First, we observed an upregulation of the SLC25A33 protein in the carotid artery ligation-induced neointima in mice. Silencing of SLC25A33 suppressed the PDGF-stimulated proliferation and migration of VSMCs and cell cycle progression. Knockdown of SLC25A33 inhibited PDGF-induced production of mtDNA and ROS, consequently inactivating the cyclic GMP-AMP synthesis (cGAS)-stimulator of interferon genes (STING)-TANK-binding kinase 1 (TBK1)-nuclear factor kappa B (NF-κB) pathway. Furthermore, the downregulation of SLC25A33 reduced carotid artery ligation-induced neointima in mice.
    Conclusion: This study suggests that targeting SLC25A33 in VSMCs could be a novel therapeutic strategy to prevent occlusive vascular diseases.
    Keywords:  DNA, mitochondrial; Mitochondrial membrane transport proteins; Muscle, smooth, vascular; NF-kappa B; Neointima; Platelet-derived growth factor; Vascular diseases
    DOI:  https://doi.org/10.4093/dmj.2024.0632
  25. Mol Biol Cell. 2025 Jul 30. mbcE25060271
    Rab14 promotes Parkin mediated mitophagy.
    Samina Momtaz, Marco Padilla-Rodriguez, Paola Cruz Flores, Natalia Rulli, Nam Yong Lee, Jean M Wilson.
      Mitochondrial degradation by mitophagy is essential to maintain cell metabolism; dysregulation can result in the accumulation of damaged mitochondria. While the Rab family of small GTPase proteins are involved with vesicular trafficking in the endocytic and biosynthetic pathways, Rab-GTPases also have a role in mitochondrial integrity. However, a role for Rab14, a trans-Golgi network (TGN)-endosomal Rab-GTPase in mitophagy has not been described. In cells knocked down for Rab14, mitochondria acquire an elongated morphology and increased levels of mitochondrial proteins, whereas overexpression of Rab14 decreased these proteins. Furthermore, mito-Keima assays show increased mitophagy upon Rab14 overexpression. Rab14-induced mitophagy is dependent on Parkin expression, as well as TBK1 and PI3K activity, placing it in the Parkin-dependent mitophagy pathway. 3D-reconstruction shows contact site formation between Rab14 and mitochondria, and inhibition of the TGN kinase PI(4)KIIIβ decreases Rab14-mitochondria contact sites and prevents Rab14-mediated mitophagy, suggesting that TGN-derived Rab14 vesicles mediate mitophagy. These results suggest that Rab14 promotes mitophagy and plays an essential role in modulating cellular metabolism. [Media: see text].
    DOI:  https://doi.org/10.1091/mbc.E25-06-0271
  26. J Neurophysiol. 2025 Aug 01.
    CUMS stress facilitates hippocampal neural mitophagy through FIS1/MFF-mediated mitochondrial fragmentation.
    Xiaoke Qiu, Shaoda Lai, Yingyi Zhang, Shengtao Huang, Han Li, Junsheng Liu, Yong Huang, Zhinan Zhang.
      The chronic unpredictable mild stress (CUMS) paradigm influences the neuronal count in the dentate gyrus (DG) region of the hippocampus, potentially linking to mitophagy induced by mitochondrial fragmentation. Fission mitochondrial 1 (FIS1)/mitochondrial fission factor (MFF) represents one of the mechanisms regulating mitochondrial fission and autophagy. Herein, we investigated the effects of CUMS on mitophagy and mitochondrial fragmentation in hippocampal DG neurons, along with their modulation of the mitochondrial fission pathway governed by FIS1/MFF. Our results demonstrated that CUMS stress augmented mitophagy in hippocampal DG neurons. Concurrently, it exacerbated the tendency towards mitochondrial fragmentation. The impact on the upstream regulatory pathway of mitochondrial fragmentation manifested as upregulation of FIS1 and downregulation of MFF, resulting in a net loss of mitochondrial content and a subsequent energy deficit. These findings suggest that CUMS stress, by modulating the FIS1/MFF balance, increase mitophagy stemming from mitochondrial fragmentation in hippocampal DG neurons.
    Keywords:  Depression; FIS1; MFF; mitochondria fragmentation; mitophagy
    DOI:  https://doi.org/10.1152/jn.00523.2024
  27. Chem Biol Interact. 2025 Jul 26. pii: S0009-2797(25)00306-0. [Epub ahead of print]420 111676
    Atrazine-induced hippocampal neurotoxicity: Involvement of Drp1-mediated mitochondrial fission.
    Jingran Yang, Ling Qi, Cheng Zhang, Ruirui Ding, Haoran Bi, Peng Li, Zhipeng Qi, Qiao Niu, Weiyi Song, Jianan Li.
      The widespread use of atrazine (ATR), a commonly applied herbicide, has raised growing concerns about its neurotoxic effects. However, the underlying molecular mechanisms remain poorly understood. In this study, we demonstrate that ATR disrupts hippocampal function by inducing Drp1-mediated mitochondrial fission. Using both in vivo and in vitro tests, we show that ATR exposure leads to mitochondrial swelling, cristae loss, and fragmentation in hippocampal neurons, correlating with impaired spatial learning and memory. ATR significantly increases Ser616-Drp1 phosphorylation, promoting excessive mitochondrial fission and exacerbating neuronal damage. In contrast, the Drp1 inhibitor Mdivi-1 effectively restores mitochondrial integrity, mitigates mitochondrial membrane potential loss, and alleviates neurotoxicity. Interestingly, ATR exposure results in a non-linear response in the expression of mitochondrial regulatory genes, suggesting complex dose-dependent effects. These findings provide novel insights into the role of mitochondrial dysfunction in ATR-induced cognitive impairment and underscore the importance of Drp1-mediated fission in herbicide neurotoxicity. Our study highlights the need for further investigation into the long-term effects of ATR exposure and suggests that targeting mitochondrial dynamics may offer a promising therapeutic strategy for ATR-induced neuronal dysfunction.
    Keywords:  Atrazine; Drp1; Hippocampus; Mitochondrial dynamics; Mitochondrial fission
    DOI:  https://doi.org/10.1016/j.cbi.2025.111676
  28. Cell Death Dis. 2025 Jul 29. 16(1): 573
    The impact of ERUPR on mitochondrial integrity mediated by PDK4.
    Priyanka Mallick, Sebabrata Maity, Rupsha Mondal, Trina Roy, Puyam Milan Meitei, Shashank Saxena, Bhavani Shankar Sahu, Oishee Chakrabarti, Saikat Chakrabarti.
      ER and mitochondrial stress are often interconnected and considered major contributors to aging as well as neurodegeneration. Coordinated induction of ERUPR and mitoUPR has been observed in diabetes and pulmonary disorders. However, in the context of aging and neurodegeneration, regulation of this intra-organellar crosstalk has remained relatively elusive. Here, we demonstrate that pyruvate dehydrogenase kinase 4 (PDK4), a mitochondrial protein, accumulates at the ER-mitochondrial contact sites (MAMs) during ER stress. Classically, PDK4 is known to phosphorylate PDHA1 (pyruvate dehydrogenase E1 subunit alpha 1) and plays a significant role in regulating the oxidative phosphorylation-driven ATP production. In this study, we propose a non-canonical kinase-independent function of PDK4; we show that it acts as a connecting link between ERUPR and mitoUPR, with significance in aging and Alzheimer's disease (AD) associated neurodegeneration. Transcriptomics analyses show increased PDK4 levels upon drug-induced ER stress. We detect elevated PDK4 levels in lysates from human AD patient and mouse models as well as in ex vivo AD models. Additionally, exogenous expression of PDK4 was found to refine ER-mitochondria communication, significantly altering mitochondrial morphology and function. Further, we also observe defective autophagic clearance of mitochondria under such conditions. It is prudent to suggest that elevated PDK4 levels could be one of the key factors connecting ERUPR with mitoUPR, a phenotypic contributor in aging and in AD-like neurodegenerative disorders.
    DOI:  https://doi.org/10.1038/s41419-025-07743-5
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