The protective effect of docosahexaenoic acid on mitochondria in a SH-SY5Y model of rotenone-induced toxicity

Polyunsaturated fatty acids in particular omega-3 fatty acids, such as docosahexaenoic acid (DHA) are essential nutrients and components of the plasma membrane. They are involved in various processes, among them synaptic development, functionality, integrity and plasticity and are therefore thought to have general neuroprotective properties. Considerable research evidence further supports beneficial effects of omega-3 fatty acids specifically on mitochondrial structure and function through their antioxidant and anti-apoptotic properties, which makes it an attractive addition in treatment options for neurodegenerative disorders, in which mitochondrial alterations are commonly observed. However, so far precise information on the underlying protective mechanisms are still lacking. Thus in this study, we utilized the most common neuronal cell line (SH-SY5Y) and induced mitochondrial oxidative stress through the addition of rotenone. To study the potential protective effect of DHA, cells were additionally pre-treated with DHA prior rotenone administration. By combining SILAC labelling, mitochondria enrichment, and subsequent proteomic analyses, we aimed to determine the capacity of DHA to alleviate mitochondrial oxidative stress in vitro and further shed light on molecular mechanisms contributing to the proposed neuroprotective effect. Indeed we confirmed a general increase in intensity of mitochondrial proteins in DHA pre-treated cells. Furthermore, we were able to define a compensatory mechanism by which the inhibition of complex I is overcome by an increased activity of the fatty acid beta oxidation in response to DHA pre-treatment.