ATP Synthase and Mitochondrial Bioenergetics Dysfunction in Alzheimer’s Disease

Abstract

Alzheimer’s Disease (AD) is the most common neurodegenerative disorder in our society, as the population ages, its incidence is expected to increase in the coming decades. The etiopathology of this disease still remains largely unclear, probably because of the highly complex and multifactorial nature of AD. However, the presence of mitochondrial dysfunction has been broadly described in AD neurons and other cellular populations within the brain, in a wide variety of models and organisms, including post-mortem humans. Mitochondria are complex organelles that play a crucial role in a wide range of cellular processes, including bioenergetics. In fact, in mammals, including humans, the main source of cellular ATP is the oxidative phosphorylation (OXPHOS), a process that occurs in the mitochondrial electron transfer chain (ETC). The last enzyme of the ETC, and therefore the ulterior generator of ATP, is the ATP synthase. Interestingly, in mammalian cells, the ATP synthase can also degrade ATP under certain conditions (ATPase), which further illustrates the crucial role of this enzyme in the regulation of cellular bioenergetics and metabolism. In this collaborative review, we aim to summarize the knowledge of the presence of dysregulated ATP synthase, and of other components of mammalian mitochondrial bioenergetics, as an early event in AD. This dysregulation can act as a trigger of the dysfunction of the organelle, which is a clear component in the etiopathology of AD. Consequently, the pharmacological modulation of the ATP synthase could be a potential strategy to prevent mitochondrial dysfunction in AD.

Cross-Talking Pathways of Forkhead Box O1 (FOXO1) Are Involved in the Pathogenesis of Alzheimer’s Disease and Huntington’s Disease

“…Subsequently, activated FOXO1 disrupts mitochondrial oxidative and phosphorylation activities (OXPHOS), resulting in deficient ATP synthesis and metabolic disorders [ 46 ]. Notably, the resultant bioenergetic deficits in astrocytes and neurons are one of the most prevalent early features of AD [ 47 ]. This is in line with evidence in HD mouse models that mutant HTT (mHTT) aggregation recruits IRS-2 to activate FOXO1 via the PI3K/Akt/FOXO1 pathway, which contributes to mitochondrial dysfunction [ 48 ].…”

“…Moreover, even in HD patients with normal glycaemia, there is substantial insulin resistance [ 50 ]. Yamamoto et al have demonstrated that activation of IRS-2 not only affects mitochondrial function but also leads to autophagy of accumulated mHTT proteins via the PI3K/Akt pathway, a branch of insulin signaling pathway highlighting the importance of insulin regulatory mechanisms for HD pathogenesis [ 47 ]. This is consistent with our results on the cross-talking pathways of FOXO1 in HD patients.…”

Artificial intelligence-driven meta-analysis of brain gene expression identifies novel gene candidates and a role for mitochondria in Alzheimer’s Disease

“…Here, the top three gene candidates included ATP5J, ATP5L and ATP5H, all of which encode subunits of the F 0 functional domain of mitochondrial complex V (also known as F 1 F 0 ATP synthase). Complex V is the final complex in the electron transport chain and produces ATP through the phosphorylation of ADP [22][23][24] . Mitochondria are increasingly shown to contribute to the development and progression of AD, with evidence suggesting both primary and secondary dysfunctional mitochondrial cascades (for reviews see 25,26 ).…”

“…Specifically, mitochondrial dysfunction not only affects AD pathology, including APP activity and β amyloid (Aβ) accumulation, but AD pathology also leads to further mitochondrial dysfunction 26 . Little research has examined a role for complex V in AD, with most studies looking at it only as a consequence rather than a driver of AD pathology (for reviews see 23, 24 ). In support of the idea that complex V dysfunction may precede AD neuropathology, two recent genome-wide association study (GWAS) meta-analyses of approximately 25,00 and 50,000 people, respectively, identified a shared ATP5H/KCTD2 locus for AD risk 27, 28 .…”

Mitochondrial Inorganic Polyphosphate (polyP) Is a Potent Regulator of Mammalian Bioenergetics in SH-SY5Y Cells: A Proteomics and Metabolomics Study

“…The metabolism of polyP in these cells still remains poorly understood, even though a study showing the effects of the mitochondrial F 0 F 1 -ATP synthase in the synthesis and degradation of the polymer in the presence of mitochondrial respiration substrates and phosphates has been recently published ( Bayev et al, 2020 ). However, additional pathways independent of the ATP synthase are probably also involved in the metabolism of polyP in mammalian cells ( Borden et al, 2021 ; McIntyre and Solesio, 2021 ; Patro et al, 2021 ). In bacteria and yeast, the metabolism of the polymer is well-described.…”