Abstract
Aging is associated with the accumulation of various deleterious changes in cells. According to the free radical and mitochondrial theory of aging, mitochondria initiate most of the deleterious changes in aging and govern life span. The failure of mitochondrial reduction-oxidation (redox) homeostasis and the formation of excessive free radicals are tightly linked to dysregulation in the Renin Angiotensin System (RAS). A main rate-controlling step in RAS is renin, an enzyme that hydrolyzes angiotensinogen to generate angiotensin I. Angiotensin I is further converted to Angiotensin II (Ang II) by angiotensin-converting enzyme (ACE). Ang II binds with equal affinity to two main angiotensin receptors—type 1 (AT1R) and type 2 (AT2R). The binding of Ang II to AT1R activates NADPH oxidase, which leads to increased generation of cytoplasmic reactive oxygen species (ROS). This Ang II-AT1R–NADPH-ROS signal triggers the opening of mitochondrial KATP channels and mitochondrial ROS production in a positive feedback loop. Furthermore, RAS has been implicated in the decrease of many of ROS scavenging enzymes, thereby leading to detrimental levels of free radicals in the cell. AT2R is less understood, but evidence supports an anti-oxidative and mitochondria-protective function for AT2R. The overlap between age related changes in RAS and mitochondria, and the consequences of this overlap on age-related diseases are quite complex. RAS dysregulation has been implicated in many pathological conditions due to its contribution to mitochondrial dysfunction. Decreased age-related, renal and cardiac mitochondrial dysfunction was seen in patients treated with angiotensin receptor blockers. The aim of this review is to: (a) report the most recent information elucidating the role of RAS in mitochondrial redox hemostasis and (b) discuss the effect of age-related activation of RAS on generation of free radicals.
Highlights
reactive oxygen species (ROS) GENERATION AND TRANSPORTROS are generated from various sources including NADPH oxidase (NOX2 and NOX4), uncoupled nitric oxide synthase (NOS), xanthine oxidase (XO), and mitochondria
MITOCHONDRIA AND ANGIOTENSIN SYSTEM: OVERVIEW It is well accepted that mitochondria are the major source of ATP, which is the fuel for many cellular processes
Evidence supporting an important role for Renin Angiotensin System (RAS) in mitochondrial function/dysfunction comes from many sources (Cook and Re, 2012; Ellis et al, 2012; Garcia et al, 2012; Gwathmey et al, 2012; Li et al, 2012; Singh et al, 2012; Wangler et al, 2012; Yu et al, 2012; Zaobornyj and Ghafourifar, 2012; Ferder et al, 2013; Sovari et al, 2013)
Summary
ROS are generated from various sources including NADPH oxidase (NOX2 and NOX4), uncoupled nitric oxide synthase (NOS), xanthine oxidase (XO), and mitochondria. Reduced coenzyme Q (QH2) diffuses to the inner side of mitochondrial membrane to the Qo site, where it transfers one electron to cytochrome c bound to complex III. Excessive ROS production due to Ang II can impair complex I and III activities, increasing electron leakage (Prathapan et al, 2014). Cytochrome b558 regulates the enzymatic activity of NADPH oxidase by transferring one electron to molecular oxygen, which gets reduced to O·2− (Bayraktutan et al, 1998). NOX4 is a source of H2O2in a variety of vascular cells including fibroblasts, endothelium, and smooth muscles This constant generation of H2O2 might be essential to maintaining cell functions in angiogenesis during wound healing (Dikalov et al, 2008). Though some studies show NOX4 playing a role in pathophysiology, the great majority shows that the physiological role of this enzyme is more relevant
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