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Structural and functional characterization of ATP synthase c-subunit leak channel and its role in AD pathogenesis

Award Number: R01AG072484
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/15/2021
PERIOD OF PERFORMANCE END DATE: 04/30/2027

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Structural and functional characterization of ATP synthase c-subunit leak channel and its role in AD pathogenesis - Abstract Mitochondrial and synaptic dysfunction are early pathological features and a driving force of Alzheimer's disease (AD) pathology. Aβ is found to accumulate abnormally in the brains of AD individuals and in an AD mouse models leading to mitochondrial Ca2+ overload and activation of mitochondrial permeability transition pore (mPTP). Prolonged opening of mPTP triggers outer mitochondrial membrane rupture, release of cytochrome c and activation of downstream cell death pathways. The mPTP has been at the center of extensive scientific research for the last several decades but it still remains as one of the most mysterious phenomena in biology today due to its controversial molecular composition and the lack of structural information of its pore. We have recently demonstrated the novel role of ATP synthase c-subunit ring in forming the channel of mPTP. Nevertheless, the gating mechanism of the ATP synthase c-subunit leak channel and conformational changes initiating its opening are yet to be discovered. In this proposal, we will use single-particle cryo-electron microscopy (cryo-EM) to identify the high- resolution structure and the open conformation of ATP synthase leak channel in the presence of channel modulators. We will also perform in situ structural analysis of ATP synthase in its functional environment within the Aβ-exposed primary hippocampal neurons and in mitochondria isolated from the mouse models of AD by using cryo-electron tomography (cryo-ET). In this project we will also investigate the direct role of ATP synthase leak channel as a novel cell death pathway in AD pathogenesis; we will test whether the pharmacological inhibition of this channel will rescue neurons from Aβ-induced cell death. Successful completion of this proposal will reveal the molecular mechanism(s) of mitochondrial permeability transition, the atomic structure of ATP synthase leak channel, and will aid in the development of new treatments for AD, targeting ATP synthase.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $0 )
2026	2025	PENNSYLVANIA STATE UNIVERSITY	500 UNIVERSITY DRIVE	HERSHEY	PA	17033	DAUPHIN	USA	Aging Research	000	4	1/30/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $699,252 )
2025	2025	PENNSYLVANIA STATE UNIVERSITY	500 UNIVERSITY DRIVE	HERSHEY	PA	17033	DAUPHIN	USA	Aging Research	000	4	3/26/2025	NON-COMPETING CONTINUATION	$642,168
2025	2025	PENNSYLVANIA STATE UNIVERSITY	500 UNIVERSITY DRIVE	HERSHEY	PA	17033	DAUPHIN	USA	Aging Research	001	4	6/13/2025	NON-COMPETING CONTINUATION	$57,084
														Subtotal = $699,252

Issue Date FY: 2024 ( Subtotal = $928,928 )
2024	2024	PENNSYLVANIA STATE UNIVERSITY	500 UNIVERSITY DRIVE	HERSHEY	PA	17033	DAUPHIN	USA	Aging Research	001	3	9/10/2024	EXTENSION WITH OR WITHOUT FUNDS	$235,291
2024	2024	PENNSYLVANIA STATE UNIVERSITY	500 UNIVERSITY DRIVE	HERSHEY	PA	17033	DAUPHIN	USA	Aging Research	000	3	4/30/2024	EXTENSION WITH OR WITHOUT FUNDS	$693,637
														Subtotal = $928,928

Grand Total All Awards = $1,628,180

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Structural and functional characterization of ATP synthase c-subunit leak channel and its role in AD pathogenesis

Award Number: R01AG072484

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 05/15/2021

PERIOD OF PERFORMANCE END DATE: 04/30/2027

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