Mitochondrial DNA (mtDNA) encodes proteins that are necessary for the production of cellular energy by the mitochondria. In neurons, shortage of this energy due to mitochondrial dysfunction triggers neurodegeneration. In our previous studies, we reported that subjects with pathogenic mutations that cause familial Alzheimer’s disease exhibit low content of cell-free mtDNA (cf-mtDNA) in cerebrospinal fluid (CSF) before the appearance of clinical signs, suggesting that a decrease in the CSF content of cf-mtDNA precedes the clinical signs of dementia. However, the source and the mechanisms of cf-mtDNA release are unclear. Moreover, the molecular mechanisms involved in regulation of mtDNA copy number and release by different genes that cause familiar Alzheimer’s disease are unknown. To explore these questions, we have now investigated the effect of APP-Swe/Ind and PSEN1dE9 mutations on mtDNA replication, transcription and release in SH-SY5Y cell clones that permanently express these mutations. We found that either APP-Swe/Ind or PSEN1d9 gene mutations both reduce mtDNA copy number, the amount of L-strand and H-strand mtDNA transcripts per cell, and the release of cf-mtDNA. In addition, we found that pharmacological inhibition of mitophagy enhances the release of cf-mtDNA in control cells, but not in cell clones expressing APP-Swe/Ind and PSEN1dE9 mutations. These results indicate the presence of an mtDNA quality control system independent of mitophagy that is impaired by APP-Swe/Ind and PSEN1dE9 mutations. Moreover, the present results show that alteration of mtDNA dynamics is a common factor of different pathogenic mutations that cause Alzheimer’s disease.

Trabajo presentado en el 19th National Meeting of the Spanish Society of Neuroscience, celebrado en Lleida (España), del 3 al 5 de noviembre de 2021

Supported by SAF2017-89791-R, CIBERNED PI2020/09-04 and CIBERNED CB06/05/0050 grants.

Peer reviewed