Dynamic Mitochondrial Proteome Under Polyamines Treatment in Cardiac Aging.

Hao Zhang,Junying Wang,Yajun Zhao,Yan Lin,Lingxu Li,Bintao Qiu,Nannan Chai,Xue Yu,Ting Liu,Peiling Wei,Meng Yan

doi:10.3389/fcell.2022.840389

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.

Highlights

Aging is a degenerative process associated with reduction of physiological function and is the most important risk factor for developing cardiovascular disease
The aim of the current study was to identify alterations in mitochondrial proteome under polyamines (Spm or Spd) stimulation with a high-throughput quantitative iTRAQ approach during the age-associated myocardial pathological changes, which may contribute to resisting cardiac aging and delaying senility
We established the map of differentially expressed mitochondrial proteome of the aging heart under polyamines stimulation, in which potential candidates were discovered and given further analysis

Summary

Introduction

Aging is a degenerative process associated with reduction of physiological function and is the most important risk factor for developing cardiovascular disease. The mechanism of cardiac aging is sophisticated, including autophagy, ubiquitinmediated turnover, apoptosis, mitochondrial quality control, and cardiac matrix homeostasis (Quarles et al, 2015). In these processes, mitochondria have a key role because cardiac function is tightly associated with an energetically demanding process. In the last few decades, several investigations have revealed the relevance of mitochondria and oxidative stress both in cardiac aging and in the development of cardiac diseases, such as heart failure, cardiac hypertrophy, and diabetic cardiomyopathy (Martín-Fernández and Gredilla, 2016). Evidence suggests that the structure of mitochondria in the heart is broken during the aging process (Dai and Rabinovitch, 2009; Liang and Gustafsson, 2020)

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