<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">PPID — Peptidylprolyl Isomerase D</th>
</tr>
<tr>
<td class="label">Symbol</td>
<td><strong>PPID</strong></td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>Peptidylprolyl Isomerase D (Cyclophilin D)</td>
</tr>
<tr>
<td class="label">Chromosome</td>
<td>4q31.3</td>
</tr>
<tr>
<td class="label">NCBI Gene</td>
<td><a href="https://www.ncbi.nlm.nih.gov/gene/54840" target="_blank">54840</a></td>
</tr>
<tr>
<td class="label">Ensembl</td>
<td><a href="https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000117595" target="_blank">ENSG00000117595</a></td>
</tr>
<tr>
<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprot/Q8WWC6" target="_blank">Q8WWC6</a></td>
</tr>
<tr>
<td class="label">Protein Class</td>
<td>Immunophilin, Mitochondrial cyclophilin</td>
</tr>
<tr>
<td class="label">Molecular Weight</td>
<td>~41 kDa</td>
</tr>
<tr>
<td class="label">Cellular Location</td>
<td>Mitochondrial matrix</td>
</tr>
<tr>
<td class="label">Diseases</td>
<td>[Alzheimer's Disease](/diseases/alzheimers), [Parkinson's Disease](/diseases/parkinsons-disease), [ALS](/diseases/amyotrophic-lateral-sclerosis)</td>
</tr>
<tr>
<th class="infobox-subheader" colspan="2">Key Information</th>
</tr>
<tr>
<td colspan="2" style="font-size:0.85em">Mitochondrial cyclophilin, mPTP regulator, cell death pathway[@tamimi2019]</td>
</tr
<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">PPID — Peptidylprolyl Isomerase D</th>
</tr>
<tr>
<td class="label">Symbol</td>
<td><strong>PPID</strong></td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>Peptidylprolyl Isomerase D (Cyclophilin D)</td>
</tr>
<tr>
<td class="label">Chromosome</td>
<td>4q31.3</td>
</tr>
<tr>
<td class="label">NCBI Gene</td>
<td><a href="https://www.ncbi.nlm.nih.gov/gene/54840" target="_blank">54840</a></td>
</tr>
<tr>
<td class="label">Ensembl</td>
<td><a href="https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000117595" target="_blank">ENSG00000117595</a></td>
</tr>
<tr>
<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprot/Q8WWC6" target="_blank">Q8WWC6</a></td>
</tr>
<tr>
<td class="label">Protein Class</td>
<td>Immunophilin, Mitochondrial cyclophilin</td>
</tr>
<tr>
<td class="label">Molecular Weight</td>
<td>~41 kDa</td>
</tr>
<tr>
<td class="label">Cellular Location</td>
<td>Mitochondrial matrix</td>
</tr>
<tr>
<td class="label">Diseases</td>
<td>[Alzheimer's Disease](/diseases/alzheimers), [Parkinson's Disease](/diseases/parkinsons-disease), [ALS](/diseases/amyotrophic-lateral-sclerosis)</td>
</tr>
<tr>
<th class="infobox-subheader" colspan="2">Key Information</th>
</tr>
<tr>
<td colspan="2" style="font-size:0.85em">Mitochondrial cyclophilin, mPTP regulator, cell death pathway[@tamimi2019]</td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">2 edges</a></td>
</tr>
</table>
PPID (Peptidylprolyl Isomerase D), also known as Cyclophilin D (CypD), is a nuclear-encoded mitochondrial cyclophilin protein that plays a critical role in regulating the mitochondrial permeability transition pore (mPTP). Located on chromosome 4q31.3, PPID encodes a 323-amino acid protein that localizes to the mitochondrial matrix where it functions as a peptidylprolyl cis-trans isomerase (PPIase) and serves as a key regulator of mitochondrial cell death pathways [1].
Cyclophilin D is distinct from other cyclophilin family members in its mitochondrial localization and its pivotal role in modulating the mPTP, a critical determinant of cell fate in response to various stressors. The mPTP is a non-specific channel that forms across the inner mitochondrial membrane under conditions of calcium overload, oxidative stress, or other pathological stimuli [2]. Opening of the mPTP leads to loss of mitochondrial membrane potential, swelling, rupture of the outer membrane, and release of pro-apoptotic factors such as cytochrome c, ultimately leading to cell death [3].
PMID: 17374512
Human cyclophilin D is a 323-amino acid protein belonging to the cyclophilin family of peptidylprolyl isomerases. The protein possesses the characteristic cyclophilin fold, consisting of an eight-stranded antiparallel β-barrel with two α-helices on the exterior [4]. The active site contains the signature CsA-binding pocket, although CypD has lower affinity for cyclosporine A compared to other cyclophilins [5].
Key structural features include:
The peptidylprolyl isomerase activity of cyclophilin D catalyzes the rate-limiting step of protein folding by facilitating rotation around the peptide bond preceding proline residues. While the physiological substrates remain incompletely characterized, CypD interacts with several mitochondrial proteins including:
Cyclophilin D is the primary regulator of the mitochondrial permeability transition pore [6]. The mPTP is a high-conductance channel whose opening is tightly regulated by CypD through the following mechanisms:
The canonical model suggests that CypD acts as a sensitizer of the mPTP, lowering the threshold for pore opening in response to calcium and oxidative stress [7]. Genetic deletion or pharmacological inhibition of CypD renders mitochondria resistant to calcium-induced pore opening, confirming its essential role in mPTP regulation [8].
PPID is ubiquitously expressed across all human tissues, with highest expression in organs with high mitochondrial content and energy demands:
| Tissue | Expression Level |
|--------|-----------------|
| Heart | Very High |
| Skeletal Muscle | Very High |
| Brain | High |
| Liver | High |
| Kidney | Moderate |
| Lung | Moderate |
| Pancreas | Moderate |
Within the central nervous system, PPID is expressed in all major neuronal populations in the cerebral cortex, hippocampus, basal ganglia, cerebellum, and brainstem [9]. Astrocytes and microglia also express PPID, though at lower levels than neurons.
Expression data from the Allen Human Brain Atlas demonstrates regional variations in PPID mRNA levels, with the hippocampus showing particularly high expression consistent with the vulnerability of this region in Alzheimer's disease [10].
Cyclophilin D plays a significant role in Alzheimer's disease pathogenesis through multiple mechanisms:
Amyloid-beta interaction: Studies demonstrate that amyloid-beta (Aβ) peptides directly interact with cyclophilin D, enhancing its binding to the mPTP and promoting mitochondrial dysfunction [11]. This interaction is thought to be a key mechanism by which Aβ induces neuronal death.
Mitochondrial dysfunction: In AD brain, CypD expression is increased in vulnerable regions, and this elevation correlates with mitochondrial dysfunction, oxidative stress, and synaptic loss [12]. CypD deficiency in APP/PS1 transgenic mice (a model of AD) significantly reduces Aβ-induced neuronal loss and improves cognitive performance [13].
Therapeutic implications: Targeting CypD represents a therapeutic strategy for AD. Small molecule inhibitors of cyclophilin D (non-immunosuppressive derivatives) have shown neuroprotective effects in cellular and animal models of AD [14].
In Parkinson's disease, cyclophilin D contributes to mitochondrial dysfunction in dopaminergic neurons, which are particularly vulnerable to mitochondrial toxins:
MPTP sensitivity: The name "Parkinson's disease" itself originates from the MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) compound, which induces parkinsonian symptoms in humans and animal models. MPTP directly induces mPTP opening, and cyclophilin D facilitates this process [15].
Oxidative stress: PD is characterized by mitochondrial complex I deficiency and increased oxidative stress. CypD is highly sensitive to oxidative modification, and ROS-promoted CypD-mPTP interaction contributes to dopaminergic neuron death [16].
PINK1/Parkin pathway: The PINK1-Parkin mitophagy pathway is impaired in PD. CypD may modulate the interplay between mPTP opening and mitophagy, though the precise mechanisms remain under investigation.
Cyclophilin D has been implicated in amyotrophic lateral sclerosis through studies showing that CypD knockout or inhibition delays disease onset and extends survival in SOD1 transgenic mice (a model of familial ALS) [17]. The mechanism involves reduced mitochondrial dysfunction and delayed motor neuron death.
Following cerebral ischemia, cyclophilin D mediates the mitochondrial cell death cascade. CypD-deficient mice show reduced infarct size and improved functional recovery after stroke, making CypD a potential therapeutic target for ischemic brain injury [18].
Several classes of cyclophilin D inhibitors have been developed:
Cyclosporine A (CsA): The original immunosuppressant CypA inhibitor also binds CypD but has limited utility due to its immunosuppressive effects and poor brain penetration [19].
Non-immunosuppressive derivatives: Novel compounds such as N-Methyl-4-isoleucine cyclosporin (Debio 025) and sanglifehrin A inhibit CypD without immunosuppression [20].
Small molecule approach: Magnesium, which antagonizes calcium-induced mPTP opening, has been explored as a neuroprotective agent in models of neurodegeneration [21].
While no CypD inhibitors have been approved for neurodegenerative diseases, several candidates have reached clinical trials:
The mitochondrial permeability transition pore represents a final common pathway for various neurodegenerative stimuli: