The impact of age-related dysregulation of the angiotensin system on mitochondrial redox balance

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.

Effects of aging on the male reproductive system

“…mtDNA is more vulnerable to ROS generated by electron transport chain (ETC) than nuclear DNA since mtDNA is not packed with histone proteins and there is no DNA repair mechanism in the mitochondria [63]. Consequently, mutations accumulate in mtDNA and lead to mitochondrial dysfunction, which in turn leads to an increase in ROS production and oxidative damage and decrease in ATP/ADP ratio [64][65][66].…”

“…Increased ROS production, decreased ATP production, and apoptosis are three features of dysfunctional mitochondria disrupted by aging. Finally, all these alterations lead to mitochondrial aberrations and activation of cellular death pathways [63,67].…”

Genetics of aging and longevity

“…Несмотря на то что ренин-ангиотензиновая система -известный регулятор артериального давления, связанный с развитием гепертензии и патофизиологией заболеваний сердца, сосудов и почек, основное действие системы на процессы старения связано с ее влиянием на функцио-нирование митохондрий и клеточное дыхание (Vajapey et al, 2014). Центральным продуктом этой системы является ангиотензин II.…”

“…Он участвует в регуляции иммунного от-вета, воспалении, росте и делении клеток через рецепторы АТ1 и АТ2 (Benigni et al, 2009). При взаимодействии ангиотензина II и рецептора AT1 происходят активация NAD(P)H оксидазы и высвобождение эндотелиальной синтазы окиси азота (eNOS), которые повышают вы-работку свободных радикалов митохондриями (Vajapey et al, 2014).…”

Macromolecular Degradation Systems and Cardiovascular Aging

“…Moreover, aging and senescence at a molecular level result in the accumulation of reactive oxygen species (ROS) generated from dysfunctional mitochondria that leads to DNA damage and increases oxidized proteins. 6 Telomere attrition is an another well-known mechanism by which cells progress toward senescence.…”