# Mitochondrial Sirtuin 3 in Parkinson's disease

> **NIH NIH R01** · MAYO CLINIC  JACKSONVILLE · 2021 · $70,359

## Abstract

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:** 10348483
- **Project number:** 3R01NS110085-03S1
- **Recipient organization:** MAYO CLINIC  JACKSONVILLE
- **Principal Investigator:** Pamela J McLean
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $70,359
- **Award type:** 3
- **Project period:** 2019-06-01 → 2024-05-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10348483

## Citation

> US National Institutes of Health, RePORTER application 10348483, Mitochondrial Sirtuin 3 in Parkinson's disease (3R01NS110085-03S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10348483. Licensed CC0.

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