SIRT3 agonists(Guangdong University of Technology)

Dysregulation of mitochondrial dynamics is a key contributor to the pathogenesis of Parkinson's disease (PD). Aberrant mitochondrial fission induced by dynamin‐related protein 1 (DRP1) causes mitochondrial dysfunction in dopaminergic (DA) neurons. However, the mechanism of DRP1 activation and its role in PD progression remain unclear. In this study, Mass spectrometry analysis is performed and identified a significant increased DRP1 acetylation at lysine residue 711 (K711) in the mitochondria under oxidative stress. Enhanced DRP1K711 acetylation facilitated DRP1 oligomerization, thereby exacerbating mitochondrial fragmentation and compromising the mitochondrial function. DRP1K711 acetylation also affects mitochondrial DRP1 recruitment and fission independent of canonical S616 phosphorylation. Further analysis reveals the critical role of sirtuin (SIRT)‐3 in deacetylating DRP1K711, thereby regulating mitochondrial dynamics and function. SIRT3 agonists significantly inhibit DRP1K711 acetylation, rescue DA neuronal loss, and improve motor function in a PD mouse model. Conversely, selective knockout of SIRT3 in DA neurons exacerbates DRP1K711 acetylation, leading to increased DA neuronal damage, neuronal death, and worsened motor dysfunction. Notably, this study identifies a novel mechanism involving aberrant SIRT3‐mediated DRP1 acetylation at K711 as a key driver of mitochondrial dysfunction and DA neuronal death in PD, revealing a potential target for PD treatment.

Hypertension may result in atrial fibrillation (AF) and lipid metabolism disorders. The Sirtuins3 (SIRT3)/AMP-activated protein kinase (AMPK) signaling pathway has the capacity to regulate lipid metabolism disorders and the onset of AF. We hypothesize that the SIRT3/AMPK signaling pathway suppresses lipid metabolism disorders, thereby mitigating salt-sensitive hypertension (SSHT)-induced susceptibility to AF.

The study involved 7-week-old male Dahl salt-sensitive that were fed either a high-salt diet (8% NaCl; DSH group) or a normal diet (0.3% NaCl; DSN group). Then DSH group was administered either oral metformin (MET, an AMPK agonist) or intraperitoneal injection of Honokiol (HK, a SIRT3 agonist). This experimental model allowed for the measurement of Systolic blood pressure (SBP), the expression levels of lipid metabolism-related biomarkers, pathological examination of atrial fibrosis, and lipid accumulation, as well as AF inducibility and AF duration.

DSH decrease SIRT3, phosphorylation-AMPK, and very long-chain acyl-CoA dehydrogenase, (VLCAD) expression, increased FASN and FABP4 expression and concentrations of free fatty acid and triglyceride, atrial fibrosis and lipid accumulation in atrial tissue, enhanced level of SBP, promoted AF induction rate and prolonged AF duration, which are blocked by MET and HK. Our results also showed that the degree of atrial fibrosis was negatively correlated with VLCAD expression, but positively correlated with the expression of FASN and FABP4.

We have confirmed that a high-salt diet can result in hypertension, and associated atrial tissue lipid metabolism dysfunction. This condition is linked to the inhibition of the SIRT3/AMPK signaling pathway, which plays a significant role in the progression of susceptibility to AF in SSHT rats.