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

TL;DR

This study shows that removing mitochondrial DNA in neuronal cells causes gene expression changes linked to Alzheimer's disease and other neurodegenerative conditions.

Contribution

The study reveals that mtDNA depletion induces transcriptional changes that mirror Alzheimer's disease molecular features.

Findings

ρ0 cell lines showed >75% differential gene expression compared to ρ+ controls.

The KEGG AD pathway was significantly enriched in DEGs.

Changes in gene expression affected lipid, insulin signaling, and immune response pathways related to AD.

Abstract

We determined whether mitochondrial DNA (mtDNA) depletion induced Alzheimer's disease (AD)‐relevant transcription changes.

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.

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.

MtDNA depletion alters gene expression in ways that recapitulate or predictably promote AD molecular phenomena.

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.

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.

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