APOE expression and secretion are modulated by mitochondrial dysfunction

Area of Science:

• Cellular Biology
• Neuroscience
• Mitochondrial Biology

Background:

• Mitochondria are crucial for cellular function, impacting processes via cell-autonomous and non-cell-autonomous mechanisms.
• Mitochondrial regulation of the secretome, including secreted factors, is increasingly recognized for its role in cellular communication.

Purpose of the Study:

• To investigate the role of mitochondrial electron transport chain (ETC) function in regulating the cellular secretome.
• To determine if ETC disruption influences the expression and secretion of Alzheimer's disease risk factors like apolipoprotein E (APOE).

Main Methods:

• Genetic and pharmacological disruption of mitochondrial ETC complexes (I, III, IV) and SLC25A transporters.
• Analysis of APOE transcript, protein levels, and secretion in various cell types, including iPSC-derived human astrocytes.
• In vivo studies using the 5xFAD mouse model to assess age- and genotype-dependent changes in mitochondrial complex I and APOE levels.

Main Results:

• Disruption of the ETC, directly or indirectly, led to a significant upregulation (up to 49-fold) of APOE transcript, protein, and secretion.
• APOE upregulation was observed across diverse cell types and in human astrocytes, indicating an inflammatory gene expression program.
• In the 5xFAD mouse model, a decline in respiratory complex I preceded an increase in brain APOE levels.

Conclusions:

• Mitochondria act as novel upstream regulators of APOE, influencing its expression and secretion.
• Mitochondrial dysfunction may contribute to APOE-related cellular processes in both health and disease, particularly in neurodegenerative conditions like Alzheimer's disease.