MtDNA‐depleted neuronal cell transcriptomes reveal Alzheimer's disease‐related changes

Abstract INTRODUCTION We determined whether mitochondrial DNA (mtDNA) depletion induced Alzheimer's disease (AD)‐relevant transcription changes. METHODS Following RNA sequencing (RNA‐seq), we identified differentially expressed genes (DEGs) between SH‐SY5Y or NT2 mtDNA‐depleted (ρ0) and intact (ρ+) cell lines and quantified concordant DEG changes. Gene set enrichment analysis and over‐representation analysis were used to determine the impact on the Kyoto Encyclopedia of Genes and Genomes (KEGG) AD and other neurodegenerative disease pathways, ascertain pathway and term enrichment in the Reactome and Gene Ontology databases, and generate Ingenuity Pathway Analysis z ‐scores. RESULTS Relative to their ρ+ comparators, ρ0 lines differentially expressed >75% of their genes. The KEGG AD pathway was significantly enriched, and equivalently altered genes ranked the AD, Parkinson's disease, ALS, and Huntington's disease KEGG pathways among the most enriched gene sets. AD‐related enriched pathways and terms reflected lipid, insulin signaling, synapse, inflammation/immune response, endosome/endocytosis, RNA, and proteostasis biology. CONCLUSION MtDNA depletion alters gene expression in ways that recapitulate or predictably promote AD molecular phenomena. Highlights MtDNA‐depleted neuronal cell lines reshuffle nuclear gene expression. The KEGG AD pathway is enriched with DEGs. Transcription‐defined pathways and terms relating to AD biology broadly change.