Mitochondrial Peroxiredoxins and Monoamine Oxidase-A: Dynamic Regulators of ROS Signaling in Cardioprotection

Abstract

An excessive increase in reactive oxygen species (ROS) levels is one of the main causes of mitochondrial dysfunction. However, when ROS levels are maintained in balance with antioxidant mechanisms, ROS fulfill the role of signaling molecules and modulate various physiological processes. Recent advances in mitochondrial bioenergetics research have revealed a significant interplay between mitochondrial peroxiredoxins (PRDXs) and monoamine oxidase-A (MAO-A) in regulating ROS levels. Both proteins are associated with hydrogen peroxide (H2O2), MAO-A as a producer and PRDXs as the primary antioxidant scavengers of H2O2. This review focuses on the currently available knowledge on the function of these proteins and their interaction, highlighting their importance in regulating oxidative damage, apoptosis, and metabolic adaptation in the heart. PRDXs not only scavenge excess H2O2, but also act as regulatory proteins, play an active role in redox signaling, and maintain mitochondrial membrane integrity. Overexpression of MAO-A is associated with increased oxidative damage, leading to mitochondrial dysfunction and subsequent progression of cardiovascular diseases (CVD), including ischemia/reperfusion injury and heart failure. Considering the central role of oxidative damage in the pathogenesis of many CVD, targeting PRDXs activation and MAO-A inhibition may offer new therapeutic strategies aimed at improving cardiac function under conditions of pathological load related to oxidative damage. Keywords: Mitochondria, Peroxiredoxin, Monoamine oxidase-A, Reactive oxygen species, Cardioprotective signaling.

Fig. 1

The interplay between MAO-A, a producer of H₂O₂, and mitochondrial PRDXs, which act as antioxidant scavengers, is crucial in the regulation of ROS levels and in the overall maintenance of the heart’s energetic balance. Increased activation of MAO-A and the generation of H₂O₂ lead to cardiolipin peroxidation and accumulation of 4-HNE inside the mitochondria. PRDXs scavenge mitochondrial H₂O₂ and help preserve mitochondrial homeostasis. When ROS levels are balanced with antioxidant mechanisms, ROS contribute to the regulation of cellular signaling pathways. However, a disbalance between antioxidant defenses and ROS levels results in oxidative damage and ultimately, mitochondrial dysfunction. Elevated MAO-A expression also promotes mitochondrial fission. In contrast, PRDX3 activation supports mitochondrial fusion, preserving both mitochondrial function and energy production. In the model of experimental DM, increased MAO-A expression can result in oxidative damage. DCA helps normalize ROS levels by reducing their excessive production due to MAO-A and enhancing PRDX3 activation under experimental DM conditions. For more details, see the text. CI-CV – respiratory chain complexes I–V; DCA – dichloroacetate; DM – diabetes mellitus; H₂O₂ – hydrogen peroxide; MAO-A – monoamine oxidase-A; MnSOD – manganese-dependent superoxide dismutase; NE – norepinephrine; PRDXs – peroxiredoxins; PRDX3 – peroxiredoxin-3; PRDX5 – peroxiredoxin-5; ROS – reactive oxygen species; 4-HNE – 4-Hydroxynonenal.