Modulatory Effects of Alpha- and Gamma-Tocopherol on the Mitochondrial Respiratory Capacity and Membrane Potential in an In Vitro Model of Alzheimer's Disease.

Aslina Pahrudin Arrozi,Wan Zurinah Wan Ngah,Hanafi Ahmad Damanhuri,Suzana Makpol

doi:10.3389/fphar.2021.698833

Aslina Pahrudin Arrozi, Wan Zurinah Wan Ngah + Show 2 more

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https://doi.org/10.3389/fphar.2021.698833

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Abstract

Increased amyloid-beta (Aβ) and amyloid precursor protein (APP) in the brains of Alzheimer’s disease (AD) patients are common pathological hallmarks mediating the disease progression. Growing evidence also suggests that mitochondrial abnormalities are an early feature in the pathogenesis of AD. Intervention with antioxidants has received great interest as a molecular strategy for the manipulation of mitochondrial function. Our previous preliminary study using in vitro cell models expressing different types of APP demonstrated that treatment with alpha-tocopherol (ATF) or gamma-tocopherol (GTF) modulates mitochondrial function by reducing mitochondrial reactive oxygen species (ROS), increasing the production of ATP and preventing apoptosis events, especially in cells expressing the mutant APP form. Thus, we hypothesized that ATF or GTF treatment might also alter mitochondrial metabolic pathways such as oxidative phosphorylation. The present study aimed to investigate the role of ATF and GTF in modulating mitochondrial oxidative metabolism using high-resolution respirometry. Our results showed that both ATF and GTF increased the respiratory capacity and membrane potential in the ROUTINE and OXPHOSCI-LINKED states as well as complex IV enzyme activity in wild-type and mutant APP-overexpressing SH-SY5Y cells. Although preliminary, these findings indicate that ATF and GTF modulate mitochondrial oxidative metabolism in APP-overexpressing cells and, in part, may contribute to the planning of strategies for utilizing vitamin E isomers against mitochondrial-related diseases such as AD.

Highlights

The accumulation of insoluble amyloid-beta (Aβ) protein in extracellular amyloid plaques in the brains of Alzheimer’s disease (AD) patients is well known as the classical pathological hallmark of the disease (Tiwari et al, 2019) together with the presence of neurofibrillary tangles (NFTs) (Gao et al, 2018)
In the present study, we aimed to investigate the potential effects of ATF and GTF in modulating mitochondrial oxidative metabolism to further elucidate the protective role of both vitamin E isomers, which may contribute to strategies against mitochondrial-related diseases such as AD
There were four respiratory capacities measured in the present study including ROUTINE, respiratory capacity in living cells controlled by cellular energy demand, energy turnover and the degree of coupling to phosphorylation, whereas the other three respiratory capacities were measured in cells that selectively permeabilized the plasma membrane of cells while the mitochondrial membrane remain intact allowing direct access to the mitochondria, which required the supply from exogenous substrates/substances to measure mitochondrial respiration

Summary

Introduction

The accumulation of insoluble amyloid-beta (Aβ) protein in extracellular amyloid plaques in the brains of Alzheimer’s disease (AD) patients is well known as the classical pathological hallmark of the disease (Tiwari et al, 2019) together with the presence of neurofibrillary tangles (NFTs) (Gao et al, 2018). A recent study showed that overexpression of the β-secretase-derived APP-CTF fragment (C99) in Effects of Tocopherol on Mitochondrial Function neuroblastoma SH-SY5Y cells triggers excessive mitochondrial morphology alterations associated with enhanced mitochondrial reactive oxygen species production independent of Aβ (Vaillant-Beuchot et al, 2021). Our group showed that the level of reactive oxygen species (ROS) in the mitochondria, activity of complex V enzyme, and cyclophilin D (CypD) and pro-caspase 3 protein expression as well as cytochrome c release were increased, followed by a decrease in ATP levels in SH-SY5Y cells overexpressing the mutant APP form (Pahrudin Arrozi et al, 2020), suggesting that the mitochondrial function in these in vitro models of AD was altered. We hypothesized that mitochondrial metabolic pathways, such as oxidative phosphorylation and membrane potential, were altered, as mitochondrial oxidative metabolism is the major site of ATP synthesis

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