Open AccessThe mitochondrial ATP synthase is a shared drug target for aging and dementia
Author(s) -
Goldberg Joshua,
Currais Antonio,
Prior Marguerite,
Fischer Wolfgang,
Chiruta Chandramouli,
Ratliff Eric,
Daugherty Daniel,
Dargusch Richard,
Finley Kim,
EsparzaMoltó Pau B.,
Cuezva José M.,
Maher Pamela,
Petrascheck Michael,
Schubert David
Publication year - 2018
Publication title -
aging cell
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.103
H-Index - 140
eISSN - 1474-9726
pISSN - 1474-9718
DOI - 10.1111/acel.12715
Subject(s) - biology , atp synthase , drug discovery , dementia , ampk , mitochondrion , microbiology and biotechnology , kinase , disease , biochemistry , protein kinase a , enzyme , medicine
Summary Aging 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‐F 1 ‐ ATP synthase ( ATP 5A) 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 ( CAMKK 2)‐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.