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Review
. 2014 Aug;1842(8):1267-72.
doi: 10.1016/j.bbadis.2013.09.003. Epub 2013 Sep 18.

Mitochondrial permeability transition pore is a potential drug target for neurodegeneration

Valasani Koteswara Rao  1 , Emily A Carlson  1 , Shirley Shidu Yan  2
Affiliations
Review

Mitochondrial permeability transition pore is a potential drug target for neurodegeneration

Valasani Koteswara Rao et al. Biochim Biophys Acta. 2014 Aug.

Abstract

Mitochondrial permeability transition pore (mPTP) plays a central role in alterations of mitochondrial structure and function leading to neuronal injury relevant to aging and neurodegenerative diseases including Alzheimer's disease (AD). mPTP putatively consists of the voltage-dependent anion channel (VDAC), the adenine nucleotide translocator (ANT) and cyclophilin D (CypD). Reactive oxygen species (ROS) increase intra-cellular calcium and enhance the formation of mPTP that leads to neuronal cell death in AD. CypD-dependent mPTP can play a crucial role in ischemia/reperfusion injury. The interaction of amyloid beta peptide (Aβ) with CypD potentiates mitochondrial and neuronal perturbation. This interaction triggers the formation of mPTP, resulting in decreased mitochondrial membrane potential, impaired mitochondrial respiration function, increased oxidative stress, release of cytochrome c, and impaired axonal mitochondrial transport. Thus, the CypD-dependent mPTP is directly linked to the cellular and synaptic perturbations observed in the pathogenesis of AD. Designing small molecules to block this interaction would lessen the effects of Aβ neurotoxicity. This review summarizes the recent progress on mPTP and its potential therapeutic target for neurodegenerative diseases including AD.

Keywords: Alzheimer's disease; Amyloid β; Cyclophilin D; Mitochondrial permeability transition pore; Neurodegeneration.

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Figures

Figure 1
Figure 1. Toxicities induced by Aβ
Aβ is known to cause neuronal toxicity by several mechanisms, including increased ROS production, induction of apoptosis, disturbing calcium homeostasis, and enhancing the vulnerability of neurons to other toxic substances, etc.
Figure 2
Figure 2. Formation of mPTP is triggered by two major noxious insults
1. calcium overload in the mitochondrial matrix, and 2. oxidative stress, which triggers a conformational change in the ANT leading to the formation of mPTP along with VDAC. This is further facilitated by CypD. mPTP opening causes mitochondrial swelling, rupture of the outer mitochondrial membrane, which finally leads to the releases of a pro-apoptotic molecules such as cytochrome c into the cytosol. If the pore opens for longer period of time, loss of membrane potential occurs that leads to the depletion of ATP, which finally triggers necrotic oncosis. Mitochondria can maintain ATP levels if the mPTP opens for a short period of time, which triggers necrotic apoptosis. Both of these processes are major contributing factors for neuronal cell death in AD. CypD inhibitors have the potential to prevent the formation of mPTP and provide protection against neuronal cell death.
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