idh3a
Introduction
<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">idh3a</th>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>IDH3A</td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>Isocitrate Dehydrogenase 3 Alpha</td>
</tr>
<tr>
<td class="label">Chromosomal Location</td>
<td>7q32.2</td>
</tr>
<tr>
<td class="label">Protein Length</td>
<td>413 amino acids</td>
</tr>
<tr>
<td class="label">Molecular Weight</td>
<td>~46 kDa</td>
</tr>
<tr>
<td class="label">Subcellular Localization</td>
<td>Mitochondrial matrix</td>
</tr>
<tr>
<td class="label">Enzyme Classification</td>
<td>EC 1.1.1.41 (NAD+-dependent)</td>
</tr>
<tr>
<td class="label">Year</td>
<td>Discovery</td>
</tr>
<tr>
<td class="label">1970s</td>
<td>IDH3A enzyme characterized</td>
</tr>
<tr>
<td class="label">1990s</td>
<td>Gene cloned and mapped to 7q32</td>
</tr>
<tr>
<td class="label">2000s</td>
<td>Mutations linked to RP</td>
</tr>
<tr>
<td class="label">2010s</td>
<td>Role in neurodegeneration established</td>
</tr>
<tr>
<td class="label">2020s</td>
<td>Metabolic therapies in trials</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/cardiac" style="color:#ef9a9a">Cardiac</a>, <a href="/wiki/fibrosis" style="color:#ef9a9a">Fibrosis</a>, <a href="/wiki/ischemia" style="color:#ef9a9a">Ischemia</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">24 edges</a></td>
</tr>
</table>
Isocitrate dehydrogenase 3 alpha (IDH3A) is a critical mitochondrial enzyme in the tricarboxylic acid (TCA) cycle that plays a pivotal role in cellular energy metabolism. This gene has garnered significant attention in neurodegeneration research due to its essential function in neuronal ATP production and its involvement in multiple neurodegenerative disease pathways. IDH3A catalyzes the rate-limiting oxidative decarboxylation step in the TCA cycle, converting isocitrate to α-ketoglutarate (α-KG) while generating NADH for the electron transport chain. Recent research has revealed that IDH3A dysfunction contributes to the metabolic deficits observed in Alzheimer's disease (AD), Parkinson's disease (PD), and other neurodegenerative disorders [1][2].
Gene Overview
Structure
IDH3A is a NAD+-dependent isocitrate dehydrogenase that functions as a heterotetramer composed of α, β, and γ subunits. Unlike its paralogs IDH1 (cytosolic, NADP+-dependent) and IDH2 (mitochondrial, NADP+-dependent), IDH3A uses NAD+ as its cofactor, making it uniquely positioned to couple TCA cycle activity with cellular NAD+ homeostasis. The enzyme undergoes allosteric regulation by adenine nucleotides: ADP activates while ATP and NADH inhibit its activity. Calcium ions serve as an additional activator, linking enzyme activity to neuronal calcium signaling [1][2].
Function
TCA Cycle Catalysis
IDH3A catalyzes the rate-limiting oxidative decarboxylation reaction:
Isocitrate + NAD+ + Mg2+ → α-Ketoglutarate + NADH + CO2 + H+
This reaction is:
- Rate-limiting in the TCA cycle (Km ~0.1-0.5 mM)
- Irreversible under physiological conditions
- Major source of NADH for oxidative phosphorylation
In neurons, IDH3A is critically important because:
- Neurons rely heavily on oxidative phosphorylation
- High ATP demand for synaptic transmission
- Mitochondrial health directly affects neuronal viability
Regulation
The enzyme is regulated by:
- Activators: ADP, calcium ions (Ca2+)
- Inhibitors: ATP, NADH, NADPH
- Post-translational modifications: Phosphorylation, acetylation
IDH3A in Neurodegeneration
Alzheimer's Disease
Metabolic dysfunction is a hallmark of AD, with multiple studies documenting reduced TCA cycle enzyme activity in AD brain tissue. IDH3A activity is diminished in hippocampal and cortical regions of AD patients, contributing to:
- Impaired glucose metabolism
- Reduced ATP production
- Energy crisis in affected neurons
- Vulnerability to amyloid-beta toxicity [3][4][5]
Parkinson's Disease
Mitochondrial dysfunction is central to PD pathogenesis. IDH3A contributes to PD through:
- Complex I deficiency affecting downstream NADH oxidation
- Increased sensitivity to mitochondrial toxins
- Dopaminergic neuron vulnerability [6]
Leigh Syndrome
IDH3A mutations cause autosomal recessive Leigh syndrome, characterized by:
- Bilateral basal ganglia lesions
- Developmental regression
- Progressive neurodegenerative phenotype
Retinitis Pigmentosa
IDH3A mutations cause autosomal dominant retinitis pigmentosa, affecting:
- Photoreceptor metabolism
- Retinal cell survival
- Progressive vision loss [8]
Therapeutic Implications
Multiple therapeutic approaches target IDH3A-related pathways:
- NAD+ precursors (nicotinamide riboside, nicotinamide mononucleotide)
- Metabolic modulators
- Mitochondrial protective agents
Drug Development
IDH3A-adjacent targets include:
- IDH1/2 mutants in brain tumors (ongoing clinical trials)
- α-Ketoglutarate analogs
- Mitochondrial biogenesis agents [9]
Expression Pattern
IDH3A expression across tissues:
- Highest in: Brain (neurons), heart, skeletal muscle
- Moderate in: Kidney, liver
- Lower in: Other tissues
In the brain, IDH3A is expressed in:
- Pyramidal neurons (hippocampus, cortex)
- Dopaminergic neurons (substantia nigra)
- Cerebellar Purkinje cells
Interaction Network
Mermaid diagram (expand to render)
Research History
Cross-Links
- [TCA Cycle](/mechanisms/citric-acid-cycle)
- [Mitochondria](/entities/mitochondrial-dynamics)
- [Alzheimer's Disease Metabolic Dysfunction](/mechanisms/alzheimers-metabolic-pathology)
- [Parkinson's Disease Mitochondrial Dysfunction](/mechanisms/parkinsons-mitochondrial-pathology)
- [Retinitis Pigmentosa](/diseases/retinitis-pigmentosa)
- [Leigh Syndrome](/diseases/leigh-syndrome)
External Links
- [NCBI Gene: IDH3A](https://www.ncbi.nlm.nih.gov/gene/3419)
- [UniProt: P00343](https://www.uniprot.org/uniprot/P00343)
- [OMIM: 147450](https://www.omim.org/entry/147450)
References
[Hamilton et al., Human molecular genetics (2020)](https://doi.org/10.1093/hmg/ddaa185)
[Tommasini-Ghelfi et al., Science advances (2019)](https://doi.org/10.1126/sciadv.aaw4543)
[Kim et al., Nature Reviews Neuroscience (2021)](https://doi.org/10.1038/s41583-021-00457-4)
[Du et al., Trends in Neurosciences (2020)](https://doi.org/10.1016/j.tins.2020.06.003)
[Ishii et al., Journal of Alzheimer's Disease (2020)](https://doi.org/10.3233/JAD-200318)
[Moreira et al., Progress in Neuro-Psychopharmacology (2022)](https://doi.org/10.1016/j.pnpbp.2022.110566)
[Wijesekera et al., Free Radical Biology and Medicine (2022)](https://doi.org/10.1016/j.freeradbiomed.2022.06.012)
[Schiff et al., Journal of Medical Genetics (2017)](https://doi.org/10.1136/jmedgenet-2017-104545)
[Arrington et al., Cell Metabolism (2023)](https://doi.org/10.1016/j.cmet.2023.04.017)Pathway Diagram
The following diagram shows the key molecular relationships involving idh3a discovered through SciDEX knowledge graph analysis:
Mermaid diagram (expand to render)