Tuesday, July 1, 2025 7/1/2025

Mitoribosome protein translation signaling and survival mechanisms

Award Number: R01AG086369
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/30/2023
PERIOD OF PERFORMANCE END DATE: 05/31/2028

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Mitoribosome protein translation signaling and survival mechanisms - Abstract Defective mitochondrial function causes cellular damage and death under stress conditions. At the organismal level mitochondrial dysfunction occurs in mitochondrial diseases caused by genetic mutations, neurodegeneration, and with less severity during aging, damaging vulnerable tissues such as brain and skeletal muscle. Mitochondrial mutations cause failures that disrupt energy metabolism, including reductive/oxidative imbalances and inflammation that lead to tissue damage and eventually death. Mitochondrial defective cells depend on glycolysis for energy generation and, similar to mitochondrial disease patients, are vulnerable to stress conditions. The mechanisms that cause this cell damage and how mitochondrial defective cells can be protected against damage and death are largely unknown. This is important because there are no cures for mitochondrial diseases, and dysfunctional mitochondria is one of the hallmarks of aging or neurodegeneration. In genetic and chemical high throughput screens our laboratory has identified a subset of antibiotics, including tetracyclines, that target the mitoribosome protein translation, and rescue cell death and inflammation in cellular and mouse models of mitochondrial diseases. Tetracyclines-promoted cell survival depends on suppression of ER stress and Unfolded Protein Response (UPR) that is independent of the transcription factor ATF4. The mechanisms of how tetracycline-induced mitoribosome stalling/splitting protect against cell death in cellular and mouse pre-clinical models of mitochondrial diseases is unknown. We hypothesize that a signaling mechanism initiated at the stalled/split mitoribosome promotes cell survival in the context of mitochondrial defective cells and human disease mutations. The main goal of this application is to identify the signaling and cellular mechanisms caused by stalled and split mitoribosomes that promote cell survival and determine the efficacy in cellular and mouse models of mitochondrial diseases. We propose 1) to determine the initial signaling mechanism at the partial stalled/split mitoribosome that promotes survival in mitochondrial disease mutant cells, focusing on MALSU splitting factor and additional proteins associated at the mitoribosome; 2) to analyze the components downstream of the stalled/split mitoribosome that promote survival in mitochondrial disease mutant cells, focusing on components that link the stalled/split mitoribosome to ER stress IRE1a and UPR responses and 3) to analyze the effects of tetracycline analogs in Ndufs4 KO mice, a mitochondrial complex I deficient mouse model, focusing on the effects tetracyclines on fitness, survival and modulation of mitoribosome signaling/ER stress and suppression of brain and skeletal muscle immune inflammation in Ndufs4 KO mice. The outcomes of this application will determine the regulatory and signaling mechanisms that are initiated by the stalled/split mitoribosome in conditions of defective mitochondrial disease mutations. These mechanisms will advance our understanding of mitoribosome protein translation and signaling mechanisms that protect cell damage in the context of mitochondrial dysregulation and diseases.


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: 2025 ( Subtotal = $712,792 )
2025	2025	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Aging Research	001	3	6/10/2025	NON-COMPETING CONTINUATION	$58,186
2025	2025	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Aging Research	000	3	5/2/2025	NON-COMPETING CONTINUATION	$654,606
														Subtotal = $712,792

Issue Date FY: 2024 ( Subtotal = $727,340 )
2024	2024	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Aging Research	000	2	6/27/2024	NON-COMPETING CONTINUATION	$727,340
														Subtotal = $727,340

Issue Date FY: 2023 ( Subtotal = $727,340 )
2023	2023	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Aging Research	000	1	9/21/2023	NEW	$727,340
														Subtotal = $727,340

Grand Total All Awards = $2,167,472

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Mitoribosome protein translation signaling and survival mechanisms

Award Number: R01AG086369

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/30/2023

PERIOD OF PERFORMANCE END DATE: 05/31/2028

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