Dynamic Mitochondrial Proteome Under Polyamines Treatment in Cardiac Aging

Abstract

Age-related alteration of mitochondria causes impaired cardiac function, along with cellular and molecular changes. Polyamines can extend the life span in mice. However, whether polyamines can affect the dynamic mitochondrial proteome, thereby preventing age-related changes in cardiac function and cardiac aging, remains unclear. In this study, we found that spermine (Spm) and spermidine (Spd) injection for 6 weeks could prevent 24-month-old rats heart dysfunction, improve mitochondrial function, and downregulate apoptosis. Using iTRAQ tools, we identify 75 mitochondrial proteins of statistically significant alteration in aging hearts, which mainly participate in important mitochondrial physiological activity, such as metabolism, translation, transport, apoptosis, and oxidative phosphorylation. Moreover, four proteins of differential expression, pyruvate dehydrogenase kinase (PDK4), trifunctional enzyme subunit alpha (HADHA), nicotinamide nucleotide transhydrogenase (NNT), and Annexin6, which were significantly associated with heart aging, were validated by Western blotting. In vitro, we further demonstrated polyamines could retard cardiomyocytes aging through downregulating the expression of PDK4 and thereby inhibiting cell apoptosis. In summary, the distinct mitochondrial proteins identified in this study suggested some candidates involved in the anti-aging of the heart after polyamines treatment, and PDK4 may provide molecular clues for polyamines to inhibit apoptosis and thus retard aging-induced cardiac dysfunction.

Spermidine Alleviates Intrauterine Hypoxia-Induced Offspring Newborn Myocardial Mitochondrial Damage in Rats by Inhibiting Oxidative Stress and Regulating Mitochondrial Quality Control

“…Moreover, SPD can promote mitochondrial biogenesis and improve mitochondrial function in the aging heart ( 43 ). Polyamines spermine and spermidine can affect the dynamic mitochondrial proteome, thereby preventing age-related changes in cardiac functions and cardiac aging ( 36 ). Other studies have also demonstrated that SPD supplementary delay cardiac aging by enhancing mitophagy and promoting mitochondrial respiration in mice ( 44 ).…”

“…The increasing numbers of preclinical and clinical studies have indicated that dietary SPD has health effects such as antiaging, cardiovascular protection, neuromodulation, and anti-inflammatory functions, such as intraperitoneal injection of SPD (50 mg/kg) in mice protects against collagen-induced arthritis by inhibiting the polarization of M1 macrophages in synovial tissue ( 50 ). Supplementation with 10 mg/kg/d of SPD reversed age-related cardiac deterioration in rats ( 36 ). More importantly, the mother was an intervention with 5 mg/kg/d of SPD during late pregnancy to improve IUH-induced cognitive and neural function decline ( 51 ) and heart oxidative stress damage in rat offspring ( 32 ).…”

“…The respiratory control ratio (RCR, state 3 divided by state 4) reflects oxygen consumption by phosphorylation (coupling). Procedures continued, as previously described ( 36 ).…”

Cardiomyocyte Pdk4 response is associated with metabolic maladaptation in aging

“…It is intriguing to speculate that the increased transcriptional expression of Pdk4 in the aged heart in the baseline state may represent an adaptive response to the age‐induced mitochondrial dysfunction. Notably, recent attempts to downregulate Pdk4 to mitigate the effects of cardiac aging have been successful in baseline conditions signifying the link between Pdk4 and aging in normal physiology (Zhang et al, 2022 ). Under I/R stress, there is a larger abundance of pyruvate in the young mice than in the aged mice, consistent with transcriptional expression of Pdk4 being higher in young mice.…”

“…Notably, recent attempts to downregulate Pdk4 to mitigate the effects of cardiac aging have been successful in baseline conditions signifying the link between Pdk4 and aging in normal physiology (Zhang et al, 2022). Under I/R stress, there is a larger abundance of pyruvate in the young mice than in the aged mice, consistent with transcriptional expression of Pdk4 being higher in young mice.…”