Protein S-glutathionlyation links energy metabolism to redox signaling in mitochondria

Abstract

At its core mitochondrial function relies on redox reactions. Electrons stripped from nutrients are used to form NADH and NADPH, electron carriers that are similar in structure but support different functions. NADH supports ATP production but also generates reactive oxygen species (ROS), superoxide (O2·-) and hydrogen peroxide (H2O2). NADH-driven ROS production is counterbalanced by NADPH which maintains antioxidants in an active state. Mitochondria rely on a redox buffering network composed of reduced glutathione (GSH) and peroxiredoxins (Prx) to quench ROS generated by nutrient metabolism. As H2O2 is quenched, NADPH is expended to reactivate antioxidant networks and reset the redox environment. Thus, the mitochondrial redox environment is in a constant state of flux reflecting changes in nutrient and ROS metabolism. Changes in redox environment can modulate protein function through oxidation of protein cysteine thiols. Typically cysteine oxidation is considered to be mediated by H2O2 which oxidizes protein thiols (SH) forming sulfenic acid (SOH). However, problems begin to emerge when one critically evaluates the regulatory function of SOH. Indeed SOH formation is slow, non-specific, and once formed SOH reacts rapidly with a variety of molecules. By contrast, protein S-glutathionylation (PGlu) reactions involve the conjugation and removal of glutathione moieties from modifiable cysteine residues. PGlu reactions are driven by fluctuations in the availability of GSH and oxidized glutathione (GSSG) and thus should be exquisitely sensitive to changes ROS flux due to shifts in the glutathione pool in response to varying H2O2 availability. Here, we propose that energy metabolism-linked redox signals originating from mitochondria are mediated indirectly by H2O2 through the GSH redox buffering network in and outside mitochondria. This proposal is based on several observations that have shown that unlike other redox modifications PGlu reactions fulfill the requisite criteria to serve as an effective posttranslational modification that controls protein function.

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“…Glycated hemoglobin (HbA1c) was measured using the in2it A1C system (Bio-Rad, Hercules, CA). The glutathione (GSH) and oxidized glutathione (GSSG) levels in the kidney were determined using commercial assay kits (Nanjing Jiancheng Company, Shanghai, China) [48]. …”

A radical shift in perspective: mitochondria as regulators of reactive oxygen species

“…However, there are indications that proteomic and allosteric regulation of mitochondrial substrate oxidation may form part of the adaptation to torpor (reviewed in Staples, 2014Staples, , 2016. Posttranslational modifications such as glutathionylation may decrease enzymatic flux and, at the same time, either decrease or increase ROS production as seen with complex I and II, respectively (reviewed in Mailloux and Treberg, 2016). Therefore, the declining substrate oxidation capacity may not necessarily lead to declining H 2 O 2 production.…”

“…For example, macromolecular supercomplexes have been implicated in altering the production of superoxide (Genova and Lenaz, 2014), whichalongside modifications such as glutathionylation -could influence mitochondrial H 2 O 2 production (Mailloux and Treberg, 2016 …”

“…Recently, it has also been proposed that energy metabolism-linked mitochondrial redox signals may be indirectly mediated via the influence of H 2 O 2 on glutathione (GSH) status -the ratio of GSH to its oxidized form, GSSG, is modulated in response to H 2 O 2 concentration. This influence on the GSH pool alters the activity of proteins both inside and outside the mitochondrion through Sglutathionylation -a reversible post-translational modification compatible with a signalling role (Mailloux and Treberg, 2016). Therefore, ROS (or H 2 O 2 at least) play roles in cell function that may require further processing by specific enzymes.…”

Caracaterização cinética da redução das 1-Cys Peroxirredoxinas por ascorbato

“…O grande sucesso evolutivo dos eucariontes se deve em parte ao desenvolvimento das cadeias respiratórias mitocondriais (Mailloux, 2016). A mitocôndria produz 80% ou mais do ATP necessário pelas células animais (Halliwell, 2013 (Turrens, 2007;Halliwell, 2007).…”