Inhibiting mtDNA transcript translation alters Alzheimer's disease-associated biology

Area of Science:

• Neuroscience
• Cell Biology
• Genetics

Background:

• Alzheimer's disease (AD) is characterized by mitochondrial structural and functional alterations.
• The precise role of mitochondrial pathology in the AD timeline remains debated.

Purpose of the Study:

• To investigate if mitochondrial dysfunction influences genes and proteins implicated in AD.
• To explore the cellular and molecular responses to inhibited mitochondrial translation.

Main Methods:

• Human neuronal cells (SH-SY5Y) and induced pluripotent stem cell (iPSC)-derived neurons were treated with chloramphenicol.
• Chloramphenicol inhibits the translation of mitochondrial DNA (mtDNA)-encoded transcripts.
• Adaptive, AD-associated gene, and AD-associated protein responses were characterized.

Main Results:

• Inhibition of mitochondrial translation led to increased mtDNA copy number and transcription in cells.
• Changes were observed in nuclear-expressed respiratory chain mRNA and protein levels.
• Consistent with AD, alterations were noted in amyloid precursor protein (APP), beta-amyloid (Aβ), apolipoprotein E (APOE), tau, and α-synuclein biology.

Conclusions:

• Primary mitochondrial dysfunction can induce compensatory organelle responses and alter nuclear gene expression.
• These mitochondrial-induced changes may mimic molecular phenomena observed in brain aging and AD.
• Mitochondrial stress can create an environment conducive to AD pathology, suggesting it could be a cause or consequence.