Anti-SIRT3 polyclonal antibody

Sirtuin-3 (SIRT3) is a mitochondria] NAD + -dependent deacetylase that is essential in regulating mitochondrial proteins and maintaining cellular antioxidant properties. It has been reported that icariin (ICA) is neuroprotective over various neurotoxicant induced oxidative stress. This study aimed to determine whether ICA exerts neuroprotective effects on rotenone (ROT)-induced neurotoxicity through activation of SIRT3. Rats treated with ROT exhibited a marked loss of dopamine (DA) neurons and a decline in motor function, along with a decrease in protein expressions of SIRT3 and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1 alpha) in the substantia nigra (SN). Administration of ICA significantly alleviated the loss of DA neurons, improved behavioral function, and concomitantly enhanced SIRT3 and PGC-1 alpha expressions. The neuroprotective effect of ICA on ROT-induced cytotoxicity was further confirmed in the PC12 cell model, which showed significant improvement in the survival of ROT-treated cells with ICA pretreatment. The cytoprotective effect of ICA was abolished in ROT-treated cells by SIRT3 inhibitor 3-(1H-1,2,3-triazol-4-yl) pyridine (3-TYP), along with a resultant decrease in PGC-1 alpha expression. In addition, knockdown of PGC-1 alpha by siRNA suppressed ICA-mediated protective effects but did not affect SIRT3 expression, indicating the role of regulation of PGC-1 alpha by SIRT3 in the protective action of ICA. Furthermore, we showed that ICA improved mitochondrial respiration, oxidative status, enhanced antioxidant enzyme SOD activity and GSH/GSSG ratio in cells treated with ROT. However, these protective effects of ICA on ROT-treated cells was markedly abolished by SIRT3 inhibitor 3-TYP. Our findings demonstrate that ICA exerts a neuroprotective role through upregulation of SIRT3.

Recent Advances: Vascular dysfunction is crucial in hypertension pathophysiology and exhibits bidirectional relationship. Metabolic disorders and oxidative stress contribute to the pathogenesis of vascular dysfunction and hypertension, which are associated with mitochondrial impairment and hyperacetylation. Mitochondrial deacetylase Sirtuin 3 (Sirt3) is critical in the regulation of metabolic and antioxidant functions. Clinical studies show that cardiovascular disease risk factors reduce Sirt3 level and Sirt3 declines with age, paralleling the increased incidence of cardiovascular disease and hypertension. An imbalance between mitochondrial acetylation and reduced Sirt3 activity contributes to mitochondrial dysfunction and oxidative stress. We propose that mitochondrial hyperacetylation drives a vicious cycle between metabolic disorders and mitochondrial oxidative stress, promoting vascular dysfunction and hypertension. Critical Issues: The mechanisms of mitochondrial dysfunction are still obscure in human hypertension. Mitochondrial hyperacetylation and oxidative stress contribute to mitochondrial dysfunction; however, regulation of mitochondrial acetylation, the role of GCN5L1 (acetyl-CoA-binding protein promoting acetyltransferase protein acetylation) acetyltransferase, Sirt3 deacetylase, and acetylation of specific proteins require further investigations. Future Directions: There is an urgent need to define molecular mechanisms and the pathophysiological role of mitochondrial hyperacetylation, identify novel pharmacological targets, and develop therapeutic approaches to reduce this phenomenon.