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CypD: The Key to the Death Door
Shaik M Fayaz, Yanamala V Raj, Rajanikant G Krishnamurthy1
1School of Biotechnology, Coordinator, DBT - Centre for Bioinformatics, National Institute of Technology Calicut, Calicut - 673601, India. rajanikant@nitc.ac.in.
Abstract:
Numerous studies have deciphered the importance of Cyclophilin D (CypD/ peptidyl prolyl cis-trans isomerase F) in the formation and regulation of mitochondrial permeability transition pore (MPTP), implicated in the cell death mechanisms in various neurological diseases. Decrease in the ATP and increase in the calcium levels are the most common aftermath consequences that are observed in these diseases. Increased calcium level leads to the persistent opening of MPTP and cell death, which is mediated by CypD. However, the underlying mechanisms that contribute to the abnormal calcium homeostasis in different diseases remain elusive. In this review, we attempted to connect the disruption of mitochondrial bioenergetics with abnormal calcium levels and MPTP. Further, various proteins that interact with the CypD and the subsequent consequences have been described. All the cell death pathways in various neurological disorders merge at CypD, which acts as a key regulatory protein in cellular demise. Agents inhibiting CypD may have a therapeutic potential for treating neurological disorders such as Alzheimer's disease, Parkinson's disease and cerebral ischemia. Further, the knowledge regarding the pathophysiological processes involved in CypD-regulated MPTP and cell death would assist in battling with these diseases.
Insights
Cyclophilin D (CypD) regulates the mitochondrial permeability transition pore (MPTP), crucial in neurological diseases. Targeting CypD may offer new treatments for conditions like Alzheimer's and Parkinson's disease.
Area of Science:
- Mitochondrial biology
- Neuroscience
- Cell death mechanisms
Background:
- Cyclophilin D (CypD) is vital in mitochondrial permeability transition pore (MPTP) formation and regulation.
- MPTP dysfunction is implicated in cell death pathways in neurological diseases.
- Abnormal calcium homeostasis and decreased ATP levels are common in these conditions.
Purpose of the Study:
- To review the link between disrupted mitochondrial bioenergetics, calcium dysregulation, and MPTP.
- To explore proteins interacting with CypD and their downstream effects.
- To highlight CypD's central role in cellular demise across neurological disorders.
Main Methods:
- Literature review focusing on CypD, MPTP, calcium homeostasis, and mitochondrial bioenergetics.
- Analysis of protein-CypD interactions and their pathological consequences.
- Synthesis of information on cell death pathways converging at CypD.
Main Results:
- CypD mediates persistent MPTP opening, leading to cell death, often triggered by elevated calcium levels.
- Mitochondrial bioenergetic disruption is connected to abnormal calcium handling and MPTP activity.
- CypD acts as a convergence point for cell death pathways in various neurological disorders.
Conclusions:
- CypD is a key regulator of cell death in neurological diseases.
- Inhibitors of CypD show therapeutic potential for Alzheimer's disease, Parkinson's disease, and cerebral ischemia.
- Understanding CypD's role in MPTP and cell death is crucial for developing new disease treatments.