The mitochondrial permeability transition pore: A molecular target for amyotrophic lateral sclerosis therapy

Abstract

Effective therapies are needed for the treatment of amyotrophic lateral sclerosis (ALS), a fatal type of motor neuron disease. Morphological, biochemical, molecular genetic, and cell/animal model studies suggest that mitochondria have potentially diverse roles in neurodegenerative disease mechanisms and neuronal cell death. In human ALS, abnormalities have been found in mitochondrial structure, mitochondrial respiratory chain enzymes, and mitochondrial cell death proteins indicative of some non-classical form of programmed cell death. Mouse models of ALS are beginning to reveal possible principles governing the biology of selective neuronal vulnerability that implicate mitochondria. This minireview summarizes work on the how malfunctioning mitochondria might contribute to neuronal death in ALS through the biophysical entity called the mitochondrial permeability pore (mPTP). The major protein components of the mPTP are enriched in mouse motor neurons. Early in the course of disease in ALS mice expressing human mutant superoxide dismutase-1, mitochondria in motor neurons undergo trafficking abnormalities and dramatic remodeling resulting in the formation of mega-mitochondria and coinciding with increased protein carbonyl formation and nitration of mPTP components. The genetic deletion of a major mPTP component, cyclophilin D, has robust effects in ALS mice by delaying disease onset and extending survival. Thus, attention should be directed to the mPTP as rational target for the development of drugs designed to treat ALS.

Low Molecular Weight Phospholipases A2 in Mammalian Brain and Neural Cells: Roles in Functions and Dysfunctions

“…These mice undergo motor neuron degeneration with typical features of mitochondriopathy [140], suggesting the involvement of mitochondrial transition pores [141]. Although there is no available data to date, it is worth contemplating that mitochondrial PLA 2 (iPLA 2 and GIIA) contribute to mitochondrial dysfunction in this disease.…”

Calcium-dependent protein folding in amyotrophic lateral sclerosis

“…But high Ca 2+ concentrations (2 mM) still lead to mPTP opening and cell death in cyclophilin D knock out mice [120]. Thus, the effects of cyclophilin D deficiency on motor neurons need to be examined in more detail [22].…”

“…1). Once intramitochondrial Ca 2+ rises above a certain threshold, the voltage-and Ca 2+ -dependent high-conductance channel in the inner membrane, known as the mitochondrial permeability transition pore (mPTP) opens leading to cell death either by apoptosis or necrosis [21,22].…”

Molecular pathways of mitochondrial dysfunctions: Possible cause of cell death in anesthesia-induced developmental neurotoxicity

“…Furthermore, mPTP is possibly located in the inner membrane pore and mainly responsible for calcium homeostasis and ROS generation (Halestrap, 2009). Another study has shown that mPTP consists of VDAC and ANT, Bax, Bcl-2, and cyclophilin D (Martin, 2010a). Regardless of these perspectives, mPTP is necessary to maintain the normal function of the mitochondria; after the mPTP opens, mitochondrial inner membrane potential collapses and ions between the matrix and the cytosol become imbalanced, the mitochondria swell as a result.…”