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Dissecting metabolic control by cytosolic-mitochondrial NAD compartmentalization

Award Number: R35GM151097
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/05/2023
PERIOD OF PERFORMANCE END DATE: 04/30/2028

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Dissecting metabolic control by cytosolic-mitochondrial NAD compartmentalization - Abstract Nicotinamide adenine dinucleotide (NAD+) is a cofactor and signaling molecule that regulates critical processes from DNA repair to axon degeneration. NAD+ levels decline with mitochondrial dysfunction, in aging, and in various age- related pathologies. Moreover, studies have repeatedly shown that increased NAD+ levels are beneficial for cellular and organismal healthspan. Multiple cellular compartments contain NAD+-synthesis and NAD+-consuming signaling proteins, but little is known about the mechanisms by which NAD+ concentrations in each organelle are appropriately tuned to metabolic and signaling demands. Mitochondria harbor up to 70% of cellular NAD+, and NAD+ acts as an electron carrier in mitochondrial respiration and as a signaling molecule through the mitochondrial sirtuins. However, it is not known how the mitochondrial NAD+ pool is established and maintained or how it contributes to cellular metabolic control. Using gene co-essentiality analysis, we recently identified a mitochondrial transporter, SLC25A51, required for the uptake of NAD+ into mitochondria. We hypothesize that SLC25A51 is a major factor in cellular NAD+ compartmentalization and a critical player in metabolic homeostasis and a cell’s response to stress. A major long- term goal of our research program is to understand how cells regulate their mitochondrial NAD+ pool and NAD+ compartmentalization to control metabolism and signaling in health and disease. In the next five years, we will focus on three areas outlined in this proposal: 1) understanding the biochemical mechanism and driving forces of mitochondrial NAD+ transport by characterizing the activity of SLC25A51 in cell-free proteoliposome transport assays; 2) determining how mitochondrial NAD+ transport is regulated, by identifying the signaling pathway and transcription factors that regulate SLC25A51 expression and by elucidating how the protein is turned over in or removed from the inner mitochondrial membrane; and 3) delineating how cytosolic-mitochondrial NAD+ compartmentalization contributes to metabolic regulation in the liver using SLC25A51 loss-of-function mouse models. The results of our studies will provide important insights into the mechanisms of cellular NAD+ compartmentalization and identify new modes of metabolic regulation relevant for human disease. This research program is aligned with our laboratory’s overall goals to understand the mechanisms of metabolic compartmentalization, and specifically the role of mitochondrial transporters, in adjusting mitochondrial function to metabolic demands and cell state, and responding to stress.


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 = $398,750 )
2026	2026	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	1033 MASSACHUSETTS AVE STE 3	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Biomedical Research and Research Training	000	4	4/21/2026	NON-COMPETING CONTINUATION	$398,750
														Subtotal = $398,750

Issue Date FY: 2025 ( Subtotal = $398,750 )
2025	2025	HARVARD COLLEGE PRESIDENT & FELLOWS OF	677 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	000	3	4/14/2025	NON-COMPETING CONTINUATION	$398,750
														Subtotal = $398,750

Issue Date FY: 2024 ( Subtotal = $398,750 )
2024	2024	HARVARD COLLEGE PRESIDENT & FELLOWS OF	677 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	000	2	3/26/2024	NON-COMPETING CONTINUATION	$358,875
2024	2024	HARVARD COLLEGE PRESIDENT & FELLOWS OF	677 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	001	2	7/29/2024	NON-COMPETING CONTINUATION	$39,875
														Subtotal = $398,750

Issue Date FY: 2023 ( Subtotal = $371,975 )
2023	2023	HARVARD COLLEGE PRESIDENT & FELLOWS OF	677 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	000	1	7/5/2023	NEW	$371,975
														Subtotal = $371,975

Grand Total All Awards = $1,568,225

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Dissecting metabolic control by cytosolic-mitochondrial NAD compartmentalization

Award Number: R35GM151097

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/05/2023

PERIOD OF PERFORMANCE END DATE: 04/30/2028

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