Effect of N-Acetylcysteine in Mitochondrial Function, Redox Signaling, and Sirtuin 3 Levels in the Heart During Cardiorenal Syndrome Type 4 Development

Type 4 cardiorenal syndrome (CRS-4) is a pathology in which chronic kidney disease (CKD) triggers the development of cardiovascular disease. CKD pathophysiology produces alterations that can affect the bioenergetics of heart mitochondria, causing oxidative stress and reducing antioxidant glutathione (GSH) levels. GSH depletion alters protein function by affecting post-translational modifications such as S-glutathionylation (RS-SG), exacerbating oxidative stress, and mitochondrial dysfunction. On the other hand, N-acetylcysteine (NAC) is an antioxidant GSH precursor that modulates oxidative stress and RS-SG. Moreover, recent studies have found that NAC can activate the Sirtuin 3 (SIRT3) deacetylase in diseases. However, the role of NAC and its effects on mitochondrial function, redox signaling, and SIRT3 modifications in the heart during CRS-4 have not been studied. This study aimed to investigate the role of NAC in mitochondrial function, redox signaling, and SIRT3 in the hearts of animals with CRS-4 at two months of follow-up. Our results showed that the oral administration of NAC (600 mg/kg/day) improved blood pressure and reduced cardiac fibrosis. NACs' protective effect was associated with preserving cardiac mitochondrial bioenergetics and decreasing these organelles' hydrogen peroxide (H₂O₂) production. Additionally, NAC increased GSH levels in heart mitochondria and regulated the redox state, which coincided with an increase in nicotinamide adenine dinucleotide oxidized (NAD⁺) levels and a decrease in mitochondrial acetylated lysines. Finally, NAC increased SIRT3 levels and the activity of superoxide dismutase 2 (SOD-2) in the heart. Thus, treatment with NAC decreases mitochondrial alterations, restores redox signaling, and decreases SIRT3 disturbances during CRS-4 through an antioxidant defense mechanism.