Altered cardiac mitochondrial dynamics and biogenesis in rat after short-term cocaine administration

Shuheng Wen,Toshihiko Aki,Koichi Uemura,Kana Unuma,Takeshi Funakoshi

doi:10.1038/s41598-021-03631-y

Shuheng Wen, Toshihiko Aki + Show 3 more

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https://doi.org/10.1038/s41598-021-03631-y

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Abstract

Abuse of the potent psychostimulant cocaine is widely established to have cardiovascular consequences. The cardiotoxicity of cocaine is mainly associated with oxidative stress and mitochondrial dysfunction. Mitochondrial dynamics and biogenesis, as well as the mitochondrial unfolded protein response (UPRmt), guarantee cardiac mitochondrial homeostasis. Collectively, these mechanisms act to protect against stress, injury, and the detrimental effects of chemicals on mitochondria. In this study, we examined the effects of cocaine on cardiac mitochondrial dynamics, biogenesis, and UPRmt in vivo. Rats administered cocaine via the tail vein at a dose of 20 mg/kg/day for 7 days showed no structural changes in the myocardium, but electron microscopy revealed a significant increase in the number of cardiac mitochondria. Correspondingly, the expressions of the mitochondrial fission gene and mitochondrial biogenesis were increased after cocaine administration. Significant increase in the expression and nuclear translocation of activating transcription factor 5, the major active regulator of UPRmt, were observed after cocaine administration. Accordingly, our findings show that before any structural changes are observable in the myocardium, cocaine alters mitochondrial dynamics, elevates mitochondrial biogenesis, and induces the activation of UPRmt. These alterations might reflect cardiac mitochondrial compensation to protect against the cardiotoxicity of cocaine.

Highlights

Abuse of the potent psychostimulant cocaine is widely established to have cardiovascular consequences
Thence, the homeostasis and normal function of mitochondria are crucial for the ideal operation of the heart, and these are sustained by mitochondrial dynamics and b iogenesis[26]
Mitochondrial dynamics and biogenesis form a delicate coping mechanism to maintain the optimal energic output of mitochondria in response to different environments, including increased oxidative stress and toxic conditions[27,28,34,35]. They are closely associated with the homeostasis of the cardiovascular system and an altered balance of mitochondrial dynamics can lead to pathological cardiac remodeling and cardiac pathogenesis[19,36,37,38]

Summary

Introduction

Abuse of the potent psychostimulant cocaine is widely established to have cardiovascular consequences. Mitochondrial dynamics and biogenesis form a delicate coping mechanism to maintain the optimal energic output of mitochondria in response to different environments, including increased oxidative stress and toxic conditions[27,28,34,35] They are closely associated with the homeostasis of the cardiovascular system and an altered balance of mitochondrial dynamics can lead to pathological cardiac remodeling and cardiac pathogenesis[19,36,37,38]. During the accumulation of mitochondrial stress, activated UPRmt promotes the recovery of the oxidative phosphorylation machinery[39], restores proteostasis[40], and detoxifies excess ROS41, accomplished by the translocation of its major regulator, activating transcription factor 5 (ATF5), and the activation of mitochondrial resident chaperones and proteases[42,43] It remains unrevealed whether UPRmt participates in resistance to the cardiotoxicity of cocaine

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