Flannery, Padraig J.

AbstractBackgroundAlzheimer’s disease (AD) is a devastating neuropathological condition where age is the greatest risk factor. There is currently an estimated global prevalence upward of 46.8 million individuals and recent efforts to combat the clinical presentation of AD through late‐stage Amyloid‐beta (Aβ) targeted therapeutic intervention has not been successful, underscoring the need for novel approaches to slow disease progression. Accumulating evidence proposes that mitochondrial and metabolic homoeostasis is an early dysfunction which occurs decades before the presentation of clinical symptoms. Indeed AD has been classified as type‐3 diabetes, suggesting the need to target metabolic modifiers to slow or even abrogate neurodegeneration. We have recently reported that targeting the oxidative phosphorylation (OXPHOS) system through mild inhibition of NADH dehydrogenase (Complex I) with our small molecules partial Complex I inhibitors (MCIi) can halt the development of cognitive and behavioral phenotypes associated with AD. We have also demonstrated that this modulation of mitochondrial complex I, through reversible inhibition at the Flavin Mononucleotide (FMN) domain, serves to enhance mitochondrial bioenergetics and function and protects against oxidative stress. We hypothesize that this mechanism of improved bioenergetics may be due to transformed OXPHOS super‐complex assembly, which can lead to a more efficient bioenergetics system and protect against extrinsic stress.MethodsTo test this hypothesis, we examined bioenergetics and the assembly of mitochondrial OXPHOS complexes and super‐complexes in mitochondria from primary cortical neurons and synaptosomes isolated from the brain tissue of non‐transgenic and 3xTgAD mice treated with MCli using respiratory XF Seahorse analysis, BNPAGE and 2D‐BNPAGE.ResultsOur analyses demonstrates that MCIi can acutely alter the assembly of super‐complexes within the OXPHOS system and protect against stress through enhanced spare respiratory capacity while preserving ATP level, which may aid in the enhancement of mitochondrial bioenergetics and function in AD.ConclusionPartial complex I inhibitors can induce positive bioenergetics through super‐complex assembly