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.
Highlights
Ischemic heart disease continues to have a high burden of disease g lobally[1]
We found that the deficiency of DJ-1 enhances the accumulation of reactive dicarbonyls in hearts following the onset of ischemia–reperfusion injury[11]
The most recognizable role of cardiac mitochondria is the production of energy via ATP synthesis, the mitochondria serve a critical function in mediating cellular homeostasis as they regulate intracellular signaling, calcium storage, fuel utilization, and cell d eath[28,29,30]
Summary
Ischemic heart disease continues to have a high burden of disease g lobally[1]. Myocardial ischemia–reperfusion injury (I/R) is a major determining factor of the severity of ischemic heart d isease[2]. Glycative stress describes the disruption of cell homeostasis by an accumulation of reactive c arbonyls[12] This condition is initiated by non-enzymatic glycosylation known as the Maillard reaction—a complex process that begins when reducing sugars bind to free amino groups in proteins, nucleotides, and lipids[13]. When occurring endogenously, this reaction is termed glycation. As a critical player in the heart’s response to injury, the disruption of mitochondrial function by glycation would likely impact recovery following myocardial I/R. We sought to determine if DJ-1 alters protein glycation in mitochondria following the onset myocardial I/R injury
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