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Published on: June 23, 2023
Deficient AMPK-SENP1-Sirt3 signaling impairs mitochondrial complex I function in Parkinson's disease model
Xiaoyu Sun1,2, Jianyi Shen3, Yimei Shu1
1Department of Neurology and Institute of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin Second Road, Shanghai, 200025, China.
Background:
Epidemiological studies have revealed increased Parkinson's disease (PD) risk among individuals exposed to pesticides like 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). MPTP is frequently used to induce PD-like symptoms in research models by disrupting mitochondrial complex I (CI) function and causing dopaminergic neuronal loss in the nigrostriatal region. However, the pathway(s) through which MPTP impairs mitochondrial CI function remain to be elucidated. In this study, we aim to identify the molecular mechanisms through which MPTP modulates CI function and define the specific subunits of mitochondrial CI affected by MPTP.
Methods:
Male mice encompassing either wild-type Sirt3 or Sirt3 K223R de-SUMOylation mutation, were intraperitoneally injected with either MPTP or saline. In vitro experiments were conducted using the SH-SY5Y cell line with or without the Sirt3 de-SUMOylation mutation. Movement performance, mitochondrial function, and protein acetylation were evaluated.
Results:
MPTP exposure, both in vitro and in vivo, disrupted the AMPK-SENP1-Sirt3 axis, leading to impairment of mitochondrial function. Specifically, MPTP suppressed activation of AMPK, impeding the entry of SENP1 into the mitochondria. The lack of mitochondrial SENP1 resulted in increased levels of SUMOylated Sirt3, which inhibited its deacetylase activity. This led to a significant increase in the acetylation of CI subunits NDUFS3 and NDUFA5, which resulted in reduced CI activity and inhibition of mitochondrial function, and eventually dopaminergic neuronal death. In this pathway, sustained deSUMOylation mutation of Sirt3 (K223R in mice, K288R in humans) mitigated the impact of MPTP on mitochondrial dysregulation, as well as dopaminergic neuronal death and behavioral deficits.
Conclusion:
The disordered AMPK-SENP1-Sirt3 pathway plays a crucial role in the MPTP-induced CI dysfunction and PD-like phenotype, which provide valuable insights into the mechanisms of PD pathogenesis.
Insights
Parkinson's disease risk is linked to pesticide exposure. MPTP impairs mitochondrial function by disrupting the AMPK-SENP1-Sirt3 pathway, leading to neuronal death. A Sirt3 mutation protected against these effects.
Area of Science:
- Neuroscience
- Mitochondrial Biology
- Biochemistry
Background:
- Epidemiological studies link pesticide exposure, such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), to increased Parkinson's disease (PD) risk.
- MPTP induces PD-like symptoms by impairing mitochondrial complex I (CI) and causing dopaminergic neuronal loss.
- The precise molecular mechanisms by which MPTP affects mitochondrial CI function are not fully understood.
Purpose of the Study:
- To identify the molecular mechanisms underlying MPTP's modulation of mitochondrial CI function.
- To define the specific subunits of mitochondrial CI that are affected by MPTP.
Main Methods:
- MPTP or saline was administered to male mice with wild-type or Sirt3 K223R de-SUMOylation mutations.
- In vitro studies utilized the SH-SY5Y cell line, with and without the Sirt3 de-SUMOylation mutation.
- Evaluated movement performance, mitochondrial function, and protein acetylation.
Main Results:
- MPTP exposure disrupted the AMPK-SENP1-Sirt3 axis, impairing mitochondrial function in vitro and in vivo.
- MPTP suppressed AMPK activation, hindering SENP1 mitochondrial entry, leading to increased SUMOylated Sirt3 and reduced deacetylase activity.
- This resulted in elevated acetylation of CI subunits NDUFS3 and NDUFA5, decreased CI activity, mitochondrial dysfunction, and dopaminergic neuronal death.
- Sustained deSUMOylation mutation of Sirt3 (K223R in mice, K288R in humans) mitigated MPTP's detrimental effects on mitochondrial function, neuronal death, and behavior.
Conclusions:
- The disordered AMPK-SENP1-Sirt3 pathway is critical in MPTP-induced CI dysfunction and PD-like phenotypes.
- These findings offer valuable insights into the pathogenesis of Parkinson's disease.
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