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.
Highlights
Mitochondrial reactive oxygen species (ROS) production is being studied more than ever due its roles in physiology and disease
Mitochondria are central to energy metabolism, generating ATP from the oxidation of nutrients and the flow of electrons and protons
The emergence of more sensitive methods of measurement has shown that redox buffering networks play a central role in intra- and extra-mitochondrial signaling, linking shifts in nutrient metabolism and flux through important redox mediating metabolites to the modulation of proteins
Summary
Mitochondrial reactive oxygen species (ROS) production is being studied more than ever due its roles in physiology and disease. A myriad of factors converge on mitochondria to influence H2O2 formation and can act as key determinants for whether or not H2O2 will be utilized in signaling or cell death This includes mitochondrial redox and bioenergetics poise, formation of supercomplexes or enzyme assembly, covalent modification, and factors that control the entry and exit of electron from sites of ROS production. Despite our widening knowledge on the importance of redox signals in modulating routine cellular functions, the molecular details surrounding how redox changes are communicated to proteins still remains enthusiastically debated This may be due to the fact that cysteines can undergo a range of redox modifications which includes sulfenylation (SUF; formation of SOH by direct SH oxidation) and protein S-glutathionylation (PGlu) [11]. Shelton et al went on to describe how PGlu reactions fulfill all these criteria and likely serve as important PTM required to modulate protein function in response to changes in redox environment. We provide an updated view on these concepts and argue that PGlu reactions form the link between mitochondrial oxidative metabolism and modulation of protein function by redox signaling
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