Objective: To clarify the protective effect of SIRT3 on Parkinson’s disease (PD) and the molecular mechanism by which it regulates mitophagy.

Background: PD involves movement disorders from dopaminergic (DA) neuron death, where mitochondrial damage is important. PINK1/Parkin-mediated mitophagy is crucial for clearing damaged mitochondria. Deacetylase SIRT3 may benefit PD by upregulating autophagy, but its role in regulating mitophagy specifically for PD protection remains unclear.

Method: In vivo, rotenone (Rot)-induced PD model was established via stereotactic injection in C57BL/6J , SIRT3-overexpression (SIRT3^+/+), and SIRT3-knockout (SIRT3^-/-) mice using CRISPR-Cas9. Two weeks after surgery, western blot (WB) analyzed f-PINK1, c-PINK1, Parkin, and p62. Immunofluorescence assessed TOM20 and LC3 co-localization. Additionally, PRKN gene (encoding Parkin) was knocked down in the SNpc of PD model to evaluate its effect on mitophagy. In vitro, rot-induced PD cell model was created using SH-SY5Y cells. SIRT3 was overexpressed or silenced via lentiviral transfection. WB detected the effects of SIRT3 modulation on mitochondrial fission/fusion. Pharmacological inhibition of fission/fusion was then used to determine how these changes impact mitophagy.

Results: In vivo, PD mice showed increased f-PINK1/c-PINK1, Parkin, and p62 levels in striatum, along with more mitophagosomes in SNpc DA neurons. Knocking down the PRKN gene in the SNpc reduced mitophagosome, confirming Parkin-mediated mitophagy was inhibited (Figure 1). Compared to the PD group, SIRT3^+/+-PD decreased these protein levels but increased mitophagosomes in DA neurons (Figure 2), while SIRT3^-/--PD produced opposite effects (Figure 3). In vitro, silencing SIRT3 in the PD cell model increased Drp1 and elevated Parkin, p62 levels. Treatment with Mdivi-1 (a mitochondrial fission inhibitor) reversed these effects, suggesting that the damage effect from SIRT3 silencing was blocked by inhibiting mitochondrial fission (Figure 4). Conversely, SIRT3 overexpression increased Mfn2 and decreased Parkin, p62 levels. Treatment with MFI8 (a mitochondrial fusion inhibitor) weakened this protective effect, suggesting that SIRT3’s promotion effect of mitophagy can be weakened by mitochondrial fusion inhibition (Figure 5).

Conclusion: SIRT3 promotes Parkin-mediated mitophagy by regulating the balance of mitochondrial fission and fusion, thereby exerting a protective effect on PD.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/study-on-the-mechanism-of-sirt3-protecting-parkinsons-disease-by-regulating-mitophagy/