P3‐058: PARTIAL INHIBITION OF MITOCHONDRIAL COMPLEX I ENHANCES MITOCHONDRIAL BIOENERGETICS VIA OXIDATIVE PHOSPHORYLATION SUPER‐COMPLEX REARRANGEMENT: IMPLICATION FOR ALZHEIMER'S DISEASE

Abstract

Alzheimer's disease (AD) is a devastating neuropathological age-related condition with an estimated current global prevalence upward of 46.8 million individuals. Recent efforts to combat the clinical presentation of AD through late- stage therapeutic intervention have met with little success. However, investigations of the biochemical deficits of the disease have highlighted the importance of mitochondrial and bioenergetics dysfunction as an early indicator of AD pathology. We have recently reported that modulation of the mitochondrial oxidative phosphorylation (OXPHOS) system through mild inhibition of complex I can abrogate the development of cognitive and behavioral phenotypes associated with neurodegeneration in AD. In tandem, we have also demonstrated that this modulation of mitochondrial complex I, through reversible inhibition at the FMN domain, serves to enhance both mitochondrial bioenergetics and function and protects against oxidative stress. We hypothesize that this mechanism of improved bioenergetics may be due to transformed OXPHOS complex and super-complex assembly, which culminates in a more efficient bioenergetics system. To test this hypothesis, we examined the assembly of mitochondrial OXPHOS complexes and super-complexes, using Blue Native Gel Electrophoresis (BNGE), in mitochondria from synaptosomes isolated from the brain tissue of non-transgenic and 3xTgAD mice treated with small molecule partial complex I inhibitors found efficacious in cognitive protection. An increased complex I association with the respirosome ( Super-Complex I+III+IV) was detected in isolated synaptosomal mitochondria following 72 hour treatment with small molecule partial complex I inhibitors. Our analyses demonstrates that complex I inhibitors alter the assembly of the OXPHOS system leading to a greater association of holo-complexes with supercomplex structure, which may aid in the enhancement of mitochondrial bioenergetics and function in AD.