Chronic exercise remodels the lysine acetylome in the mouse hippocampus

Abstract

Physical exercise benefits hippocampal function through various molecular mechanisms. Protein acetylation, a conserved and widespread post-translational modification, is involved in the synaptic plasticity and memory. However, whether exercise can change global acetylation and the role of acetylated proteins in the hippocampus have remained largely unknown. Herein, using healthy adult mice running for 6 weeks as exercise model and sedentary mice as control, we analyzed the hippocampal lysine acetylome and proteome by Liquid chromatography-tandem mass spectrometry. As a result, we profiled the lysine acetylation landscape for the hippocampus and identified 3,876 acetyl sites and 1,764 acetylated proteins. A total of 272 acetyl sites on 252 proteins were differentially regulated by chronic exercise, among which 18.58% acetylated proteins were annotated in mitochondria. These proteins were dominantly deacetylated and mainly associated with carbon-related metabolism, the Hippo signaling pathway, ribosomes, and protein processing. Meanwhile, 21 proteins were significantly expressed and enriched in the pathway of complement and coagulation cascades. Our findings provide a new avenue for understanding the molecular mechanisms underlying the benefits of exercise for hippocampal function and can contribute to the promotion of public health.

Acetylome analyses provide novel insights into the effects of chronic intermittent hypoxia on hippocampus-dependent cognitive impairment

“…Furthermore, our study revealed that, when exposed to CIH, Got2, a crucial enzyme involved in mitochondrial metabolism, undergoes acetylation at six lysine residues, K90, K82, K302, K309, K396, and K404. Our findings align with existing evidence that acetylation inhibits the activity of mitochondrial enzymes ( Qian et al, 2022 ). Moreover, our findings suggest that chronic intermittent hypoxia (CIH)-induced lysine acetylation may have detrimental effects on the mitochondrial tricarboxylic acid (TCA) cycle and oxidative phosphorylation pathways within the hippocampus.…”

“…Once the beads were washed and the bound peptides were eluted using trifluoroacetic acid, we combined the eluted peptides, vacuum-dried them, desalted them, and prepared them for analysis. More specific formulations for the inhibitors and NETN buffer can be found elsewhere ( Qian et al, 2022 ). LC-MS/MS analysis was conducted at PTM Biolab in Hangzhou, China.…”

“…However, only a few proteins, such as those involved in phosphorylation, glycosylation, methylation, ubiquitylation, and acetylation, have been extensively investigated ( Narita et al, 2019 ). Among the many types of PTMs that occur in proteins, lysine acetylation plays critical roles in regulating memory and the balance between neuroprotection and neurodegeneration ( Schueller et al, 2020 ; Qian et al, 2022 ). Lysine acetylation is a reversible PTM that affects protein function through various mechanisms, including altering charge, structure, stability, and interactions with other molecules.…”

Folate-deficiency induced acyl-CoA synthetase short-chain family member 2 increases lysine crotonylome involved in neural tube defects

“…The sequence model composed of specific amino acids was analyzed by Motif-x (10 amino acids downstream and upstream of crotonylation sites). Once protein enrichment was completed, function x = 2log 10 (p value) ran to convert the p value and one-way hierarchical clustering to category (Qian et al, 2022).…”

“…Enrichment of differentially modified proteins relevant to all identified proteins for each category of GO analysis, including cellular compartment, biological process, and molecular function was detected in two-tailed Fisher's exact test. We considered GO terms significant at a corrected p < 0.05 and used DAVID 6.8 to perform GO term enrichment (Qian et al, 2022).…”