DJ-1 attenuates the glycation of mitochondrial complex I and complex III in the post-ischemic heart

• Type of Material: Article
• Authors: Yvanna Pantner, Emory University; Rohini Polavarapu, Emory University; Lih-Shen Chin, Emory University; Lian Li, Emory University; Yuuki Shimizu, Nagoya University; John Calvert, Emory University
• Language: English
• Date: 2021-09-30
• Publisher: NATURE PORTFOLIO
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2021
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41598-021-98722-1
• Title of Journal or Parent Work: SCIENTIFIC REPORTS
• Volume: 11
• Issue: 1
• Start Page: 19408
• End Page: 19408
• Keywords: END-PRODUCTS; Multidisciplinary Sciences; STRESS; DISEASE; METHYLGLYOXAL; METABOLISM; DYSFUNCTION; DAMAGE; Science & Technology - Other Topics; DICARBONYLS; ISCHEMIA-REPERFUSION INJURY; Science & Technology; PROTEIN DJ-1/PARK7
• Research Categories: Health Sciences, Pharmacology

Abstract

DJ-1 is a ubiquitously expressed protein that protects cells from stress through its conversion into an active protease. Recent work found that the active form of DJ-1 was induced in the ischemic heart as an endogenous mechanism to attenuate glycative stress—the non-enzymatic glycosylation of proteins. However, specific proteins protected from glycative stress by DJ-1 are not known. Given that mitochondrial electron transport proteins have a propensity for being targets of glycative stress, we investigated if DJ-1 regulates the glycation of Complex I and Complex III after myocardial ischemia–reperfusion (I/R) injury. Initial studies found that DJ-1 localized to the mitochondria and increased its interaction with Complex I and Complex III 3 days after the onset of myocardial I/R injury. Next, we investigated the role DJ-1 plays in modulating glycative stress in the mitochondria. Analysis revealed that compared to wild-type control mice, mitochondria from DJ-1 deficient (DJ-1 KO) hearts showed increased levels of glycative stress following I/R. Additionally, Complex I and Complex III glycation were found to be at higher levels in DJ-1 KO hearts. This corresponded with reduced complex activities, as well as reduced mitochondrial oxygen consumption ant ATP synthesis in the presence of pyruvate and malate. To further determine if DJ-1 influenced the glycation of the complexes, an adenoviral approach was used to over-express the active form of DJ-1(AAV9-DJ1ΔC). Under I/R conditions, the glycation of Complex I and Complex III were attenuated in hearts treated with AAV9-DJ1ΔC. This was accompanied by improvements in complex activities, oxygen consumption, and ATP production. Together, this data suggests that cardiac DJ-1 maintains Complex I and Complex III efficiency and mitochondrial function during the recovery from I/R injury. In elucidating a specific mechanism for DJ-1’s role in the post-ischemic heart, these data break new ground for potential therapeutic strategies using DJ-1 as a target.