When S-nitrosylation gets to mitochondria: from signaling to age-related diseases

Significance: Cysteines have an essential role in redox signaling, transforming an oxidant signal into a biological response. Among reversible cysteine post-translational modifications, S-nitrosylation acts as a redox-switch in several pathophysiological states, such as ischemia/reperfusion, synaptic transmission, cancer, and muscular dysfunctions. Recent Advances: Growing pieces of in vitro and in vivo evidence argue for S-nitrosylation being deeply involved in development and aging, and playing a role in the onset of different pathological states. New findings suggest it being an enzymatically regulated cellular process, with deep impact on mitochondrial structure and function, and in cellular metabolism. In light of this, the recent discovery of the denitrosylase S-nitrosoCoA (coenzyme A) reductase takes on even greater importance and opens new perspectives on S-nitrosylation as a general mechanism of cellular homeostasis. Critical Issues: Based on these recent findings, we aim at summarizing and elaborating on the established and emerging crucial roles of S-nitrosylation in mitochondrial metabolism and mitophagy, and provide an overview of the pathophysiological effects induced by its deregulation. Future Directions: The identification of new S-nitrosylation targets, and the comprehension of the mechanisms through which S-nitrosylation modulates specific classes of proteins, that is, those impinging on diverse mitochondrial functions, may help to better understand the pathophysiology of aging, and propose lines of intervention to slow down or extend the onset of aging-related diseases.