Modulation of Mitochondrial Dynamics by the Angiotensin System in Dopaminergic Neurons and Microglia

Renin-angiotensin system (RAS) dysfunctions have been associated to life-spam, and aging-related diseases, including neurodegenerative diseases, such as Parkinson's disease, and the neuroinflammatory associated processes. Mitochondrial dysfunctions play a major role in aging-related diseases, including dopaminergic neurodegeneration and neuroinflammation. However, the mechanisms of RAS/mitochondria interactions remain to be clarified. In the present work, we studied the role of major RAS components in the mitochondrial dynamics in dopaminergic neurons and microglia using in vitro and in vivo models. In dopaminergic neurons, we observed that activation of the RAS pro-oxidative/pro-inflammatory axis (Angiotensin II/Angiotensin type-1 receptor, AT1/NADPH oxidase complex) produces a dysregulation of mitochondrial dynamics towards mitochondrial fission, via Drp1 phosphorylation at Ser616 and translocation to mitochondria. However, activation of the RAS antioxidative/anti-inflammatory axis, using Angiotensin 1-7, counteracts this effect. RAS components also modulated the microglial inflammatory response through mitochondrial dynamic changes. After interferon-γ-induced activation of human microglial cells, we observed increased mitochondrial fission and superoxide production that was inhibited by Angiotensin 1-7 treatment. Angiotensin 1-7 also inhibited mitochondrial metabolic changes induced by pro-inflammatory microglial activation. The role of RAS in mitochondrial dynamic changes was confirmed in vivo using the LPS-induced inflammation model in wild-type, AT1-KO, and AT2-KO mice. The effect of Angiotensin 1-7 is mediated by IL-10, specifically by decreasing the post-transcriptional phosphorylated Drp1 form, and translocation of STAT3 to mitochondria. Angiotensin 1-7, acting on mitochondrial Angiotensin 1-7 receptors (Mas/Mas related receptors), increased the phosphorylated form of STAT3 at Ser727, which is mediated by mitochondrial PKA activation. In conclusion, the present findings show the role of RAS components in modulation of mitochondrial dynamics and mitochondrial function, revealing the associated signaling pathways. The results lead to better understanding of the effects of RAS dysfunction in aging-related diseases, and particularly dopaminergic degeneration and neuroinflammation in Parkinson's disease.