Chronic mitochondrial DNA depletion alters MAPT splicing and increases tau levels

Background In Alzheimer's disease (AD), tau protein aggregates to form neurofibrillary tangles (NFTs). The cellular changes favoring AD brain NFT formation remain incompletely understood. AD brains also display mitochondrial defects, including reduced mitochondrial DNA (mtDNA) copy number. Objective We considered whether mtDNA depletion alters tau homeostasis. Methods We assessed tau mRNA using short-read mRNA sequencing and PCR, and tau protein using immunochemistry, in SH-SY5Y cells with chronic mtDNA depletion (ρ0). Results mtDNA depletion increased tau expression and resulted in alternatively spliced isoforms, elevated 4R and exon 4a-containing MAPT transcripts, and consistently detectable big tau protein. ρ0 cells also displayed an elevated MAPT exon 13 3’Untranslated Region (UTR): Coding DNA sequence (CDS) ratio. Phosphorylation at amino acid positions 217 and 181 decreased. Conclusions Mitochondrial dysfunction affects tau expression, splicing, and 3’UTR retention while increasing tau protein levels and modifying its phosphorylation. These studies hold AD relevance as they provide evidence for a relationship between two AD-associated phenomena, defective mitochondrial function and altered MAPT regulation.