Mitochondria-Targeting Antioxidant Provides Cardioprotection through Regulation of Cytosolic and Mitochondrial Zn2+ Levels with Re-Distribution of Zn2+-Transporters in Aged Rat Cardiomyocytes

Abstract

Aging is an important risk factor for cardiac dysfunction. Heart during aging exhibits a depressed mechanical activity, at least, through mitochondria-originated increases in ROS. Previously, we also have shown a close relationship between increased ROS and cellular intracellular free Zn2+ ([Zn2+]i) in cardiomyocytes under pathological conditions as well as the contribution of some re-expressed levels of Zn2+-transporters for redistribution of [Zn2+]i among suborganelles. Therefore, we first examined the cellular (total) [Zn2+] and then determined the protein expression levels of Zn2+-transporters in freshly isolated ventricular cardiomyocytes from 24-month rat heart compared to those of 6-month rats. The [Zn2+]i in the aged-cardiomyocytes was increased, at most, due to increased ZIP7 and ZnT8 with decreased levels of ZIP8 and ZnT7. To examine redistribution of the cellular [Zn2+]i among suborganelles, such as Sarco/endoplasmic reticulum, S(E)R, and mitochondria ([Zn2+]SER and [Zn2+]Mit), a cell model (with galactose) to mimic the aged-cell in rat ventricular cell line H9c2 was used and demonstrated that there were significant increases in [Zn2+]Mit with decreases in [Zn2+]SER. In addition, the re-distribution of these Zn2+-transporters were markedly changed in mitochondria (increases in ZnT7 and ZnT8 with no changes in ZIP7 and ZIP8) and S(E)R (increase in ZIP7 and decrease in ZnT7 with no changes in both ZIP8 and ZnT8) both of them isolated from freshly isolated ventricular cardiomyocytes from aged-rats. Furthermore, we demonstrated that cellular levels of ROS, both total and mitochondrial lysine acetylation (K-Acetylation), and protein-thiol oxidation were significantly high in aged-cardiomyocytes from 24-month old rats. Using a mitochondrial-targeting antioxidant, MitoTEMPO (1 µM, 5-h incubation), we provided an important data associated with the role of mitochondrial-ROS production in the [Zn2+]i-dyshomeostasis of the ventricular cardiomyocytes from 24-month old rats. Overall, our present data, for the first time, demonstrated that a direct mitochondria-targeting antioxidant treatment can be a new therapeutic strategy during aging in the heart through a well-controlled [Zn2+] distribution among cytosol and suborganelles with altered expression levels of the Zn2+-transporters.

Mitochondria-targeted antioxidant protects against irradiation-induced salivary gland hypofunction

“…It has been used to protect against ROS-associated disorders, such as oxalate induced kidney injury as well as urolithiasis, heart failure, and sudden cardiac death 17 , 18 . It is also reported to improve cardiovascular performance in older patients 19 . MitoTEMPO pretreatment enhanced the mitochondrial antioxidant capacity of adipose-derived stem cells 20 .…”

Reduction of elevated proton leak rejuvenates mitochondria in the aged cardiomyocyte

“…However, the resulting enhancement in diastolic function is likely to require downstream changes, as the functional benefit took up to 8 weeks to reach full effect, and required post-translational modifications of contractile protein elements ( Chiao et al, 2020 ). It is increasingly recognized that mitochondrial function, including redox status and energetics, has far-reaching effects, including epigenetic alterations and post-translational modifications ( Olgar et al, 2019 ).…”

Reduction of Elevated Proton Leak Rejuvenates Mitochondria in the Aged Cardiomyocyte

“…However, the resulting enhancement in diastolic function is likely to require downstream changes, as the functional benefit took up to 8 weeks to reach full effect, and required post-translational modifications of contractile protein elements (Chiao et al, 2020). It is increasingly recognized that mitochondrial function, including redox status and energetics, has far-reaching effects, including epigenetic alterations and post-translational modifications (Olgar et al, 2019). ANT1 appears to mediate the pathological mitochondrial proton leak in the aged mouse heart.…”