*7.3. Mitophagy, ROS, and OS in Kidney Diseases*

The dysregulation of mitophagy has been previously reported in renal diseases [177,178]. At biological levels, ROS are involved in mitophagy regulation. Upon mitochondrial damage, depolarization, or mitochondrial OS, mitophagy is triggered. ROS promote the recruitment of phosphatase and tensin homolog (PTEN)-induced putative kinase 1 (Pink1) in the outer mitochondrial membrane (OMM) [179]. The latter leads to the recruitment and phosphorylation of parkin to begin mitophagy [180]. In the AKI models, Pink1 and parkin are upregulated after damage [44,109,164]. The upregulation of these proteins is related to ROS and mtROS increase. Furthermore, in CKD models, both proteins are augmented [120,167,169]. For instance, in the 5/6 nephrectomy model, levels of Pink1, parkin, microtubule-associated protein 1A/1B-light chain 3 phosphatidylethanolamine conjugate (LC3-II), and sequestosome (p62) increase in a temporal course way [120]. However, in both cases, mitophagy has been reported impaired. Although the levels of LC3-II increase, the accumulation of p62 is evident, suggesting dysfunctional mitophagy [120]. p62 accumulation is considered a marker of mitophagy malfunction. In kidney injury, mitophagosome

accumulation is evident by increasing Pink1, parkin, and p62 [181]. Together, these data suggest that ROS induce Pink1 and parkin translocation to mitochondria, but the high ROS levels exacerbate mitophagy machinery, damaging it. Mitophagy damage is supported, because antioxidants can increase mitophagy flux in AKI and CKD models [44,181].

On the other hand, excessive autophagy has been described in models of UUO, which triggers endothelial dysfunction [182]. Consistent with this, Chen et al. [183] found that treatment with NaHS, an exogenous H2S donor, in UUO mice decreases the expression levels of LC3-II/I, beclin-1, and AMPK proteins. On the contrary, the p62, CBS, and CSE levels increase compared to in the sham groups. Therefore, H2S is considered a protective mechanism, because it moderates OS that promotes the dysregulation of autophagy.
