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Integrative Proteomics and Phosphoproteomics Profiling Reveals Molecular Pathways in hypoxia adaptation of brain tissue in Lasiopodomys brandtii

ABSTRACT: Exposure to high-altitude hypoxic environments may lead to dysfunction in the central nervous system. Research on the hypoxic response mechanisms of hypoxia-tolerant animals can provide insights for animal conservation and the treatment of ischemic brain injury. In this study, we focused on Brandt's voles and simulated oxygen environments at altitudes of 100m, 3000m, 5000m, and 7000m within a hypoxic chamber. After 24 hours of exposure, brain tissue was collected for quantitative proteomic and phosphoproteomic analyses. A total of 3,947 proteins and 8,572 phosphosites were quantified. Proteomic data revealed that more differentially expressed (DE) proteins were downregulated than upregulated, with significant enrichment in pathways that inhibit protein synthesis and leukocyte activation, suggesting a strategy for energy conservation in Brandt's voles under hypoxic conditions. Additionally, approximately 43% of the DE proteins were identified as candidate genes in other hypoxia-tolerant species. Phosphoproteomic analysis found that phosphoproteins in the downregulated cluster were significantly enriched in vascular smooth muscle contraction and adaptive immune system, which contribute to enhancing oxygen transport to the brain tissue and reducing energy consumption. Furthermore, many DE proteins and phosphoproteins were related to endocytosis, cytoskeleton organization, and synaptic regulation, which may be strategies employed by Brandt's voles to protect brain tissue from hypoxic damage and maintain cognitive function. Utilizing the KSEA algorithm, we predicted that 10 kinase activities in Brandt's voles are significantly influenced by hypoxia, four of which belonging to the CAMK kinase family. Immunoblot validated that the changes in CAMK2A activity were consistent with predictions, suggesting that CAMK may play a crucial role in the hypoxic response. In conclusion, our findings indicate that Brandt's voles cope with hypoxia by enhancing oxygen transport, reducing energy consumption, and activating neuroprotective mechanisms.

ORGANISM(S): Lasiopodomys Brandtii

SUBMITTER: Han Cheng

PROVIDER: PXD056880 | iProX | Thu Oct 17 00:00:00 BST 2024

REPOSITORIES: iProX

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Integrative Proteomic and Phosphoproteomic Profiling Reveals Molecular Mechanisms of Hypoxic Adaptation in Brandt's Voles (<i>Lasiopodomys brandtii</i>) Brain Tissue.

Wang Panqin P Liu Yongyan Y Du Yimeng Y Gao Yiwen Y Shao Tian T Guo Weifeng W Wang Zhenlong Z Cheng Han H

Cells 20250401 7

Rapid ascent to high altitudes by unacclimatized individuals significantly increases the risk of brain damage, given the brain's heightened sensitivity to hypoxic conditions. Investigating hypoxia-tolerant animals can provide insights into adaptive mechanisms and guide prevention and treatment of hypoxic-ischemic brain injury. In this study, we exposed Brandt's voles to simulated altitudes (100 m, 3000 m, 5000 m, and 7000 m) for 24 h and performed quantitative proteomic and phosphoproteomic anal ...[more]

PMID: 40214481

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Project description:Intermittent hypoxia is a common stressor in estuarine and coastal habitats due to the diurnal and tidal cycles of oxygen availability. Oxygen deficiency results in energy stress by limiting aerobic ATP production, while reoxygenation may lead to oxidative injury due to the excessive production of reactive oxygen species (ROS) in mitochondria. Mitochondria are a key intracellular target of hypoxia-reoxygenation (H/R) stress due to their central role in ATP production, ROS generation and stress signaling. Marine intertidal bivalves such as the Pacific oyster Crassostrea gigas are adapted to frequent H/R cycles in the intertidal zone and maintain mitochondrial integrity and aerobic function despite frequent oxygen fluctuations. To gain insight into the molecular responses of mitochondria of the hypoxia-tolerant Pacific oyster to H/R stress, we studied changes in oxidative phosphorylation (OXPHOS) capacity, proton leak and activity of the electron transport system enzymes (ETS) in gill mitochondria of C. gigas. We furthermore investigated shifts in mitochondrial proteome and phosphoproteome after 24 h of hypoxia and 1 h of post-hypoxic recovery. Oyster mitochondria maintained normal ETS and OXPHOS capacity during H/R stress, despite a slight but significant decline in cytochrome c oxidase (Complex IV) activity after reoxygenation. Fifty total proteins and 36 phosphoproteins were differentially abundant in mitochondria of H/R exposed oysters compared with the controls. Rearrangements of the mitochondrial (phospho)proteome during H/R stress involved upregulation of mitochondrial ETS (most notably Complexes I and IV) and iron-binding proteins (frataxin and ferrochelatase) as well as suppression of the metabolic pathways that channel electrons to ubiquinone, possibly as a mechanism to limit ROS production due to the iron overload and reverse flow of electrons through ETS. H/R stress also led to upregulation of a mitophagic activator serine/threonine protein phosphatase PGAM5 and dephosphorylation of metalloendopeptidase OMA1 indicating stimulation of mitochondrial quality control mechanisms during reoxygenation. Changes in the overall abundance and phosphorylation levels of several key proteins involved in the mitochondrial protein homeostasis (including subunits of the mitochondrial ribosome, mitochondrial inner membrane translocase and elongation factor G) are consistent with the suppression of the protein synthesis during hypoxia, likely as an energy-saving mechanism. Overall, our study indicates that shifts in the mitochondrial (phospho-)proteome play an important role in responses of oysters to H/R stress and might complement adaptations of anaerobic metabolism and metabolic rate depression in ensuring hypoxic survival and rapid recovery in this hypoxia-tolerant intertidal species.

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Integrative Proteomics and Phosphoproteomics Profiling Reveals Molecular Pathways in hypoxia adaptation of brain tissue in Lasiopodomys brandtii

Publications

Integrative Proteomic and Phosphoproteomic Profiling Reveals Molecular Mechanisms of Hypoxic Adaptation in Brandt's Voles (<i>Lasiopodomys brandtii</i>) Brain Tissue.

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Dataset Information

Integrative Proteomics and Phosphoproteomics Profiling Reveals Molecular Pathways in hypoxia adaptation of brain tissue in Lasiopodomys brandtii

Publications

Integrative Proteomic and Phosphoproteomic Profiling Reveals Molecular Mechanisms of Hypoxic Adaptation in Brandt's Voles (&lt;i&gt;Lasiopodomys brandtii&lt;/i&gt;) Brain Tissue.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Integrative Proteomic and Phosphoproteomic Profiling Reveals Molecular Mechanisms of Hypoxic Adaptation in Brandt's Voles (<i>Lasiopodomys brandtii</i>) Brain Tissue.