Squamosamide Derivative FLZ Diminishes Aberrant Mitochondrial Fission by Inhibiting Dynamin-Related Protein 1.

Hanyu Yang,Cheng Ju,Hui Liu,Dan Zhang,Zihong Zhang,Lu Wang,Xiuqi Bao,Fangyuan Li,Fangyu Yuan,Caixia Zang,Junmei Shang,Xu Yang

doi:10.3389/fphar.2021.588003

Abstract

Mitochondrial dysfunction is involved in the pathogenesis of Parkinson’s disease (PD). Mitochondrial morphology is dynamic and precisely regulated by mitochondrial fission and fusion machinery. Aberrant mitochondrial fragmentation, which can result in cell death, is controlled by the mitochondrial fission protein, dynamin-related protein 1 (Drp1). Our previous results demonstrated that FLZ could correct mitochondrial dysfunction, but the effect of FLZ on mitochondrial dynamics remain uncharacterized. In this study, we investigated the effect of FLZ and the role of Drp1 on 1-methyl-4-phenylpyridinium (MPP+)–induced mitochondrial fission in neurons. We observed that FLZ blocked Drp1, inhibited Drp1 enzyme activity, and reduced excessive mitochondrial fission in cultured neurons. Furthermore, by inhibiting mitochondrial fission and ROS production, FLZ improved mitochondrial integrity and membrane potential, resulting in neuroprotection. FLZ curtailed the reduction of synaptic branches of primary cultured dopaminergic neurons caused by MPP+ exposure, reduced abnormal fission, restored normal mitochondrial distribution in neurons, and exhibited protective effects on dopaminergic neurons. The in vitro research results were validated using an MPTP-induced PD mouse model. The in vivo results revealed that FLZ significantly reduced the mitochondrial translocation of Drp1 in the midbrain of PD mice, which, in turn, reduced the mitochondrial fragmentation in mouse substantia nigra neurons. FLZ also protected dopaminergic neurons in PD mice and increased the dopamine content in the striatum, which improved the motor coordination ability of the mice. These findings elucidate this newly discovered mechanism through which FLZ produces neuroprotection in PD.

Highlights

Mitochondria are the primary organelles involved in the production of cellular erobic respiration
Excessive mitochondrial fragmentation often led to the accumulation of mitochondria in the perinuclear area (Trevisan et al, 2018), It was noted that FLZ treatment significantly increased the cellular area occupied by mitochondria (Figures 2D–F, p 0.0253 vs. MPP+ treated group)
Exposure to FLZ alone did not affect mitochondrial dynamics in normal cells. These results indicated that FLZ treatment could improve mitochondrial dynamics by alleviating abnormal mitochondrial fragmentation and correcting abnormal mitochondria distribution in neurons challenged with MPP+

Summary

Introduction

Mitochondria are the primary organelles involved in the production of cellular erobic respiration. They provide the necessary energy needed by cells through the oxidative phosphorylation of cellular respiration to produce ATP. Mitochondria are highly dynamic organelles that continuously undergo fission and fusion cycles (McBride et al, 2006). The two opposing processes of fission and fusion are critical events in numerous physiological processes, including programmed cell death, calcium homeostasis, autophagy, redox signaling, and innate immunity (Suliman and Piantadosi, 2016; Smith et al, 2012). Normal mitochondrial dynamics are a balance of mitochondrial division and fusion that affects the number, size, and location of mitochondria to meet the needs of the physiological activities occurring in cells. Due to the essential role of dynamic mitochondrial homeostasis in eukaryotic cells in maintaining normal cell homeostasis, considerable research has focused on the role of mitochondrial dynamics in metabolic, cardiovascular, neoplastic, and neurodegenerative diseases

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Results

Conclusion