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Abstract
Hexokinase-II (HK-II) and dynamin-related protein 1 (Drp1) regulate mitochondrial function differently. This study was designed to investigate the cardioprotective effect of ginsenoside Rg5 (Rg5) with emphasis on the regulation of mitochondrial HK-II and Drp1. Saturated acid palmitate (PA) stimulation increased lactate accumulation and induced cellular acidification by impairing the activity of pyruvate dehydrogenase (PDH) in cardiomyocytes, leading to HK-II dissociation from mitochondria. Rg5 improved PDH activity and prevented cellular acidification by combating fatty-acid oxidation, contributing to protecting mitochondrial HK-II. HK-II binding to mitochondria prevented mitochondrial Drp1 recruitment, whereas Drp1 activation decreased the content of mitochondrial HK-II, demonstrating the reciprocal control for binding to mitochondria. Rg5 promoted Akt translocation to mitochondria and increased HK-II binding to mitochondria while coordinately suppressing Drp1 recruitment and mitochondrial fission. Akt inhibitor triciribine or knockdown of Akt with small interfering RNA diminished the effects of Rg5, indicating that Rg5 inhibited Drp1 activation and promoted HK-II mitochondrial binding through Akt activation. Rg5 prevented the opening of mitochondrial permeability transition pore and increased ATP production, resultantly increasing cardiomyocyte resistance to hypoxia/reoxygenation injury. Meanwhile, Rg5 prevented cell apoptosis with increased HK-II binding and reduced Drp1 recruitment to mitochondria in isoproterenol-induced ischemic heart of mice. Taken together, these findings not only established a previously unrecognized role of ginsenosides in cardioprotection but also suggest that mitochondrial HK-II binding and Drp1 recruitment could be targeted therapeutically to prevent ischemic injury in the heart.
Highlights
The heart has a very high energy demand and uses fatty acid and glucose as energy substrates
HK-II binds to outer mitochondrial membrane via connection with voltage-dependent anion channel 1 (VDAC), which interacts with the adenine nucleotide translocase (ANT), forming a contact site between the outer and inner membranes.[10]
HK-II binding to mitochondria protects cardiomyocyte survival by increasing energy efficiency
Summary
The heart has a very high energy demand and uses fatty acid and glucose as energy substrates. HK-II induction is mediated through Akt/ mTORC1 pathway.[20] In cardiomyocytes, HK-II has an Akt consensus sequence at position Thr[473], which can be directly phosphorylated by Akt activation.[21,22] Mitochondria fission is mediated through Drp[1] activation and inactivation of Drp[1] by phosphorylating at Ser 637 residue is shown to prevent mitochondrial fission with its resultant consequences.[18,19]. Rg5 inhibited Drp[1] activation and preserved mitochondrial HK-II via Akt activation, thereby protecting the cell against I/R insult These findings established a previously unrecognized role of ginsenosides in the regulation of mitochondrial function and suggest that mitochondrial Drp[1] recruitment and HK-II binding could be targeted therapeutically to prevent I/R injury in the heart
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