alexa Mitochondrial ATP Synthase: Is the Molecular Engine of Life also an Efficient Death Machine?

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Mitochondrial ATP Synthase: Is the Molecular Engine of Life also an Efficient Death Machine?

Following the initial studies by Hunter and Haworth on the “Ca2+- induced membrane transition” [1-3], a plethora of studies addressing the pharmacology, bioenergetics and structure of the Mitochondrial Permeability Transition (MPT) pore have allowed us to slowly decipher the pathophysiological relevance of this mitochondrial entity [4-6]. Although most of the MPT pore regulatory aspects were envisaged a few years after its discovery, it has taken decades and different approaches to reveal some of its structural aspects (see below).Pharmacological inhibition of the MPT pore with Adenine Nucleotide Translocator (ANT) and Cyclophilin D (CypD) ligands led to the long lasting and widespread notion that the MPT pore was formed by the ANT acting as a channel component and CypD as a regulatory factor. In this model, ADP, ATP and the ANT ligand bonkrekate would inhibit pore opening by directly binding to ANT whereas CypD inhibition with Cyclosporin A would inhibit a conformational change mediated by CypD on a proline due to its peptidyl-prolylcis-trans isomerase activity. Although this hypothesis was widely accepted and a plethora of evidence indeed pointed towards a central role of this mitochondrial translocator as a MPT pore constituent [5], experiments with mouse lacking the two major isoforms of ANT demonstrated its dispensability for MPT to ensue [7]. It is important to mention that the pore detected in these knockout animals was insensitive to ANT ligands and threefold more resistant to Ca2+, whereas CsA further inhibited its opening. On the other hand, mitochondria from CypD knockout mice were also resistant to Ca2+ (twofold), oxidative stress and desensitized to CsA [8-10]. Overall, these results strongly suggested that ANT and CypD were MPT pore regulatory factors.

Citation: Gutierrez-Aguilar M, Baines CP (2014) Mitochondrial ATP Synthase: Is the Molecular Engine of Life also an Efficient Death Machine?. Bioenergetics 3:e119. doi: 10.4172/2167-7662.1000e119

 
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