Lipid-induced NOX2 activation inhibits autophagic flux by impairing lysosomal enzyme activity.

Autophagy is a catabolic process involved in maintaining energy and organelle homeostasis. The relationship between obesity and the regulation of autophagy is cell type specific. Despite adverse consequences of obesity on cardiac structure and function, the contribution of altered cardiac autophagy in response to fatty acid overload is incompletely understood. Here, we report the suppression of autophagosome clearance and the activation of NADPH oxidase (Nox)2 in both high fat-fed murine hearts and palmitate-treated H9C2 cardiomyocytes (CMs). Defective autophagosome clearance is secondary to superoxide-dependent impairment of lysosomal acidification and enzyme activity in palmitate-treated CMs. Inhibition of Nox2 prevented superoxide overproduction, restored lysosome acidification and enzyme activity, and reduced autophagosome accumulation in palmitate-treated CMs. Palmitate-induced Nox2 activation was dependent on the activation of classical protein kinase Cs (PKCs), specifically PKCßII. These findings reveal a novel mechanism linking lipotoxicity with a PKCß-Nox2-mediated impairment in pH-dependent lysosomal enzyme activity that diminishes autophagic turnover in CMs.

Redox regulation of mitochondrial ATP synthase.

Reversible cysteine oxidative post-translational modifications (Ox-PTMs) represent an important mechanism to regulate protein structure and function. In mitochondria, redox reactions can modulate components of the electron transport chain (ETC), the F(1)F(0)-ATP synthase complex, and other matrix proteins/enzymes. Emerging evidence has linked Ox-PTMs to mitochondrial dysfunction and heart failure, highlighting some potential therapeutic avenues. Ox-PTMs can modify a variety of amino acid residues, including cysteine, and have the potential to modulate the function of a large number of proteins. Among this group, there is a selected subset of amino acid residues that can function as redox switches. These unique sites are proposed to monitor the cell's oxidative balance through their response to the various Ox-PTMs. In this review, the role of Ox-PTMs in the regulation of the F(1)F(0)-ATP synthase complex is discussed in the context of heart failure and its possible clinical treatment.

Cysteine oxidative posttranslational modifications: emerging regulation in the cardiovascular system.

In the cardiovascular system, changes in oxidative balance can affect many aspects of cellular physiology through redox-signaling. Depending on the magnitude, fluctuations in the cell's production of reactive oxygen and nitrogen species can regulate normal metabolic processes, activate protective mechanisms, or be cytotoxic. Reactive oxygen and nitrogen species can have many effects including the posttranslational modification of proteins at critical cysteine thiols. A subset can act as redox-switches, which elicit functional effects in response to changes in oxidative state. Although the general concepts of redox-signaling have been established, the identity and function of many regulatory switches remains unclear. Characterizing the effects of individual modifications is the key to understand how the cell interprets oxidative signals under physiological and pathological conditions. Here, we review the various cysteine oxidative posttranslational modifications and their ability to function as redox-switches that regulate the cell's response to oxidative stimuli. In addition, we discuss how these modifications have the potential to influence other posttranslational modifications' signaling pathways though cross-talk. Finally, we review the increasing number of tools being developed to identify and quantify the various cysteine oxidative posttranslational modifications and how this will advance our understanding of redox-regulation.