Lycopene prevents Di-(2-ethylhexyl) phthalate-induced mitophagy and oxidative stress in mice heart via modulating mitochondrial homeostasis

Phthalates (PAEs), as a general term for a class of compounds, are used to an extreme extent in domestic products as plasticizers [1]. PAEs and plastic molecules did not form a solid covalent bond but were connected by van der Waals forces or hydrogen bonds to maintain independent chemical properties. So they can easily migrate to the environment in various processes [2] and be widely found in soil, food, air, sediment, and indoor dust [3]. Among them, due to its versatility, Di-(2-Ethylhexyl) phthalate (DEHP), which has become the most widely applicable PAEs, is used in various fields such as industrial production, daily necessities, and medical equipment production, robustness and relatively low cost [4]. Cerebrovascular disease (CVD) has become a common human disease and the leading cause of human death, especially in middle-aged and older people over 50. DEHP exposure can induce toxic damage to the heart [5]. Many studies indicate that ingestion of DEHP can cause an increased cardiovascular response by disrupting gene expression in mice's heart tissue [6]. Although significant efforts have been made to study the toxicity of DEHP to the heart, the potential mechanism of DEHP-induced myocardial cell damage is still unclear.

Lycopene (LYC) is a red component of fruits and vegetables through photosynthesis [7,8]. LYC has the highest antioxidant potential among carotenoids and is the family of fat-soluble antioxidants [9]. Thus, generally, it relates to reducing the hazard of CVD [10]. The in-depth study of LYC shows many beneficial effects, especially the potential protective effect on the heart. A previous study has statistically determined that an increase in LYC intake will reduce the risk of CVD [11,12]. One study demonstrated that LYC intake inhibited oxidative stress and related inflammatory reactions caused by postprandial lipids [13]. An evidence manifested that ISO can induce cardiotoxicity in rats leading to oxidative stress, and LYC can protect the heart from ISO damage through its own antioxidant capacity and free radical scavenging activity. [14]. Consequently, previous studies suggest that mechanisms related to antioxidants may be an important way for LYC to prevent cardiovascular diseases. Studies on the protective effects and mechanisms of LYC against cardiac injury due to DEHP exposure need to be increased at this stage.

Mitochondria, the center of energy metabolism in the body, is the site of oxidative metabolism in eukaryotes, which accounts for 40% of the total cell volume. The maintenance of mitochondrial homeostasis is fundamental to the survival and function of cells [15]. Cardiac cells obtain energy mainly through ATP produced by mitochondrial oxidative phosphorylation. Alterations in mitochondrial function affect cell metabolism and severely affect systemic metabolism, health, and longevity [16]. It confirms in people with diabetes that mitochondrial dysfunction and mitochondrial biogenesis may be related to cardiovascular diseases caused by cardiac cell metabolic disorders [17]. Sirtuin1(SIRT1) is a member of the SIR2 homologous protein family, catalyzing NAD+-dependent protein deacetylation [18]. Concomitantly, SIRT1 has been shown to cooperate with the peroxisome proliferator-activated receptor γ co-activator 1α (PGC-1α) to improve metabolic signaling pathways by activating PGC-1α [19]. The decrease in PGC-1α gene expression causes chronic pro-inflammatory reactions. Inflammatory conditions are one of the contributing factors to the development of chronic diseases [20]. PGC-1α mediates downstream nuclear respiratory factor-1 (NRF1) transcriptional regulatory circuits.

NRF1 works synergistically with PGC-1α and promotes multiple nuclear-encoded genes [21]. Mitochondrial dynamics refers to the continuous division and fusion of mitochondria to provide energy for cells, which is critical to maintaining normal mitochondrial metabolism. Related studies show that mitochondrial fusion can protect the integrity of mtRNA function in skeletal muscle [5]. Recent research indicated that increased levels of mitochondrial fusion could reduce cardiac dysfunction [22]. As a kind of selective Autophagy, mitophagy encapsulates and fuses with lysosomes and degrades damaged mitochondria through the macroautophagy pathway, thereby maintaining the homeostasis of the mitochondrial network and the quality and quantity of mitochondria [23]. When depolarization occurs in the mitochondria, PINK1 aggregates on the outer mitochondrial membrane (OMM) to phosphorylate ubiquitin, so that the mitochondria recruit Parkin to the damaged mitochondrial membrane, and Parkin is also phosphorylated by PINK1. This process activates the activity of Parkin E3 ubiquitin ligase and induces the autophagy membrane to wrap mitochondria to initiate mitophagy [24].

Previous studies illustrate that modulation of mitochondrial dynamics is one way in whichDEHP induces brain toxicity [25], and LYC can reduce DEHP-induced testicular oxidative stress in mice through the Nrf2 signaling pathway [26]. However, there is no report on the recovery of DEHP-induced cardiac mitochondrial dysfunction by LYC. This study aimed to determine whether LYC was effective in treating DEHP-induced mitochondrial dysfunction. LYC may be able to protect against the onset of DEHP-induced cardiotoxicity in mice by a mechanism that has yet to be demonstrated.

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