Gerontoxanthone I and Macluraxanthone Induce Mitophagy and Attenuate Ischemia/Reperfusion Injury

Abstract

Mitophagy is a crucial process in controlling mitochondrial biogenesis. Balancing mitophagy and mitochondrial functions is required for maintaining cellular homeostasis. In this study, we found that Gerontoxanthone I (GeX1) and Macluraxanthone (McX), xanthone derivatives isolated from Garcinia bracteata C. Y. Wu ex Y. H. Li, induced Parkin puncta accumulation and promoted mitophagy. GeX1 and McX treatment induced the degradation of mitophagy-related proteins such as Tom20 and Tim23. GeX1 and McX directly stabilized PTEN-induced putative kinase 1 (PINK1) on the outer membrane of the mitochondria, and then recruited Parkin to mitochondria. This significantly induced phosphorylation and ubiquitination of Parkin, suggesting that GeX1 and McX mediate mitophagy through the PINK1-Parkin pathway. Transfecting ParkinS65A or pretreated MG132 abolished the induction effects of GeX1 and McX on mitophagy. Furthermore, GeX1 and McX treatment decreased cell death and the level of ROS in an ischemia/ reperfusion (IR) injury model in H9c2 cells compared to a control group. Taken together, our data suggested that GeX1 and McX induce PINK1-Parkin-mediated mitophagy and attenuate myocardial IR injury in vitro.

Mitophagy in Human Diseases

“…Gerontoxanthone I (GeX1) and macluraxanthone (McX), which have been proposed to elicit protective effects against myocardial IR injury, have been shown to promote PINK1 stabilization and Parkin phosphorylation and induce the degradation of mitophagy-related proteins, such as TOMM20 and TIMM23, inducing mitophagy through the PINK1-Parkin pathway [ 428 ].…”

Using 13C‐NMR dereplication to aid in the identification of xanthones present in the stem bark extract of Calophyllum brasiliense

“…30 Macluraxanthone (1) has also been isolated from different species of the Clusiaceae, e.g. Garcinia opaca, 24 G. ovalifolia, 31 G. speciose, 32 G. bracteata 33 and Rheedia gardneriana 34 and Calophyllaceae, e.g. Calophyllum soulattri, 35 C. inophyllum, 36,37 C. caledonicum, 38 C. blancoi 25 and Mesua ferrea, 39 and has been reported as having antioxidant, antimalarial, cytotoxic, and antiischemic activities.…”

“…Calophyllum soulattri, 35 C. inophyllum, 36,37 C. caledonicum, 38 C. blancoi 25 and Mesua ferrea, 39 and has been reported as having antioxidant, antimalarial, cytotoxic, and antiischemic activities. 32,33,[39][40][41][42][43] It is important to mention that, even though most of the experimental chemical shifts values for the various protons and carbons of 1 coincided with those reported for macluroxanthone (1) (Table 1), 24,25 the HMBC experiment allowed the correct assignment of the C-8a and C-9a carbon signals, on the basis of the observed correlations between the proton of the hydroxyl group at C8 and the C-8a carbon, and between the H-2 proton and the C-9a carbon (Figure S7, Supporting Information Table S1).…”

Mitophagy Regulation Following Myocardial Infarction

“…Moreover, deletion of PINK1 in this context abrogates the beneficial effect of hydrogen, suggesting that over-activation of PINK1/parkin-mediated mitophagy is essential for the anti-apoptotic and anti-inflammatory effect of hydrogen during cardiac I/R [ 95 ]. Furthermore, several studies showed that pharmacological activation of PINK1/parkin-mediated mitophagy is cardioprotective following H/R [ 103 , 104 , 105 ].…”