PXD064694-1

PXD064694 is an original dataset announced via ProteomeXchange.

Title	Astrocytic glycogen induces ATAD3A oligomerization-dependent mitochondrial fragmentation to exacerbate neuropathology and delay recovery after ischemic stroke
Description	Ischemic stroke induces pathological glycogen deposition in astrocytes, but its role in post-injury neural dysfunction remains undefined. We firstly intend to identify the glycogen granule proteome after ischemic stroke via glycogen pulldown for protein mass spectrometry detection. KEGG pathway analysis of the glycogen granule proteome revealed highly enriched mitochondrial-related functional signals, such as respiratory chain complexes, mitochondrial respirasomes, and mitochondrial membrane protein complexes. GO functional annotation of biological processes revealed enrichment of genes related to mitochondrial electron transport, respiratory chain complexes, and mitochondrial ATP synthesis. To explore detailed mitochondrial biological processes in detail, we summarized mitochondrial function gene sets from the mitoproteome database and intersected them with many glycogen-enriched proteins. The data revealed that glycogen stress granules are related mainly to oxidative phosphorylation subunits, assembly factors and electron carriers; mitochondrial dynamics (such as MFF, DNM1L, and GDAP1), homeostasis, and quality control (such as AFG3L2, CLPB, and ATAD3A). Evidence from our experimental data has shown that ATAD3A oligomerization requires the accumulation of astrocytic glycogen stress granules. Under physiological conditions, ATAD3A does not oligomerize, and mitochondria do not exhibit obvious dysfunction in nonglycogen stress granule-deposited cells. To explore what candidate partners are involved with ATAD3A. The proximity-biotinylating enzyme TurboID was reconstituted with ATAD3A to detect biotinylated proteins adjacent to ATAD3A. We next constructed a stable ATAD3A-TurboID cell line (or primary astrocytes). Pulldown biotinylated proteins were subjected to quantitative high-resolution mass spectrometry. Based on the above mass spectrometry data and a series of experimental results, we found that: glycogen-laden astrocytes in the ischemic penumbra undergo HDAC3-dependent mitochondrial fragmentation via a stress granule-mediated mechanism, exacerbating neuronal injury and hindering functional recovery. Mechanistic studies demonstrate that glycogen aggregates sequester cytoplasmic HDAC3, enabling its translocation to mitochondria. There, HDAC3 deacetylates outer mitochondrial membrane protein ATAD3A, promoting oligomerization-driven mitochondrial fission. Astrocyte-specific ATAD3A ablation prevents stroke-induced synaptic disorganization, neural circuit disruption, and cognitive deficits. Therapeutically, combined administration of cotadutide (a glycogen-depleting GLP-1/GCGR agonist) and HDAC3 inhibitor RGFP966 reverses glycogen accumulation, rescues mitochondrial architecture/function, and restores synaptic plasticity and circuit reorganization, thereby accelerating sensorimotor recovery.
HostingRepository	PRIDE
AnnounceDate	2025-06-06
AnnouncementXML	Submission_2025-06-06_00:33:35.388.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Hongrui Zhu
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	Orbitrap Exploris 480; Q Exactive Plus

Revision	Datetime	Status	ChangeLog Entry
0	2025-06-05 08:53:54	ID requested
⏵ 1	2025-06-06 00:33:35	announced

Dataset with its publication pending

submitter keyword: Stroke,Glycogen,ATAD3A

Hongrui Zhu
contact affiliation	First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China
contact email	zhuhongrui@mail.ustc.edu.cn
lab head
Hongrui Zhu
contact affiliation	First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China
contact email	zhuhongrui@mail.ustc.edu.cn
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD064694
     1. Label: PRIDE project
     2. Name: Astrocytic glycogen induces ATAD3A oligomerization-dependent mitochondrial fragmentation to exacerbate neuropathology and delay recovery after ischemic stroke