Astrocytic <scp>HSP60</scp> Deletion Induced Astrocyte Senescence and Inhibited Neuroregeneration via Modulating the <scp>S1P</scp> /Truncated‐ <scp>BDNF</scp> Pathway

Heat Shock Protein 60 (HSP60) plays a critical role in maintaining mitochondrial function in astrocytes and has a significant impact on central nervous system (CNS) health. However, how HSP60 regulates the mitochondrial function of astrocytes to inhibit neuroregeneration remains unknown. In this study, we generated astrocyte-specific HSP60 knockout male mice to investigate the consequences of HSP60 deficiency. Firstly, our results confirmed that HSP60 deficiency caused abnormal expression of mitochondrial function-related genes, causing significant mitochondrial dysfunction, which triggered cellular senescence in astrocytes. Moreover, the alterations of 5-hydroxytryptamine 2A receptor (5-HT2AR), glucocorticoid receptor (GR), dopamine D2 receptor (D2R), and N-methyl-D-aspartate receptor subunit 2A (NR2A) expression suggested a disruption in neurotransmission and synaptic plasticity. Additionally, the increased levels of site-1 protease (S1P), truncated brain-derived neurotrophic factor (truncated-BDNF), and synaptophysin indicate synaptic structural and functional impairments. Expectedly, our findings demonstrated mitochondrial dysfunction and cellular senescence in astrocytes, leading to altered expression of neurotransmitter receptors in the cortex, as well as reduced neuronal numbers and neurotransmitter levels in the hippocampus after the deletion of HSP60 in astrocytes of the male mice. Notably, Urolithin A (UA) and the S1P inhibitor, PF429242, were found to alleviate astrocyte senescence and promote neuronal regeneration by inhibiting truncated BDNF expression. In conclusion, our study revealed that HSP60 deficiency in astrocytes induces mitochondrial dysfunction and cellular senescence via the S1P/truncated-BDNF pathway, resulting in disrupted neurotransmitter receptor expression, synaptic protein alterations, and impaired neuroregeneration. These insights underscored the importance of HSP60 in CNS health and provided promising avenues for developing treatments for neurodegenerative disorders.