# Mitochondrial Sirtuin 3 in Parkinson's disease

> **NIH NIH R01** · MAYO CLINIC  JACKSONVILLE · 2022 · $476,492

## Abstract

The overall aim of this application is to investigate mechanisms of alpha-synuclein (αsyn)-induced
mitochondrial dysfunction in Lewy body diseases (LBD). Despite its predominant localization in the
cytosol, αsyn localizes to mitochondria in post-mortem LBD brains. Within the mitochondria, αsyn
accumulation can impair complex I and IV function, decrease membrane potential, increase levels of
reactive oxygen species, and increase apoptosis associated with cytochrome c release from the
mitochondria. Together these data suggest an increase in mitochondrial αsyn expression and/or
abnormal accumulation of toxic aggregates interferes with mitochondrial function. Maintaining
mitochondrial health is essential to prevent neuronal cell death in the brain. Sirtuin 3 (SIRT3) is a
NAD+-dependent protein deacetylase exclusively localized to the mitochondria where it regulates
mitochondrial processes including protein deacetylation, organelle biogenesis, and oxidative stress.
SIRT3 is expressed at high levels in the brain and other nervous system tissues, and can act as a pro-
survival factor, playing an essential role in protecting neurons under conditions of excitotoxicity and
rescuing neuronal loss in neurodegenerative models. Experimental evidence indicates that SIRT3-
induced neuroprotection against oxidative stress is partially mediated by enhancement of mitochondrial
biogenesis and integrity. As we consider sirtuin-based drug therapies for diseases of ageing, it is
important to determine if modulating SIRT3 can protect against neurodegeneration where mitochondrial
dysfunction has been demonstrated to play a role. This proposal will investigate how mitochondrial
SIRT3 contributes to αsyn-induced mitochondrial dysfunction in 3 coordinated aims. In aim 1 we will
perform comprehensive mitochondrial function analyses to reveal how αsyn accumulation leads to
mitochondrial damage and the role of SIRT3 therein using patient-derived cells and postmortem brain.
In aim 2 we will interrogate the SIRT3 regulated acetylome to identify novel targets of αsyn-associated
mitochondrial dysfunction, and in aim 3 we will validate SIRT3 as a novel target for therapeutic
intervention in PD in a comprehensive in vivo approach using genetic overexpression and
pharmacological activation. The proposed rigorous analysis of various mitochondrial aspects will
dissect causes from consequences and reveal the cross-talk between αsyn, SIRT3, and mitochondrial
signaling pathways as well as oxidative and protein stress responses.

## Key facts

- **NIH application ID:** 10409706
- **Project number:** 5R01NS110085-04
- **Recipient organization:** MAYO CLINIC  JACKSONVILLE
- **Principal Investigator:** Pamela J McLean
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $476,492
- **Award type:** 5
- **Project period:** 2019-06-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10409706

## Citation

> US National Institutes of Health, RePORTER application 10409706, Mitochondrial Sirtuin 3 in Parkinson's disease (5R01NS110085-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10409706. Licensed CC0.

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