Global Transcriptomic Shifts in Mitochondrial DNA-Depleted Neuronal Cells Reveal Alzheimer's Disease-Related Pathway Changes
Background: Mitochondrial dysfunction, a prominent feature of Alzheimer's disease (AD), could represent a cause or consequence of the disease. Objective: We determined the extent to which mitochondrial dysfunction due to mitochondrial DNA (mtDNA) depletion induces transcription changes that link to AD phenomena. Methods: We performed a transcriptomic survey of human neuronal SH SY5Y and NTERA 2/NT2 mtDNA-depleted (?0) and intact (?+) cell lines. Differentially expressed genes (DEGs) between SH-SY5Y or NT2 ?0 and ?+ cells were identified using edgeR, and we used the Equivalent Change Index (ECI) approach to quantify concordant DEG behavior across the cell lines. Gene set enrichment and over representation analysis (GSEA; ORA) were used to determine impact on the KEGG Alzheimer's and other neurodegenerative disease pathways, ascertain pathway and term enrichment in the Reactome and Gene Ontology databases, and generate activation z-scores in the Ingenuity Pathway Analysis (IPA) database. Results: Relative to their ?+ comparators, ?0 lines differentially expressed >75% of their genes, and >20% more than doubled or halved expression. The KEGG Alzheimer's pathway was significantly enriched, and ECI-identified genes ranked the Alzheimer's, Parkinson's, ALS, and Huntington's KEGG pathways among the most enriched gene sets. There was broad enrichment of pathways and terms relating to AD phenomena, which reflected lipid, insulin signaling, inflammation/immune response, synapse, endosome/endocytosis, RNA, and proteostasis biology. Conclusion: In neuronal cell lines, mitochondrial dysfunction due to mtDNA depletion alters gene expression in ways that recapitulate or predictably promote AD molecular phenomena. Overall design: RNA-seq profiling of SY5Y and NT2 cell lines with and without mitochondrial depletion