Integrating mitochondrial gene expression data to model the effects of respirasome supercomplex formation on reactive oxygen species production in Alzheimer's disease models

Abstract

Background

In the past decade, Alzheimer's disease (AD) researchers have found that the formation of amyloid aggregates occurs after dysregulation of respiratory chain activity.

Objective

Using our developing mathematical model to identify potential therapeutic targets for AD treatment.

Methods

We have constructed a mathematical model for AD that incorporates enzyme activities and kinetics, and protein and mRNA expression levels.

Results

Our analyses of gene expression in AD brains provide complimentary evidence that changes in mitochondrial energy production and biogenesis accompany AD pathogenesis. Using this data, we created a mitochondrial model of electron transport chain supercomplex assembly.

Conclusions

By carrying out sensitivity analyses of responses to oxidative stress and effects of gene expression on energy production, we demonstrate how oxidative stress and energy deficits change the initial antioxidant defense system and impact the progression of AD. We investigated the impact of gene expression changes in 9 genes as new therapeutic options via metabolic flux analysis of supercomplex assembly. Through careful analysis, we propose that UQCRC1 may be an effective therapy option for in vitro AD treatment testing.