Clinical observations have suggested that mitochondrial dysfunction is among the earliest manifestations of Alzheimer’s disease (AD) and constitutes a hallmark pathological feature of this neurological disorder. Previous studies have also identified impaired mitochondrial oxidative phosphorylation (OXPHOS) as a feature of mitochondrial defects in AD individuals and AD animal models. Compromised mitochondrial OXPHOS efficiency results in lowered mitochondrial bioenergetics and exaggerated production of free radicals.

Indeed, ATP deficiency and oxidative damage are characteristics of brains from AD patients. Impaired mitochondrial OXPHOS efficiency is closely associated with dysfunction of mitochondrial respiratory enzymes, including mitochondrial complex I to IV, as well as the defect of F1FO-ATP synthase.

Previous studies have mostly focused on the dysfunction of mitochondrial complex IV in AD. However, this concept has been recently challenged. In fact, in addition to mitochondrial respiratory enzyme defects, increasing evidence implicates the dysfunction of mitochondrial F1FO-ATP synthase in AD.

The mitochondrial F1FO-ATP synthase, which includes three components (F1, FO and the peripheral stalk), is a critical mitochondrial OXPHOS enzyme involved in the regulation of mitochondrial ATP production and in the maintenance of the mitochondrial membrane potential. The F1FO-ATP synthase can both synthesize ATP and degrade ATP when operating in reverse to generate proton backflow, increasing mitochondrial membrane potential when it is critically low.

In addition to its vital function in mitochondrial OXPHOS, recent studies have shown that this enzyme contributes to the formation of the mitochondrial permeability transition pore (mPTP) through the interaction of its oligomycin sensitivity conferring protein (OSCP) subunit with cyclophilin D (CypD), the key regulator of mPTP.

Extensive formation of mPTP is a severe mitochondrial pathological event that leads to collapsed mitochondrial membrane potential (mΔΨ), decreased mitochondrial OXPHOS capacity, elevated reactive oxygen species (ROS) generation and, eventually, cell death. Indeed, mPTP activation is thought to be a key mechanism of mitochondrial stress in AD and has been proposed to underlie its characteristic synaptic dysfunction and cognitive decline. Given its role in mitochondrial OXPHOS and mPTP formation, the deregulation of mitochondrial F1FO-ATP synthase may predispose to compromised OXPHOS efficiency and sensitized mPTP formation, which are two hallmark mitochondrial defects in AD.

However, to date information on the dysfunction of F1FO-ATP synthase in AD has remained limited. Accordingly, the underlying molecular mechanisms causing the defect of this enzyme in AD remain unresolved.

In this study, researchers compare the levels of major F1FO-ATP synthase subunits in the brains from AD individuals, mild cognitive impairment (MCI) patients and non-AD control subjects, and find a selective decrease in the levels of OSCP during the progression of AD.

They also find that, in a mouse model of AD that overexpresses the human form of amyloid beta (Aβ), the loss of OSCP is more prominent in synaptic mitochondria. In addition to OSCP loss, authors also detect a direct physical interaction between OSCP and Aβ in the brains from AD cases, as well as in AD mice. Such OSCP aberrations disrupt F1FO-ATP synthase stability, leading to severe mitochondrial dysfunction and synaptic injury.

Further in vivo studies show the deleterious impact of F1FO-ATP synthase dysfunction on the development of mitochondrial defects in AD mice. Importantly, the restoration of OSCP ameliorates the Aβ-mediated mitochondrial dysfunction and synaptic injury in mouse or human neurons, further supporting the role of OSCP deregulation in mitochondrial dysfunction under Aβ-rich conditions.

Therefore, mitochondrial F1FO-ATP synthase dysfunction that results from OSCP aberrations may constitute a primary AD event that can be prevented by OSCP protection, suggesting OSCP as a potential new therapeutic target for AD.

http://www.nature.com/ncomms/2016/160506/ncomms11483/full/ncomms11483.html