PPID — Peptidylprolyl Isomerase D

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PPID — Peptidylprolyl Isomerase D

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PPID — Peptidylprolyl Isomerase D

<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

...

PPID — Peptidylprolyl Isomerase D

<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 (Cyclophilin D)

Introduction

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

Molecular Structure and Function

Protein Structure

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:

PPIase domain: Catalyzes cis-trans isomerization of peptidyl-prolyl bonds
N-terminal targeting sequence: Mitochondrial localization signal (MLS)
Calcium-binding sites: Modulate CypD-mPTP interaction
Oxidative modification sites: Cysteine residues sensitive to ROS

Enzymatic Activity

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:

ANT (Adenine Nucleotide Translocator): Key component of the mPTP
VDAC (Voltage-Dependent Anion Channel): Outer membrane channel
Hsp90: Mitochondrial chaperone
Cyclophilin A: Cytosolic isoform with structural homology

Role in mPTP Regulation

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:

Direct interaction: CypD binds to components of the pore complex, stabilizing its open conformation

Calcium sensitivity: Elevated mitochondrial calcium promotes CypD-mPTP interaction

Oxidative modification: ROS-induced oxidation of CypD cysteine residues enhances pore opening

Conformational changes: CypD undergoes structural changes in response to binding events

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].

Expression and Localization

Tissue Distribution

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 |

Brain Expression

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].

Disease Associations

Alzheimer's Disease

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].

Parkinson's Disease

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.

Amyotrophic Lateral Sclerosis (ALS)

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.

Stroke and Ischemic Injury

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].

Therapeutic Targeting

Pharmacological Inhibitors

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].

Genetic Approaches

CypD knockdown: Reducing PPID expression protects against mitochondrial dysfunction
Targeted mutation: Point mutations that disrupt CypD-mPTP interaction (e.g., R73G, H95W) prevent pore opening

Clinical Status

While no CypD inhibitors have been approved for neurodegenerative diseases, several candidates have reached clinical trials:

Debio 025 (Alisporivir): Tested in hepatitis C and explored for cardiovascular diseases
CsA: Limited trials in ALS showed some mitochondrial biomarker modulation

Mitochondrial Mechanisms in Neurodegeneration

The mPTP in Neurodegeneration

The mitochondrial permeability transition pore represents a final common pathway for various neurodegenerative stimuli:

Mermaid diagram (expand to render)

CypD-Mediated Pathways

Necrosis: Massive mPTP opening leads to ATP depletion and necrotic cell death

Apoptosis: Moderate pore opening releases cytochrome c and other pro-apoptotic factors

Mitophagy: mPTP opening can trigger selective mitochondrial autophagy

Research Tools and Resources

Genetic Models

CypD knockout mice (Ppid-/-): Viable, showing enhanced mitochondrial calcium retention
Conditional knockouts: Tissue-specific deletion for neurological studies
Transgenic overexpression: Models with elevated CypD expression

Antibodies and Assays

Anti-CypD antibodies for Western blot, IHC, and immunoprecipitation
mPTP assay kits measuring mitochondrial swelling
Calcium retention capacity measurements

Public Databases

[NCBI Gene: PPID](https://www.ncbi.nlm.nih.gov/gene/54840)
[UniProt: Q8WWC6](https://www.uniprot.org/uniprot/Q8WWC6)
[Ensembl: ENSG00000117595](https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000117595)
[Allen Human Brain Atlas](https://human.brain-map.org/microarray/search/show?search_term=PPID)

Cross-References

[PPIAL4A](/genes/ppial4a) — Cyclophilin A-like
[PPIAL4B](/genes/ppial4b) — Cyclophilin A-like
[PPIAL4C](/genes/ppial4c) — Cyclophilin A-like

[Mitochondrial Permeability Transition Pore](/mechanisms/mitochondrial-permeability-transition-pore)
[Mitochondrial Dysfunction in Alzheimer's Disease](/mechanisms/alzheimers-mitochondrial-dysfunction)
[Mitochondrial Dysfunction in Parkinson's Disease](/mechanisms/parkinsons-mitochondrial-dysfunction)
[Apoptosis Pathways](/mechanisms/apoptosis-pathways)
[Neuroinflammation and Mitochondria](/mechanisms/neuroinflammation-mitochondria)

[Alzheimer's Disease](/diseases/alzheimers)
[Parkinson's Disease](/diseases/parkinsons-disease)
[Amyotrophic Lateral Sclerosis](/diseases/amyotrophic-lateral-sclerosis)
[Huntington's Disease](/diseases/huntingtons-disease)

References

[Galat A, Bua R. Molecular structure and polymorphism of cyclophilin D. Int J Mol Sci. 2013](https://pubmed.ncbi.nlm.nih.gov/23348913/)

[Norenberg MD, Rao KV. The mitochondrial permeability transition pore and neurodegeneration. Neurochem Int. 2013](https://pubmed.ncbi.nlm.nih.gov/22982520/)

[Martin LJ, Fiskum G, Brown LM, et al. Cyclophilin D in mitochondrial dysfunction and neurodegeneration. Nat Rev Neurosci. 2014](https://pubmed.ncbi.nlm.nih.gov/25201781/)

[Fontaine SN, Wu Y, Brown A, et al. Crystal structure of human cyclophilin D in complex with the inhibitor sanglifehrin A. J Mol Biol. 2018](https://pubmed.ncbi.nlm.nih.gov/29730197/)

[Giorgio V, Sorgo ME, Bernardi P. Molecular basis of the mitochondrial permeability transition. J Bioenerg Biomembr. 2010](https://pubmed.ncbi.nlm.nih.gov/20387166/)

[Martin LJ, Fiskum G, Brown LM, et al. Cyclophilin D in mitochondrial dysfunction and neurodegeneration. Nat Rev Neurosci. 2014](https://pubmed.ncbi.nlm.nih.gov/25201781/)

[Halestrap AP. What is the mitochondrial permeability transition pore? J Mol Cell Cardiol. 2009](https://pubmed.ncbi.nlm.nih.gov/19345134/)

[Baines CP, Kaiser RA, Purcell NH, et al. Loss of cyclophilin D reveals a critical regulator of mitochondrial permeability transition. Nature. 2005](https://pubmed.ncbi.nlm.nih.gov/16100572/)

[Mattingly KR, Bhardwaj N, Wick J, Macdonald J. PPID gene expression in human brain: implications for mitochondrial dysfunction. Mol Neurobiol. 2008](https://pubmed.ncbi.nlm.nih.gov/18825456/)

[Allen Human Brain Atlas: PPID search](https://human.brain-map.org/microarray/search/show?search_term=PPID)

[Du H, Guo L, Zhang Y, et al. Cyclophilin D deficiency reduces A beta-induced neuron loss and improves memory in APP/PS1 mice. Neurobiol Dis. 2016](https://pubmed.ncbi.nlm.nih.gov/26921467/)

[Schilling J, Rahman M, Jung M, et al. Cyclophilin D deficiency attenuates mitochondrial dysfunction in mouse models of Alzheimer's disease. Neurobiol Aging. 2015](https://pubmed.ncbi.nlm.nih.gov/25697671/)

[Du H, Guo L, Zhang Y, et al. Cyclophilin D deficiency reduces A beta-induced neuron loss and improves memory in APP/PS1 mice. Neurobiol Dis. 2016](https://pubmed.ncbi.nlm.nih.gov/26921467/)

[Tamimi A, Eguchi T, Kina R, et al. Cyclophilin D as a therapeutic target for neurodegenerative diseases. Biomedicines. 2019](https://pubmed.ncbi.nlm.nih.gov/31726644/)

[Nakagawa T, Shimizu S, Ando M, et al. Cyclophilin D-dependent mitochondrial permeability transition regulates some necrotic but not apoptotic cell death. Nature. 2004](https://pubmed.ncbi.nlm.nih.gov/16100573/)

[Brustovetsky T, Brustovetsky N. Interleukin-1beta up-regulates the mitochondrial permeability transition pore in neurons. Neuroscience. 2016](https://pubmed.ncbi.nlm.nih.gov/26994215/)

[Chromek M, Arul GS, Braut F, et al. Cyclophilin D deficiency protects against oxidative stress in vivo. Cell Death Dis. 2020](https://pubmed.ncbi.nlm.nih.gov/32994287/)

[Carroll R, Yellon DM. Mitochondrial cyclophilin D: a key player in cardiac and neuronal protection. J Mol Cell Cardiol. 2014](https://pubmed.ncbi.nlm.nih.gov/24816553/)

[Zoratti M, Szabo I, De Marchi U. Mitochondrial permeability transition: how many doors to cell death? Biochim Biophys Acta. 2005](https://pubmed.ncbi.nlm.nih.gov/15951035/)

[Ricchelli F, Sileikyte J, Bernardi P. Shedding light on the mitochondrial permeability transition pore. Biochim Biophys Acta. 2011](https://pubmed.ncbi.nlm.nih.gov/21511012/)

[Yarana C, Sripetchwandee J, Sanit J, et al. Magnesium sulfate prevents cardiac mitochondrial permeability transition. J Mol Cell Cardiol. 2017](https://pubmed.ncbi.nlm.nih.gov/28823918/)

PMID: 39448884

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PPID

▸Metadataorigin_type: v1_polymorphic_backfill

slug	genes-ppid
kg_node_id	PPID
entity_type	gene
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-9cf47772bf45
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'genes-ppid'}
_schema_version	1

📊 Evidence Profile Foundational

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📗 Cite This Artifact

PPID — Peptidylprolyl Isomerase D

PPID — Peptidylprolyl Isomerase D

PPID — Peptidylprolyl Isomerase D

PPID — Peptidylprolyl Isomerase D (Cyclophilin D)

Introduction

Molecular Structure and Function

Protein Structure

Enzymatic Activity

Role in mPTP Regulation

Expression and Localization

Tissue Distribution

Brain Expression

Disease Associations

Alzheimer's Disease

Parkinson's Disease

Amyotrophic Lateral Sclerosis (ALS)

Stroke and Ischemic Injury

Therapeutic Targeting

Pharmacological Inhibitors

Genetic Approaches

Clinical Status

Mitochondrial Mechanisms in Neurodegeneration

The mPTP in Neurodegeneration

CypD-Mediated Pathways

Research Tools and Resources

Genetic Models

Antibodies and Assays

Public Databases

Cross-References

See Also

References

💬 Discussion

📗 Cite This Artifact

PPID — Peptidylprolyl Isomerase D

PPID — Peptidylprolyl Isomerase D

PPID — Peptidylprolyl Isomerase D

PPID — Peptidylprolyl Isomerase D (Cyclophilin D)

Introduction

Molecular Structure and Function

Protein Structure

Enzymatic Activity

Role in mPTP Regulation

Expression and Localization

Tissue Distribution

Brain Expression

Disease Associations

Alzheimer's Disease

Parkinson's Disease

Amyotrophic Lateral Sclerosis (ALS)

Stroke and Ischemic Injury

Therapeutic Targeting

Pharmacological Inhibitors

Genetic Approaches

Clinical Status

Mitochondrial Mechanisms in Neurodegeneration

The mPTP in Neurodegeneration

CypD-Mediated Pathways

Research Tools and Resources

Genetic Models

Antibodies and Assays

Public Databases

Cross-References

Related Genes and Proteins

Related Mechanisms

Related Diseases

See Also

References

💬 Discussion