BL-918 activates PINK1/Parkin signaling pathway to ameliorate the progression of Parkinson's disease

  • J Biol Chem. 2024 Jul 9:107543. doi: 10.1016/j.jbc.2024.107543.
Yi Wang  1 ,  Siyuan Luo  2 ,  Huili Su  1 ,  Zhimeng Wang  3 ,  Ling Chu  4 ,  Conggang Zhang  5
Affiliations
  • 1. School of Pharmaceutical Sciences, Tsinghua University, Beijing, 100084, China; State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing, 100084, China.
  • 2. School of Pharmaceutical Sciences, Tsinghua University, Beijing, 100084, China.
  • 3. School of Pharmaceutical Sciences, Tsinghua University, Beijing, 100084, China; State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing, 100084, China. Electronic address: [email protected].
  • 4. School of Pharmaceutical Sciences, Tsinghua University, Beijing, 100084, China. Electronic address: [email protected].
  • 5. School of Pharmaceutical Sciences, Tsinghua University, Beijing, 100084, China; State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing, 100084, China. Electronic address: [email protected].
PMID: 38992440 DOI: 10.1016/j.jbc.2024.107543
Abstract

The pathogenesis of Parkinson's disease (PD) has been associated with mitochondrial dysfunction. Given that the PINK1/Parkin pathway governs mitochondrial quality control by inducing Mitophagy to remove damaged mitochondria, therapeutic approaches to activate PINK1/Parkin-mediated Mitophagy have the potential in the treatment of PD. Here, we have identified a new small molecule, BL-918, as an inducer of Mitophagy via activating the PINK1/Parkin pathway. BL-918 triggers PINK1 accumulation and Parkin mitochondrial translocation to initiate PINK1/Parkin-mediated Mitophagy. We found that mitochondrial membrane potential and mitochondrial permeability transition (mPT) pore were involved in BL-918-induced PINK1/Parkin pathway activation. Moreover, we showed that BL-918 mitigated PD progression in MPTP-induced PD mice in a PINK1-dependent manner. Our results unravel a new activator of the PINK1/Parkin signaling pathway and provide a potential strategy for the treatment of PD and Other Diseases with dysfunctional mitochondria.

Keywords
Mitochondrial quality control; Mitophagy; PINK1; Parkin; Parkinson’s disease.
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