Established Principles and Emerging Concepts on the Interplay between Mitochondrial Physiology and S-(De)nitrosylation: Implications in Cancer and Neurodegeneration
Figure 4
Effects of NO on mitochondrial dynamics and mitophagy. Mitochondrial network is dynamically regulated by fusion/fission events. Fusion between adjacent mitochondria (on the right) relies on the activity of Mfn1, Mfn2, and Opa1 which act in concert to mediate the merge of the outer and inner membrane, respectively. Although the presence of S-nitrosylated Opa1 has been observed, no role for this modification has been still proposed. Conversely, Drp1 has been reported to undergo several posttranslational modifications which modulate its fission activity (on the left), such as phosphorylation (not shown in the figure) and S-nitrosylation. Once S-nitrosylated and driven by mitochondria depolarization (low ), Drp1 is recruited onto the outer mitochondrial membrane by means of the recognition of its anchor protein Fis1. There, SNO-Drp1 multimerizes and acts to tighten the target organelle in order to share the depolarized portion from the healthy part. Although there is the possibility for a fragmented mitochondrion to refuse by means of Mfns and Opa1-mediated activity, frequently a depolarized organelle is targeted for its selective removal by autophagy (mitophagy). PINK1, which is normally degraded by PARL, is stabilized and recruits Parkin onto the outer membrane of an impaired mitochondrion and, in turn, catalyzes the covalent addition of an ubiquitin (Ub) tail to several protein targets. Ubiquitinated Mfns are extracted from the membrane and degraded via the proteasome in order to inhibit refusion processes, whereas ubiquitination of VDAC1 is required for mitochondria to be recognized and embedded by p62/LC3-bound autophagosome and ultimately degraded by lysosome-contained acid hydrolases. Parkin can undergo S-nitrosylation-mediated inactivation of its ubiquitin E3 ligase activity, thereby inhibiting mitophagy and disbalancing fusion/fission dynamics.
