SIRT3 - Sirtuin 3

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SIRT3 - Sirtuin 3

Overview

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SIRT3 - Sirtuin 3

Overview

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">SIRT3 - Sirtuin 3</th>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>SIRT3</td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>Sirtuin 3</td>
</tr>
<tr>
<td class="label">Chromosomal Location</td>
<td>11p15.5</td>
</tr>
<tr>
<td class="label">NCBI Gene ID</td>
<td>23410</td>
</tr>
<tr>
<td class="label">OMIM</td>
<td>604479</td>
</tr>
<tr>
<td class="label">Ensembl ID</td>
<td>ENSG00000142092</td>
</tr>
<tr>
<td class="label">UniProt</td>
<td>Q9NWU1</td>
</tr>
<tr>
<td class="label">Approach</td>
<td>Status</td>
</tr>
<tr>
<td class="label">SRT1720</td>
<td>Preclinical</td>
</tr>
<tr>
<td class="label">NAD+ precursors (NR, NMN)</td>
<td>Phase 2</td>
</tr>
<tr>
<td class="label">Honokiol</td>
<td>Preclinical</td>
</tr>
<tr>
<td class="label">Gene therapy (AAV-SIRT3)</td>
<td>Research</td>
</tr>
<tr>
<td class="label">Approach</td>
<td>Status</td>
</tr>
<tr>
<td class="label">SIRT3 activators</td>
<td>Preclinical</td>
</tr>
<tr>
<td class="label">NAD+ boosters</td>
<td>Clinical</td>
</tr>
<tr>
<td class="label">Gene therapy</td>
<td>Research</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">ALS</a>, <a href="/wiki/alzheimer" style="color:#ef9a9a">ALZHEIMER</a>, <a href="/wiki/alzheimer's-disease" style="color:#ef9a9a">ALZHEIMER'S DISEASE</a>, <a href="/wiki/aging" style="color:#ef9a9a">Aging</a>, <a href="/wiki/als" style="color:#ef9a9a">Als</a></td>
</tr>
<tr>
<td class="label">SciDEX Hypotheses</td>
<td><a href="/hypothesis/h-seaad-v4-5a7a4079" style="color:#ce93d8" title="Score: 0.68">SIRT3-Mediated Mitochondrial Deacetylati...</a><br><a href="/hypothesis/h-0e614ae4" style="color:#ce93d8" title="Score: 0.45">Mitochondrial-Nuclear Epigenetic Cross-T...</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">725 edges</a></td>
</tr>
</table>

Sirt3 Sirtuin 3 plays an important role in the study of neurodegenerative diseases. This page provides comprehensive information about this topic, including its mechanisms, significance in disease processes, and therapeutic implications.

Pathway Diagram

Mermaid diagram (expand to render)

Introduction

Sirt3 Sirtuin 3 is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes. [@smad]

SIRT3 is a member of the sirtuin family of NAD+-dependent deacetylases, primarily localized to mitochondria. It plays a critical role in regulating mitochondrial function, metabolism, and cellular stress responses. [@transcriptional]

Gene Overview

Function

SIRT3 is the primary mitochondrial deacetylase, regulating key metabolic enzymes and proteins involved in:

Mitochondrial protein acetylation: Deacetylates over 20 mitochondrial proteins, including IDH2, SDH, GDH, LCAD, and HSD17B10
ATP production: Modulates electron transport chain complex activity to optimize oxidative phosphorylation
[ROS](/entities/reactive-oxygen-species) detoxification: Activates SOD2 (manganese superoxide dismutase) by deacetylation to reduce oxidative stress
Fatty acid oxidation: Activates LCAD (long-chain acyl-CoA dehydrogenase) to promote fatty acid metabolism
Ketogenesis: Regulates HMGCS2 to enhance ketone body production during fasting

Disease Associations

Alzheimer's Disease

SIRT3 expression is reduced in AD brains and AD mouse models
SIRT3 deacetylates SOD2 to protect [neurons](/entities/neurons) from [Aβ](/proteins/amyloid-beta)-induced oxidative stress
SIRT3 activation promotes mitochondrial biogenesis and improves Therapeutic potential: SIRT3 activators (e.g., honokiol, cognitive function
resveratrol derivatives) are being investigated

Parkinson's Disease

SIRT3 is the primary mitochondrial deacetylase and plays a critical protective role in dopaminergic neurons. SIRT3 protects dopaminergic neurons from mitochondrial dysfunction through:

Complex I protection: SIRT3 deacetylates complex I subunits to maintain electron transport chain function—directly relevant to PD given the well-established complex I deficiency in PD substantia nigra. PMID: 25933439(https://pubmed.ncbi.nlm.nih.gov/25933439/)
MnSOD activation: SIRT3 deacetylates manganese superoxide dismutase (MnSOD), enhancing its enzymatic activity to reduce oxidative stress in dopaminergic neurons.
IDH2 activation: SIRT3 deacetylates isocitrate dehydrogenase 2 (IDH2), increasing NADP+/NADPH production crucial for reducing glutathione and combating oxidative stress.

Sirtuin Pathway Dysfunction Hypothesis

The [Sirtuin Pathway Dysfunction Hypothesis in Parkinson's Disease](/hypotheses/sirtuin-pathway-dysfunction-parkinsons) identifies SIRT3 as a key mitochondrial guardian whose dysfunction contributes to PD pathogenesis:

Genetic evidence: SIRT3 rs3729620 variant associated with PD risk in Chinese cohort. PMID: 28552878(https://pubmed.ncbi.nlm.nih.gov/28552878/)

Biochemical evidence: SIRT3 expression reduced in PD patient brain tissue and models.

Preclinical evidence: SIRT3 overexpression protects against MPTP-induced dopaminergic neurodegeneration. PMID: 25933439(https://pubmed.ncbi.nlm.nih.gov/25933439/)

Therapeutic Implications

SIRT3 activation is a promising therapeutic approach for PD:

The [NADAPT Study (NCT06162013)](/clinical-trials/nadapt-study-nad-replenishment-parkinsonism-nct06162013) evaluates NAD+ precursor supplementation that indirectly enhances SIRT3 activity through increased NAD+ substrate.

See the [Sirtuin Pathway Dysfunction Validation Experiment](/experiments/sirtuin-pathway-dysfunction-parkinsons) for detailed study design including SIRT3-targeted interventions.

Amyotrophic Lateral Sclerosis (ALS)

SIRT3 levels are decreased in ALS models and patient tissues
Protects motor neurons from mitochondrial dysfunction and oxidative stress
SIRT3 deacetylase activity is protective in SOD1 and [TDP-43](/proteins/tdp-43) models

Huntington's Disease

SIRT3 ameliorates mitochondrial dysfunction in HD models
Protects against mutant [huntingtin](/proteins/huntingtin-protein)-induced metabolic deficits

Expression Pattern

SIRT3 is highly expressed in:

Brain: [Hippocampus](/brain-regions/hippocampus), cerebral [cortex](/brain-regions/cortex), basal ganglia, cerebellum
High energy-demand tissues: Heart, liver, kidney, skeletal muscle
Neuronal subtypes: Particularly enriched in dopaminergic neurons

Therapeutic Targeting

Key Publications

Hirschey MD, et al. SIRT3 regulates mitochondrial protein acetylation. Nature. 2010;464(7285):121-125. PMID: 20203689(https://pubmed.ncbi.nlm.nih.gov/20203689/)

Song R, et al. SIRT3 improves mitochondrial function and alleviates β-amyloid-induced neuronal damage. Neurobiology of Aging. 2018;70:98-107. PMID: 29953874(https://pubmed.ncbi.nlm.nih.gov/29953874/)

Liu L, et al. SIRT3 protects dopaminergic neurons from mitochondrial dysfunction. Parkinsonism Relat Disord. 2019;69:28-34. PMID: 31257023(https://pubmed.ncbi.nlm.nih.gov/31257023/)

Shi H, et al. SIRT3 activation attenuates ALS-like pathology. Cell Death Discov. 2021;7(1):137. PMID: 34112784(https://pubmed.ncbi.nlm.nih.gov/34112784/)

Wu Y, et al. SIRT3 deficiency exacerbates mitochondrial dysfunction in models of Huntington's disease. Neurotherapeutics. 2022;19(2):516-530. PMID: 35094321(https://pubmed.ncbi.nlm.nih.gov/35094321/)

External Links

[NCBI Gene: SIRT3](https://www.ncbi.nlm.nih.gov/gene/23410)
[UniProt: SIRT3](https://www.uniprot.org/uniprot/Q9NWU1)
[OMIM: SIRT3](https://www.omim.org/entry/604479)
[Allen Brain Atlas: SIRT3](https://human.brain-map.org/search?query=SIRT3)

Overview

Background

The study of Sirt3 Sirtuin 3 has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.

Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.

References

[Unknown, - TGF-beta signaling in neurodegeneration (n.d.)](https://pubmed.ncbi.nlm.nih.gov/27451067/)

[Unknown, - SMAD proteins in neural development (n.d.)](https://pubmed.ncbi.nlm.nih.gov/25009184/)

[Unknown, - Transcriptional regulation in AD (n.d.)](https://pubmed.ncbi.nlm.nih.gov/24668245/)

[Unknown, - Neuroinflammation and TGF-beta (n.d.)](https://pubmed.ncbi.nlm.nih.gov/25997342/)

[Unknown, - Astrocyte function in neurodegeneration (n.d.)](https://pubmed.ncbi.nlm.nih.gov/26245252/)

From the [SciDEX Exchange](/exchange) — scored by multi-agent debate

[Mitochondrial-Nuclear Epigenetic Cross-Talk Restoration](/hypothesis/h-0e614ae4) — <span style="color:#ffd54f;font-weight:600">0.45</span> · Target: SIRT3

Pathway Diagram

The following diagram shows the key molecular relationships involving SIRT3 - Sirtuin 3 discovered through SciDEX knowledge graph analysis:

Mermaid diagram (expand to render)

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SIRT3 - Sirtuin 3

SIRT3 - Sirtuin 3

Overview

SIRT3 - Sirtuin 3

Overview

Pathway Diagram

Introduction

Gene Overview

Function

Disease Associations

Alzheimer's Disease

Parkinson's Disease

Sirtuin Pathway Dysfunction Hypothesis

Therapeutic Implications

Amyotrophic Lateral Sclerosis (ALS)

Huntington's Disease

Expression Pattern

Therapeutic Targeting

Key Publications

See Also

External Links

Overview

Background

References

Related Hypotheses

Pathway Diagram