The Dual Function of Reactive Oxygen/Nitrogen Species in Bioenergetics and Cell Death: The Role of ATP Synthase

Abstract

Reactive oxygen species (ROS) and reactive nitrogen species (RNS) targeting mitochondria are major causative factors in disease pathogenesis. The mitochondrial permeability transition pore (PTP) is a mega-channel modulated by calcium and ROS/RNS modifications and it has been described to play a crucial role in many pathophysiological events since prolonged channel opening causes cell death. The recent identification that dimers of ATP synthase form the PTP and the fact that posttranslational modifications caused by ROS/RNS also affect cellular bioenergetics through the modulation of ATP synthase catalysis reveal a dual function of these modifications in the cells. Here, we describe mitochondria as a major site of production and as a target of ROS/RNS and discuss the pathophysiological conditions in which oxidative and nitrosative modifications modulate the catalytic and pore-forming activities of ATP synthase.

Figure 1

Schematic representation of ATP synthase and PTP. Dimers of ATP synthase that form the PTP are shown from a lateral view. F₁ catalytic part of ATP synthase is from bovine crystal structure (PDB 2WSS, modified by PyMOL 1.3 software) and is composed of α, β, and γ subunits in red, yellow, and blue, respectively, as indicated in the left part of the dimer. F_O and lateral stalk subunits are also indicated in the left part in pink, light-blue, and green regions. On the right part of the dimer arrows indicate the critical cysteine residues modified by ROS/RNS in pathophysiological conditions. Cysteines are highlighted in cyan.

Figure 2

Lateral view of a section of the catalytic core of ATP synthase (PDB 2WSS, modified by PyMOL 1.3 software) composed of α, β, and γ subunits in red, yellow, and blue, respectively. Critical cysteine residues subjected to posttranslational modifications are highlighted in cyan. Distances between α-Cys251 and α-Cys201 or α-Cys251 and γ-Cys78 are indicated by black dashed lines and are 12 Å or 61.5 Å, respectively.

Figure 3

Lateral view of a section of the catalytic core of ATP synthase (PDB 2WSS, modified by PyMOL 1.3 software) composed of α, β, and γ subunits in red, yellow, and blue, respectively. Critical β-Tyr345 and β-Tyr368 residues that might be modified by RNS are highlighted in gray.