S-Glutathionylation and S-Nitrosylation in Mitochondria: Focus on Homeostasis and Neurodegenerative Diseases

Abstract

Redox post-translational modifications are derived from fluctuations in the redox potential and modulate protein function, localization, activity and structure. Amongst the oxidative reversible modifications, the S-glutathionylation of proteins was the first to be characterized as a post-translational modification, which primarily protects proteins from irreversible oxidation. However, a growing body of evidence suggests that S-glutathionylation plays a key role in core cell processes, particularly in mitochondria, which are the main source of reactive oxygen species. S-nitrosylation, another post-translational modification, was identified >150 years ago, but it was re-introduced as a prototype cell-signaling mechanism only recently, one that tightly regulates core processes within the cell’s sub-compartments, especially in mitochondria. S-glutathionylation and S-nitrosylation are modulated by fluctuations in reactive oxygen and nitrogen species and, in turn, orchestrate mitochondrial bioenergetics machinery, morphology, nutrients metabolism and apoptosis. In many neurodegenerative disorders, mitochondria dysfunction and oxidative/nitrosative stresses trigger or exacerbate their pathologies. Despite the substantial amount of research for most of these disorders, there are no successful treatments, while antioxidant supplementation failed in the majority of clinical trials. Herein, we discuss how S-glutathionylation and S-nitrosylation interfere in mitochondrial homeostasis and how the deregulation of these modifications is associated with Alzheimer’s, Parkinson’s, amyotrophic lateral sclerosis and Friedreich’s ataxia.

Redox Regulation of Mitochondrial Potassium Channels Activity

“…The S-glutathionylation is an oxidative and reversible modification that involves the attachment of glutathione to the cysteine residue of the protein of interest [88]. This process is abundant in mitochondria.…”

Mitochondria Need Their Sleep: Redox, Bioenergetics, and Temperature Regulation of Circadian Rhythms and the Role of Cysteine-Mediated Redox Signaling, Uncoupling Proteins, and Substrate Cycles

“…This nitrosative stress can induce chronic inflammation and apoptosis, contributing to sleep–wake disturbance [ 42 , 176 ]. For example, excess amyloid-β peptide in the brain of Alzheimer’s disease patients (who are prone to sleep disorders) promotes high levels of • NO that lead to S-nitrosylation of the mitochondrial fission protein DRP1, causing mitochondrial fission/fragmentation, mitophagy and neuronal damage [ 44 , 85 , 177 , 178 ]. Therefore, reports on metabolic syndrome and neurodegenerative diseases indicate disturbed redox-regulated rhythmicity, one of the redox–bioenergetics–temperature regulatory components of sleep–wake phases.…”

“…Gut microbiota dysbiosis can lead to damage-associated molecular patterns (DAMPs), inflammasome activation and excessive • NO production that is immunosuppressive. • NO-mediated S-nitrosylation of mitochondrial CI-V and DRP1 can lead to mitophagy ( Section 5.4.2 ) [ 178 ]. The risk of developing metabolic syndrome and cancer is associated with night-shift workers such as nurses, likely due to circadian rhythm disruption [ 192 ].…”

Redox Imbalance in Neurological Disorders in Adults and Children

“…Particularly, these molecules can cause post-translational modification (PTMs) in proteins, leading to structural changes that lead to protein destabilization and aggregation. An example of this is represented by both S-nitrosylation and S-glutathionylation in reactive thiols by the protein disulfide isomerase [ 76 ]. S-nitrosylation consists of the addition of a nitric oxide to the thiol group of a cysteine, while S-glutathionylation is referred to a glutathione group (GSH) added at the thiol group of a cysteine [ 77 ].…”