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Structure, Turnover and Safeguard of Mitochondria

Award Number: R35GM144103
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: 01/01/2022
PERIOD OF PERFORMANCE END DATE: 12/31/2026

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Structure, Turnover and Safeguard of Mitochondria - Summary Mitochondria are essential organelles that control the life and death of cells. Mitochondria are highly dynamic: They grow, divide, and fuse, and when they eventually become damaged, undergo degradation Mitochondrial division is mediated by a dynamin-related GTPase, DRP1, while fusion is mediated by two dynamin-related GTPases, OPA1 and mitofusin. These GTPases are mutated in human diseases, including neurodevelopmental disorder, Charcot-Marie-Tooth neuropathy, and optic atrophy. Altered activities of these proteins have also been linked to metabolic syndrome, cardiovascular disease, and age-related neurodegeneration. My laboratory’s goal is to decipher the molecular mechanisms that control mitochondrial structure and translate the fundamental biology to disease interventions. In the past two decades, we have identified and characterized the three essential GTPases in the core reactions of membrane fusion and division. The roles of mitochondrial dynamics are ever-expanding, and now include size control of mitochondria, their distribution and turnover, and differentiation of neurons, cardiomyocytes, stem cells, and immune cells. Most recently, it became evident that the mechanisms of mitochondrial division and fusion are much more complex than initially imagined, involving inter-organelle interactions and a feedback response that monitors and tunes their balance. The emerging new biology is transforming the field of mitochondrial structure and dynamics. In the next 5 years, we will address the important questions raised by this intellectual evolution. First, to our surprise, we found that DRP1 shapes the endoplasmic reticulum (ER) into tubules that form contract sites with mitochondria. DRP1-produced ER-mitochondria contact sites strongly promote mitochondrial division. We will investigate how DRP1 creates ER-mitochondria contact sites that specifically function in mitochondrial division, associates with the ER, and deforms the ER membrane. Second, we discovered a physiological pathway of mitochondrial turnover via DRP1-controlled, Parkin/PINK1- independent mitophagy in mice. This pathway’s most upstream event is to recognize and mark damaged mitochondria by ubiquitination of mitochondrial proteins. Our initial experiments suggested that ubiquitination occurs in two phases – reversible initiation and committed amplification. We will determine what ubiquitinates mitochondria in each phase, and how the ubiquitin ligase complexes recognize and label damaged mitochondria in vivo. Third, we found the first example of a stress response (MitoSafe) that senses and adjusts the mitochondrial structure by controlling the balance between fusion and division. We will explore the molecular basis of MitoSafe and its physiological roles in mice. The MIRA grant will enable us to discover the new logics of mitochondrial structure and its physiological role and regulation in vivo.


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 = $581,247 )
2026	2026	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Biomedical Research and Research Training	000	5	12/23/2025	NON-COMPETING CONTINUATION	$523,122
2026	2026	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Biomedical Research and Research Training	001	5	3/16/2026	NON-COMPETING CONTINUATION	$58,125
														Subtotal = $581,247

Issue Date FY: 2025 ( Subtotal = $581,247 )
2025	2025	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Biomedical Research and Research Training	002	4	8/6/2025	NON-COMPETING CONTINUATION	$58,125
2025	2025	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Biomedical Research and Research Training	001	4	12/17/2024	NON-COMPETING CONTINUATION	$523,122
2025	2024	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Biomedical Research and Research Training	000	3	11/6/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $581,247

Issue Date FY: 2024 ( Subtotal = $671,381 )
2024	2024	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Biomedical Research and Research Training	001	3	5/20/2024	NON-COMPETING CONTINUATION	$58,125
2024	2024	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Biomedical Research and Research Training	000	3	11/27/2023	NON-COMPETING CONTINUATION	$523,122
2024	2024	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Biomedical Research and Research Training	002	3	8/14/2024	SUPPLEMENT FOR EXPANSION	$90,134
														Subtotal = $671,381

Issue Date FY: 2023 ( Subtotal = $596,917 )
2023	2023	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Biomedical Research and Research Training	000	2	12/19/2022	NON-COMPETING CONTINUATION	$523,122
2023	2023	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Biomedical Research and Research Training	002	2	6/14/2023	SUPPLEMENT FOR EXPANSION	$15,670
2023	2023	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Biomedical Research and Research Training	001	2	4/5/2023	NON-COMPETING CONTINUATION	$58,125
														Subtotal = $596,917

Issue Date FY: 2022 ( Subtotal = $380,635 )
2022	2022	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Biomedical Research and Research Training	000	1	12/22/2021	NEW	$340,731
2022	2022	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Biomedical Research and Research Training	001	1	5/26/2022	SUPPLEMENT FOR EXPANSION	$39,904
														Subtotal = $380,635

Grand Total All Awards = $2,811,427

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Structure, Turnover and Safeguard of Mitochondria

Award Number: R35GM144103

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: 01/01/2022

PERIOD OF PERFORMANCE END DATE: 12/31/2026

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