AUTHOR=Zhang Yajun , Wang Yuqian , Dou Haiping , Wang Shanshan , Qu Danyang , Peng Xin , Zou Ning , Yang Liu 

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

JOURNAL=Frontiers in Molecular Neuroscience

VOLUME=Volume 17 - 2024

YEAR=2024

URL=https://www.frontiersin.org/journals/molecular-neuroscience/articles/10.3389/fnmol.2024.1394886

DOI=10.3389/fnmol.2024.1394886

ISSN=1662-5099

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.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 (ShamSham), hypoxic-ischemic (HI), and caffeine-treated (Caffeine) groups.Key findings: Our findings included 1999 sites of lysine acetylation across 1123 proteins, with quantifiable changes noted in 1342 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 (MAPTMapt), 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 MAPTMapt through sirtuin 2 (SITR2), promoted MAPTMapt 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.