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Hum Mol Genet. 2017 May 15;26(10):1915-1926. doi: 10.1093/hmg/ddx100.

Sirt3 protects dopaminergic neurons from mitochondrial oxidative stress.

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Departments of Pediatrics, Neurology and Physiology, Northwestern University Feinberg School of Medicine, Anne & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, USA.
The Ken & Ruth Davee Department of Neurology.
Department of Radiology, Lurie Cancer Institute.
Department of Pediatrics.
Department of Physiology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.


Age-dependent elevation in mitochondrial oxidative stress is widely posited to be a major factor underlying the loss of substantia nigra pars compacta (SNc) dopaminergic neurons in Parkinson's disease (PD). However, mechanistic links between aging and oxidative stress are not well understood. Sirtuin-3 (Sirt3) is a mitochondrial deacetylase that could mediate this connection. Indeed, genetic deletion of Sirt3 increased oxidative stress and decreased the membrane potential of mitochondria in SNc dopaminergic neurons. This change was attributable to increased acetylation and decreased activity of manganese superoxide dismutase (MnSOD). Site directed mutagenesis of lysine 68 to glutamine (K68Q), mimicking acetylation, decreased MnSOD activity in SNc dopaminergic neurons, whereas mutagenesis of lysine 68 to arginine (K68R), mimicking deacetylation, increased activity. Introduction of K68R MnSOD rescued mitochondrial redox status and membrane potential of SNc dopaminergic neurons from Sirt3 knockouts. Moreover, deletion of DJ-1, which helps orchestrate nuclear oxidant defenses and Sirt3 in mice led to a clear age-related loss of SNc dopaminergic neurons. Lastly, K68 acetylation of MnSOD was significantly increased in the SNc of PD patients. Taken together, our studies suggest that an age-related decline in Sirt3 protective function is a major factor underlying increasing mitochondrial oxidative stress and loss of SNc dopaminergic neurons in PD.

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