Modeling the effects of respirasome supercomplex formation on AD progression by incorporation of mitochondrial gene expression data: Molecular and cell biology/mitochondrial function/energetics. (7th December 2020) - Shelton, Morgan
Abstract: Background: Alzheimer's disease is a specific form of dementia characterized by the aggregation of amyloid‐β plaques and tau tangles. New research has found that the formation of these aggregates occurs after dysregulation of respiratory chain activity. Proteomic and genomic data show that these changes are also related to unique gene expression patterns. Supercomplexes (SCs) are assemblages of multiple, functional respiratory complexes. After individual complexes have formed, respiratory complexes (RC) I, III, and IV begin to associate and form SCs. SCs are stable intermediates between respirasomes and individual complexes. We investigated the impact of our observed gene expression changes on new therapeutic options via metabolic flux analysis of SC assembly. Method: Total RNA was isolated from 80‐180 mg of frozen brain tissue from 11 AD and 5 control samples. Total RNA was quantified and assessed for purity using Nanodrop and Bioanalyzer analysis. cDNA was prepared and applied to the Human Mitochondrial Energy Metabolism and the Mitochondria RT² Profiler™ PCR Arrays. The qPCR data was then analyzed using Qiagen RT 2 Profiler PCR Array Data Analysis version 3.5. Gene expression changes were incorporated into the mathematical model created in CellDesigner 4.2 and these were converted into a series of mathematical equations by SBMLsqueezer. This file was imported into COPASI, a biological pathway simulation program. Treatment data were found using COPASI's time course task. Each treatment represented a mathematical change in gene expression of a selected enzyme. Result: We investigated 9 mitochondrial genes known to be important for efficient SC assembly. In all cases, the concentration of the gene products was decreased in the AD brain samples. After simulation of respirasome assembly using a reduced model only UQCRC1 treatment increased the percent of CI sequestration into respirasomes. Conclusion: Our results indicate that protective changes in expression of UQCRCI, a component of electron transport chain respiratory complex III may serve as a potential avenue for AD therapeutics. This work also highlights the importance of metabolic enzyme activity in maintaining proper respiratory activity.We would like to acknowledge support for this work from the Alzheimer's and Related Diseases Research Award Fund and the Commonwealth Health Research Board.