A Quantitative Tissue-Specific Landscape of Protein Redox Regulation during Aging

Abstract

Highlights d A comprehensive and quantitative map of the mouse cysteine redox proteome in vivo d Redox networks are highly tissue selective and underlie tissue-specific biology d Cysteine thiol redox sensitivity is encoded by local electrostatic gating d Identification of redox-modified protein disease networks that remodel in aged mice

Immunological Techniques to Assess Protein Thiol Redox State: Opportunities, Challenges and Solutions

“…Unexpectedly, reciprocal reduced and reversibly oxidized catalyst-free Click PEGylation workflows revealed the ATP synthase is substantially (~65%) oxidized before and after fertilization (Figure 4) [116]. To place our findings in context, the median oxidation of thiols in the mammalian proteome is~12% [41] and the Oximouse dataset (see [91]) reveals C244 and C294 are~20% reversibly oxidized. Substantial reversible thiol oxidation is consistent with a distinct subset of thiols being persistently oxidized (≥20%) and tissue specific redox signatures [91].…”

“…Redox proteomic affords hypothesis-free, systematic, and quantitative global thiol proteome profiling [90]. For example, state-of-the-art cysteine reactive phosphate tag technology coupled to tandem mass tag multiplexing identified and quantified 171,000 thiols modification events in mammalian tissues [91] (i.e.,~80% of the total thiol proteome was assessed). Low-throughout immunological techniques (e.g.,~2 thiols per experiment or 0.0009% of the human thiol proteome) may seem redundant when one can quantify the redox state of thousands of protein thiols in parallel in a single experiment.…”

“…For example, redox proteomics studies often fail to detect hydrophobic protein thiols [98]. Even state-of-the-art cysteine reactive phosphate tag technology was unable to detect two hydrophobic complex I subunits (i.e., ND6 and ND4L [91,99]). Their hydrophobicity makes proteomics, yet alone redox proteomics, challenging [100].…”

Effects of Oxidative Stress on Protein Translation: Implications for Cardiovascular Diseases

“…Several excellent reviews describe genetic variants of TTN and their effects on the etiology and progression of cardiomyopathies [119,120]. In addition, TNN was recently (2020) found to represent a heart-specific protein from the "cysteine redox network" in the Oximouse model [121]. It was demonstrated that TNN is prone to significant modifications via thiol oxidation during aging, leading to cardiomyopathies (for details see [121]).…”

“…In addition, TNN was recently (2020) found to represent a heart-specific protein from the "cysteine redox network" in the Oximouse model [121]. It was demonstrated that TNN is prone to significant modifications via thiol oxidation during aging, leading to cardiomyopathies (for details see [121]). To understand whether TTN expression can be controlled by uORFs, Cadar and co-authors investigated the 5 UTR of TTN and identified two uORFs that suppressed TTN translation in non-stressed cardiac HL-1 cell line and primary neonatal rat ventricular myocytes [122].…”