ATP synthase and Alzheimer’s disease: putting a spin on the mitochondrial hypothesis

Abstract

It is estimated that over 44 million people across the globe have dementia, and half of these cases are believed to be Alzheimer’s disease (AD). As the proportion of the global population which is over the age 60 increases so will the number of individuals living with AD. This will result in ever-increasing demands on healthcare systems and the economy. AD can be either sporadic or familial, but both present with similar pathobiology and symptoms. Three prominent theories about the cause of AD are the amyloid, tau and mitochondrial hypotheses. The mitochondrial hypothesis focuses on mitochondrial dysfunction in AD, however little attention has been given to the potential dysfunction of the mitochondrial ATP synthase in AD. ATP synthase is a proton pump which harnesses the chemical potential energy of the proton gradient across the inner mitochondrial membrane (IMM), generated by the electron transport chain (ETC), in order to produce the cellular energy currency ATP. This review presents the evidence accumulated so far that demonstrates dysfunction of ATP synthase in AD, before highlighting two potential pharmacological interventions which may modulate ATP synthase.

The Causal Role of Lipoxidative Damage in Mitochondrial Bioenergetic Dysfunction Linked to Alzheimer’s Disease Pathology

“…Complex V has a central role in cellular energy (as ATP) supply. Figure 4 shows the structure of the mitochondrial ATP synthase in light of current knowledge [ 147 , 148 ].…”

“…Available evidence demonstrates that ATP synthase is a selectively damaged vital protein. This modification consists of the nonenzymatic modification of different complex V subunits by reactive compounds generated from lipid peroxidation (lipoxidation-derived protein damage) [ 18 , 141 , 147 , 149 ]. The lipoxidation damage mostly and preferentially affects the α and β subunits [ 149 ], although the specific residues targeted are still unknown.…”

“…The two domains are connected by a peripheral and central stalk. For additional structural and functional details see [ 147 , 148 ]. Functionally, the F0 domain is a trans-membrane channel that translocates protons and F1, a synthase domain that binds to ADP and inorganic phosphate and synthesizes ATP.…”

“…The oxidative and lipoxidative non-enzymatic modificationm—ediated by reactive oxygen species (ROS) and carbonyl species (RCS), respectively—of ATP synthase observed during early stages of AD pathology mostly and preferentially affects the α and β subunits. Reproduced and modified with permission from [ 147 ].…”

Lipid Peroxidation and Antioxidant Supplementation in Neurodegenerative Diseases: A Review of Human Studies

“…The onset of familial AD relates to genetic mutations in enzymes that are involved in amyloid precursor protein (APP) processing, whereas the etiology of sporadic AD is still unclear [ 102 ]. The complex and heterogeneous AD pathophysiology is dominated by two main hallmarks: overproduction and extracellular deposition of Aß and the formation of intracellular neurofibrillary tangles (NFTs), consisting of hyperphosphorylated tau protein [ 103 ]. The aberrant aggregations of Aβ and tau create an overall cytotoxic environment that results in the disturbance of neuronal cell shape and function, including the disturbance of ATP production, axonal transport, and synaptic signaling, together leading to severe cognitive and motor impairment characteristic for AD [ 104 ].…”