5-HT has been reported to possess significant effects on cardiac activities, but activation of 5-HTR on the cell membrane failed to illustrate the controversial cardiac reaction. Because 5-HT constantly comes across the cell membrane via 5-HT transporter (5-HTT) into the cytoplasm, whether 5-HTR is functional present on the cellular organelles is unknown. Here we show 5-HTR3 and 5-HTR4 were located in cardiac mitochondria, and regulated mitochondrial activities and cellular functions. Knock down 5-HTR3 and 5-HTR4 in neonatal cardiomyocytes resulted in significant increase of cell damage in response to hypoxia, and also led to alternation in heart beating. Activation of 5-HTR4 attenuated mitochondrial Ca2+ uptake under the both normoxic and hypoxic conditions, whereas 5-HTR3 augmented Ca2+ uptake only under hypoxia. 5-HTR3 and 5-HTR4 exerted the opposite effects on the mitochondrial respiration: 5-HTR3 increased RCR (respiration control ratio), but 5-HTR4 reduced RCR. Moreover, activation of 5-HTR3 and 5-HTR4 both significantly inhibited the opening of mPTP. Our results provided the first evidence that 5-HTR as a GPCR and an ion channel, functionally expressed in mitochondria and participated in the mitochondria function and regulation to maintain homeostasis of mitochondrial [Ca2+], ROS, and ATP generation efficiency in cardiomyocytes in response to stress and O2 tension.
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Funding: research grants held by YCG (973 Project No. 2013CB531206, 973 Project
No. 2012CB517803 and NSF No. 81170236, No. 31127001, No. 81570245 and No. 31221002).
- Arrhythmias Energy metabolism
Wang, Q., Zhang, H., Xu, H., Guo, D., Shi, H., Li, Y., Zhang, W., & Gu, Y. (2016). 5-HTR3 and 5-HTR4 located on the mitochondrial membrane and functionally regulated mitochondrial functions. Scientific Reports, 6, . https://doi.org/10.1038/srep37336