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NAD subcellular compartmentalization drives resilience to aging-associated neurodegeneration

Award Number: RF1AG097611
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/06/2026
PERIOD OF PERFORMANCE END DATE: 07/31/2030

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NAD subcellular compartmentalization drives resilience to aging-associated neurodegeneration - Project Summary/Abstract: NAD is an essential cellular metabolite whose proper supply and regulation are required to maintain healthy neurons that form functional axons and synapses. NAD depletion is a hallmark of neurodegenerative disease and associated with cerebral ischemia, excitotoxicity, and DNA damage. Aging, the strongest risk for neurodegeneration, also coincides with NAD decline. NAD is compartmentalized in three primary subcellular pools—nuclear, cytosolic, and mitochondrial—with particular biosynthetic enzymes (NMNAT1, 2 & 3) associated with each. NAD is exchanged freely between the nuclear and cytosolic pools, but it cannot diffuse across the mitochondrial matrix membrane. SARM1, the chief executioner of programmed axon degeneration, is activated by reduced NAD and triggers axon degeneration by further depleting NAD in the cytosol. Surprisingly, our preliminary data demonstrates that loss of mitochondrial rather than cytosolic NAD is the proximate cause of SARM1-dependent axon degeneration, and that manipulations that increase and maintain mitochondrial NAD enhance neuronal resilience. We find that the mitochondrial NAD biosynthetic enzyme, NMNAT3, promotes axonal survival when cytosolic NAD falls, as does the mitochondrial NAD importer, SLC25A51. We also identified a previously unrecognized mitochondrial NAD exporter, and found that it conversely promotes and accelerates axon degeneration by depleting mitochondrial NAD. Experimental manipulations or pathological changes that alter mitochondrial NAD concentration likely affect neuronal resilience by influencing necessary NAD-dependent processes in the mitochondria, e.g. Sirt3-mediated deacetylation. In this proposal, we outline experiments to elucidate the regulation of the subcellular compartmentalization of NAD and its central role mediating neuronal resilience in health and disease using tissue-specific gene knockout and viral addback approaches. In addition to NAD biosynthesis, we will also interrogate the role of mitochondrial NAD homeostasis and its effects on vital processes within the mitochondria, including deacetylation. Finally, we will define the function of a putative mitochondrial NAD exporter we identified, and determine its role in cellular metabolism. Together, these proposed investigations will lay crucial groundwork to pursue targeting mitochondrial NAD maintenance as a therapeutic strategy for neuronal injury and degenerative disease.


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 = $3,210,431 )
2026	2026	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Aging Research	000	1	8/5/2026	NEW	$3,210,431
														Subtotal = $3,210,431

Grand Total All Awards = $3,210,431

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NAD subcellular compartmentalization drives resilience to aging-associated neurodegeneration

Award Number: RF1AG097611

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/06/2026

PERIOD OF PERFORMANCE END DATE: 07/31/2030

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