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Review
. 2022 May 12;23(10):5418.
doi: 10.3390/ijms23105418.

Role of Mitochondrial Dynamics in Cocaine's Neurotoxicity

Shuheng Wen  1 , Toshihiko Aki  1 , Takeshi Funakoshi  1 , Kana Unuma  1 , Koichi Uemura  1
Affiliations
Review

Role of Mitochondrial Dynamics in Cocaine's Neurotoxicity

Shuheng Wen et al. Int J Mol Sci. .

Abstract

The dynamic balance of mitochondrial fission and fusion maintains mitochondrial homeostasis and optimal function. It is indispensable for cells such as neurons, which rely on the finely tuned mitochondria to carry out their normal physiological activities. The potent psychostimulant cocaine impairs mitochondria as one way it exerts its neurotoxicity, wherein the disturbances in mitochondrial dynamics have been suggested to play an essential role. In this review, we summarize the neurotoxicity of cocaine and the role of mitochondrial dynamics in cellular physiology. Subsequently, we introduce current findings that link disturbed neuronal mitochondrial dynamics with cocaine exposure. Finally, the possible role and potential therapeutic value of mitochondrial dynamics in cocaine neurotoxicity are discussed.

Keywords: Drp1; cocaine; endoplasmic reticulum; mitochondrial dynamics; mitochondrial fission; mitochondrial fusion.

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Conflict of interest statement

S.W. receives a scholarship funded by the Cooperation Program between Tokyo Medical and Dental University (TMDU), Sony Corporation, and Sony Group Corporation. The funders had no role in the design of the study, in the collection, analyses, or interpretation of data, in the writing of the manuscript, or in the decision to publish the results.

Figures

Figure 1
Figure 1
Chemical structure of cocaine and its action on dopaminergic neurons. Cocaine antagonizes dopamine reuptake from the synaptic cleft through dopamine transporters. This leads to an increase in the levels of dopamine in the cleft, boosting the effects of dopamine in the central nervous system.
Figure 2
Figure 2
Effects of cocaine on neuronal cells. Cocaine enters the central nervous system by crossing and/or disrupting the blood–brain barrier (BBB). After entering neuronal cells, cocaine and its metabolites induce subcellular stress within mitochondria and the endoplasmic reticulum (ER). The aggregation of dopamine induced by cocaine also results in oxidative stress during the degradation of dopamine. Overwhelmed stress and direct damage from cocaine lead to mitochondrial dysfunction which results in cell death.
Figure 3
Figure 3
General aspects of mitochondrial fission and fusion mediated by a panel of regulating molecules. DRP1, which ordinarily resides in cytosol, is recruited to mitochondrial outer membranes upon activation through, e.g., phosphorylation at Ser-616. DRP1 assembles into a ring-like structure and act as scissors to promote mitochondrial division. Mitochondrial fusion consists of two consecutive processes: outer and inner membrane fusions. The former process is mediated by MFN1/2, while the latter is mainly executed through OPA1.
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