Do Autophagy Enhancers/ROS Scavengers Alleviate Consequences of Mild Mitochondrial Dysfunction Induced in Neuronal-Derived Cells?

Odeya Damri,Galila Agam,Sarya Natur

doi:10.3390/ijms22115753

Abstract

Mitochondrial function is at the nexus of pathways regulating synaptic-plasticity and cellular resilience. The involvement of brain mitochondrial dysfunction along with increased reactive oxygen species (ROS) levels, accumulating mtDNA mutations, and attenuated autophagy is implicated in psychiatric and neurodegenerative diseases. We have previously modeled mild mitochondrial dysfunction assumed to occur in bipolar disorder (BPD) using exposure of human neuronal cells (SH-SY5Y) to rotenone (an inhibitor of mitochondrial-respiration complex-I) for 72 and 96 h, which exhibited up- and down-regulation of mitochondrial respiration, respectively. In this study, we aimed to find out whether autophagy enhancers (lithium, trehalose, rapamycin, and resveratrol) and/or ROS scavengers [resveratrol, N-acetylcysteine (NAC), and Mn-Tbap) can ameliorate neuronal mild mitochondrial dysfunction. Only lithium (added for the last 24/48 h of the exposure to rotenone for 72/96 h, respectively) counteracted the effect of rotenone on most of the mitochondrial respiration parameters (measured as oxygen consumption rate (OCR)). Rapamycin, resveratrol, NAC, and Mn-Tbap counteracted most of rotenone’s effects on OCR parameters after 72 h, possibly via different mechanisms, which are not necessarily related to their ROS scavenging and/or autophagy enhancement effects. The effect of lithium reversing rotenone’s effect on OCR parameters is compatible with lithium’s known positive effects on mitochondrial function and is possibly mediated via its effect on autophagy. By-and-large it may be summarized that some autophagy enhancers/ROS scavengers alleviate some rotenone-induced mild mitochondrial changes in SH-SY5Y cells.

Highlights

Mitochondria are most widely known as the power workshop of the cell, due to their production of adenosine triphosphate (ATP) through the electron transport chain and oxidative phosphorylation (OXPHOS) pathways [1]
Mitophagy is the organelle’s quality control pathway which helps cells to selectively eliminate and recycle damaged and uncoupled mitochondria that are beyond repair, while preserving healthy mitochondria functioning above a certain threshold, preventing further damage leading to cell death
We examined in the SH-SY5Y cells whether any of the autophagy enhancers trehalose [33], rapamycin [34], and lithium [35], or the reactive oxygen species (ROS) scavengers NAC [36] and Mn-Tbap [37], or resveratrol, both an autophagy enhancer and a ROS scavenger [38], reverse the consequences of mild mitochondrial dysfunction

Summary

Introduction

Mitochondria are most widely known as the power workshop of the cell, due to their production of adenosine triphosphate (ATP) through the electron transport chain and oxidative phosphorylation (OXPHOS) pathways [1]. Besides their role in energy production, mitochondria play crucial roles in a myriad of cellular functions, including differentiation, cell cycle, cell growth, intracellular Ca+2 buffering and generation of reactive oxygen species (ROS) [2]. Mitophagy (autophagy of mitochondria) is the organelle’s quality control pathway which helps cells to selectively eliminate and recycle damaged and uncoupled mitochondria that are beyond repair, while preserving healthy mitochondria functioning above a certain threshold, preventing further damage leading to cell death.

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