The mitochondrial ATP synthase is a shared drug target for aging and dementia

Abstract

SummaryAging is a major driving force underlying dementia, such as that caused by Alzheimer's disease (AD). While the idea of targeting aging as a therapeutic strategy is not new, it remains unclear how closely aging and age‐associated diseases are coupled at the molecular level. Here, we discover a novel molecular link between aging and dementia through the identification of the molecular target for the AD drug candidate J147. J147 was developed using a series of phenotypic screening assays mimicking disease toxicities associated with the aging brain. We have previously demonstrated the therapeutic efficacy of J147 in several mouse models of AD. Here, we identify the mitochondrial α‐F1‐ATP synthase (ATP5A) as a target for J147. By targeting ATP synthase, J147 causes an increase in intracellular calcium leading to sustained calcium/calmodulin‐dependent protein kinase kinase β (CAMKK2)‐dependent activation of the AMPK/mTOR pathway, a canonical longevity mechanism. Accordingly, modulation of mitochondrial processes by J147 prevents age‐associated drift of the hippocampal transcriptome and plasma metabolome in mice and extends lifespan in drosophila. Our results link aging and age‐associated dementia through ATP synthase, a molecular drug target that can potentially be exploited for the suppression of both. These findings demonstrate that novel screens for new AD drug candidates identify compounds that act on established aging pathways, suggesting an unexpectedly close molecular relationship between the two.

A curcumin derivative J147 ameliorates diabetic peripheral neuropathy in streptozotocin (STZ)-induced DPN rat models through negative regulation AMPK on TRPA1

“…: 1146963-51-0) when screening compounds from plants with the ability to reverse brain aging cells and molecular marker. Several reports suggest that J147 can reverse memory deficits, enhance the production of new brain cells, and retard the progression of Alzheimer's disease in rats 16,17 .Related the study of molecular mechanisms have found that J147 combines with the proteins mitochondrial proteins via ATP synthase, there by promoting aging cells, mice and fruit flies to look younger 17 . Besides, Lian et al 18 reports that J147 improves the depression-like behavior in mouse models caused by chronic stress, and its mechanism may involve the regulation of cAMP/pCREB/ BDNF pathway.…”

Deciphering the ‘Elixir of Life’: Dynamic Perspectives into the Allosteric Modulation of Mitochondrial ATP Synthase by J147, a Novel Drug in the Treatment of Alzheimer's Disease

“…Among the numerous pathogenic proteins identified, mitochondrial ATP synthase (mATP synthase) has been recently explored as a viable therapeutic target, having been implicated in the progression of the disease. [10] Decreased activity of mitochondrial electron transport chain enzymes or F 1 F 0 -ATPase (ATP synthase complex V) is likely to alter brain ATP synthesis and lead to the production of reactive oxygen species, which in intense cases, causes neuronal cell death. [11,12] ATP synthase is also implicated in the neurofibrillary degeneration of AD and depicted by the cytosolic accumulation of this mitochondrial protein.…”

“…[13] Reports by Goldberg et al revealed that J147 (N-(2,4-dimethylphenyl)-2,2,2-trifluoro-N'-[(E)-(3-methoxyphenyl)methylidene]acetohydrazide), a derivative of curcumin, therapeutically binds to the α-F1 subunit of mATP synthase (ATP5A) with high affinity and allosterically modulates its activity (Figure 1). [10] JI47 successfully slowed down progression of AD, countered memory loss and enhances the generation of new brain cells, hence it was described as the 'elixir of life'.…”

“…As such, J147 has proven to be effective against the treatment of AD, with evidence of disease reversal in mice models. [10] In modulating the activity of mATP synthase, J147 protect neuronal cells from multiple toxicities associated with the aging brain whilst regulating the levels of other molecules, including ATP. The inhibitory activity of J147 at the allosteric site of mATP synthase could influence the motions and activity of the different components (subunits) of this protein, which, coordinately drive the overall regula-tory activity of ATP synthase which majorly include ATP hydrolysis and synthesis.…”

“…The inhibitory activity of J147 at the allosteric site of mATP synthase could influence the motions and activity of the different components (subunits) of this protein, which, coordinately drive the overall regula-tory activity of ATP synthase which majorly include ATP hydrolysis and synthesis. [10,[14][15][16] Moreover, an indepth understanding into the molecular mechanisms associated with the therapeutic activity of J147 will provide essential insights that could drive the structure-based design of potent allosteric modulators of mATP synthase with respect to the amelioration of AD-related pathologies. Therefore, in this study, we employed advanced bio-computational approaches and molecular modeling tools to provide molecular perspectives and conformational dynamics that reflect the modulatory activity of J147 towards mATP synthase.…”