Caffeine improves mitochondrial dysfunction in the white matter of neonatal rats with hypoxia-ischemia through deacetylation: a proteomic analysis of lysine acetylation

Yajun Zhang; Yuqian Wang; Haiping Dou; Shanshan Wang; Danyang Qu; Xin Peng; Ning Zou; Liu Yang

doi:10.3389/fnmol.2024.1394886

Caffeine improves mitochondrial dysfunction in the white matter of neonatal rats with hypoxia-ischemia through deacetylation: a proteomic analysis of lysine acetylation

Front Mol Neurosci. 2024 Apr 30:17:1394886. doi: 10.3389/fnmol.2024.1394886. eCollection 2024.

Authors

Yajun Zhang^#¹, Yuqian Wang^#², Haiping Dou², Shanshan Wang², Danyang Qu², Xin Peng², Ning Zou², Liu Yang^{2

3}

Affiliations

¹ Department of Anesthesiology, Dalian Women and Children's Medical Group, Dalian, Liaoning, China.
² Department of Pediatrics, The Second Hospital of Dalian Medical University, Dalian, Liaoning, China.
³ Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China.

^# Contributed equally.

Abstract

Aims: White matter damage (WMD) is linked to both cerebral palsy and cognitive deficits in infants born prematurely. The focus of this study was to examine how caffeine influences the acetylation of proteins within the neonatal white matter and to evaluate its effectiveness in treating white matter damage caused by hypoxia-ischemia.

Main methods: We employed a method combining affinity enrichment with advanced liquid chromatography and mass spectrometry to profile acetylation in proteins from the white matter of neonatal rats grouped into control (Sham), hypoxic-ischemic (HI), and caffeine-treated (Caffeine) groups.

Key findings: Our findings included 1,999 sites of lysine acetylation across 1,123 proteins, with quantifiable changes noted in 1,342 sites within 689 proteins. Analysis of these patterns identified recurring sequences adjacent to the acetylation sites, notably YKacN, FkacN, and G ^* ^* ^* GkacS. Investigation into the biological roles of these proteins through Gene Ontology analysis indicated their involvement in a variety of cellular processes, predominantly within mitochondrial locations. Further analysis indicated that the acetylation of tau (Mapt), a protein associated with microtubules, was elevated in the HI condition; however, caffeine treatment appeared to mitigate this over-modification, thus potentially aiding in reducing oxidative stress, inflammation in the nervous system, and improving mitochondrial health. Caffeine inhibited acetylated Mapt through sirtuin 2 (SITR2), promoted Mapt nuclear translocation, and improved mitochondrial dysfunction, which was subsequently weakened by the SIRT2 inhibitor, AK-7.

Significance: Caffeine-induced changes in lysine acetylation may play a key role in improving mitochondrial dysfunction and inhibiting oxidative stress and neuroinflammation.

Keywords: caffeine; high performance liquid chromatography; lysine acetylation; microtubule associated protein tau; tandem mass spectrometry; white matter damage.

Grants and funding

The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. This work was supported by grants from the National Natural Science Foundation of China [grant number 82201896] and the Foundation of Liaoning Province Education Administration [grant number LJKMZ20221294].