Investigating DJ-1 homologs in maintaining genome integrity through glycation repair of macromolecules: Implications in regulating mitochondrial health

Abstract

The current thesis work focuses on DJ-1 superfamily proteins and their role in protection against toxic glycating carbonyls such as Methylglyoxal (MG) and Glyoxal (GO). Our study reveals that yeast DJ-1 homologs (Hsp31 paralogs) play a pivotal function in maintaining carbonyl homeostasis as their absence elevates chronic glycation of cellular macromolecules such as DNA, RNA, and proteins. Glycation-associated damage is enhanced in cells lacking Hsp31 paralogs. Additionally, the work establishes the possible connections between Parkinson’s disease-associated human DJ-1 and mitochondrial health during carbonyl stress. The global health of mitochondria is severely affected during GO stress in the absence of yeast DJ-1 homologs, and the mitochondrial translocation of Hsp31 paralogs abrogated this damage. Besides, our study also deciphered a novel mechanism of the mitochondrial location of DJ-1 homologs that governs their distribution in the presence and absence of stress. The study described in this thesis is divided into three subcategories. Chapter 1 summarizes the available literature relevant to carbonyl stress and its detrimental effects, the detoxification mechanism, DJ-1 superfamily proteins across species and their diverse functions, and mitochondrial localization mechanisms. Chapter 2 deciphers the role of Hsp31 paralogs in providing cellular and macromolecular protection during carbonyl stress. Chapter 3 describes the functions of Hsp31 paralogs in preserving mitochondrial health during carbonyl stress