Role of Mitochondrial Dynamics in Cocaine’s Neurotoxicity

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.

Cocaine perturbs mitovesicle biology in the brain

“…Thus, analysis of the brain of cocaine‐intoxicated male and female mice revealed the presence of sex‐independent changes in proteins that are crucial for maintenance of mitochondrial homeostasis. These data are consistent with the presence of cocaine‐induced mitochondrial alterations under our experimental conditions and are in full agreement with what was previously published by other independent groups (Funakoshi et al., 2019; Thangaraj et al., 2020; Thornton et al., 2021; Wen et al., 2022).…”

“…This hypothesis assumes compromised mitochondrial homeostasis after repetitive cocaine exposure, a cocaine-induced effect that was previously shown by several research groups (Funakoshi et al, 2019;Thangaraj et al, 2020;Wen et al, 2022;reviewed in Thornton et al, 2021), and found in the in vitro (Figure 5) and in vivo (Figure 4) experiments described here. In particular, mitochondria hyperpolarisation in cocaine-treated cells (Figure 5d) indicated an accumulation of H + protons in the IMS, suggesting a downstream block of oxidative phosphorylation (as previously reported; Cunha-Oliveira et al, 2013a, 2013bYuan & Acosta, 2000) at the level of the ETC Complex V, where, under physiological conditions, the H + gradient is dissipated to generate ATP.…”

“…We have previously shown both in vitro and in vivo that mitovesicle secretion is enhanced when damaged mitochondria accumulate (D'Acunzo et al., 2021), likely a homeostatic mechanism to eliminate detrimental mitochondrial material from the cell and mitigate the intracellular production of reactive oxygen species (ROS). Cocaine is a well‐established inducer of mitochondrial impairment in all brain areas, especially after prolonged exposure (as reviewed in Thornton et al., 2021), and cocaine validated biological activities include the stimulation of mitochondrial fission via phosphorylation of DRP1 and a block of mitophagy (Funakoshi et al., 2019; Thangaraj et al., 2020; Wen et al., 2022), an intracellular quality control pro‐survival mechanism that reduces the mass of damaged mitochondria (D'Acunzo et al., 2019; Di Rita, D'Acunzo, et al., 2018; Di Rita, Peschiaroli, et al., 2018; Di Rita et al., 2021).…”

The complexity of cortical folding is reduced in chronic cocaine users

“…However, the relationship between altered CCF in OFC and the duration of cocaine abuse suggests that this alteration may follow local neurotoxic or neuroplastic effects 49 . This observation is consistent with evidence from animal studies that shows that repeated exposure to cocaine can induce long‐lasting changes in brain morphology, including inhibition of neurite extension, reduction in endoplasmatic reticulum dilation, abnormal lysosomal proteolysis and altered neuronal mitochondrial dynamics 50 . Notably, these cocaine‐dependent cellular and molecular adaptations have been associated with changes in the dynamics of gene expression mediated by epigenetic changes, including DNA methylation, histone modifications and microRNAs 51 .…”

“…49 This observation is consistent with evidence from animal studies that shows that repeated exposure to cocaine can induce long-lasting changes in brain morphology, including inhibition of neurite extension, reduction in endoplasmatic reticulum dilation, abnormal lysosomal proteolysis and altered neuronal mitochondrial dynamics. 50 Notably, these cocainedependent cellular and molecular adaptations have been associated…”