Thursday, July 3, 2025 7/3/2025

Mitochondrial mRNA structure as a driver of Leigh Syndrome

Award Number: F30HD107939
ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 01/01/2022
PERIOD OF PERFORMANCE END DATE: 05/31/2025

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Mitochondrial mRNA structure as a driver of Leigh Syndrome - Leigh syndrome (LS) is a mitochondrial disease that causes irreversible developmental regression in children. Currently, no treatment options are available, and most children do not live to see their second birthday. LS is biochemically characterized by defective mitochondrial bioenergetics due to a variety of possibly mutated mitochondrial proteins, which can be encoded in both mitochondrial and nuclear DNA. Here, we will focus on two LS proteins: leucine rich pentacotripeptide repeat motif containing protein (LRPPRC), and transactivator of COXI (TACO1). Loss of LRPPRC decreases stability of all mRNAs, and also leads to loss of mRNA polyadenylation and the appearance of aberrant mitochondrial translation. Loss of TACO1 specifically prevents translation of COX1 mRNA. Despite this knowledge, the molecular mechanisms involved remain unknown. RNAs fold into complex structures that are integral to the diverse mechanisms underlying RNA regulation of gene expression. Recent development of RNA structure profiling through the application of structure-probing chemicals combined with high-throughput sequencing (such as DMS-MaPseq) has opened a new field that enormously expands the amount of RNA structural information available. With this technology available, here we propose to test the hypothesis that mutations in either LRPPRC or TACO1 lead to a downstream defect in the folding of mitochondrial mRNAs and subsequently to aberrant mtDNA gene expression. To test this hypothesis, we will follow two Aims and will use human cell lines knockout (KO) for each gene, which we are generating by using innovative CRISPR-Cas9 gene-editing approaches. In Aim 1, the KO lines will be reconstituted with wild-type or disease mutant gene variants and characterized physiologically in terms of cellular and mitochondrial bioenergetics, mitochondrial RNA processing and stability, as well as mitochondrial translation. Preliminary data on already available LRPPRC-KO cell lines have informed mitochondrial phenotypes compatible with those of LS patients. This will follow with establishment of in-cello mRNA binding sites of these proteins in wild-type cells using PAR-CLIP approaches. Finally, we will utilize ribosome-profiling assays to determine whether LRPPRC and TACO1 are binding their target mRNAs during translation. In Aim 2 we will use DMS-MaPseq to probe the native structures of the entire mitochondrial transcriptome in the KO and reconstituted cell lines. To ensure success in this undertaking, we will capitalize on our collaboration with Dr. Silvia Rouskin, the pioneer of DMS-MaPseq. We expect to answer basic questions regarding how these proteins interact with mRNA, affect their folding, and ultimately their stability, modification and translation. To fully understand the basic pathogenic mechanisms underlying the several LS forms is critical to the NICHD mission and a fundamental pre-requisite to develop therapeutics to target this kind of disorders. With this perspective, the proposed project is tailored to my training towards becoming a skilled physician scientist.


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 = $35,135 )
2025	2025	UNIVERSITY OF MIAMI	1320 S DIXIE HWY STE 1200	CORAL GABLES	FL	33146	MIAMI-DADE	USA	Child Health and Human Development Extramural Research	001	4	6/23/2025	NON-COMPETING CONTINUATION	-$18,839
2025	2025	UNIVERSITY OF MIAMI	1320 S DIXIE HWY STE 1200	CORAL GABLES	FL	33146	MIAMI-DADE	USA	Child Health and Human Development Extramural Research	000	4	12/19/2024	NON-COMPETING CONTINUATION	$53,974
														Subtotal = $35,135

Issue Date FY: 2024 ( Subtotal = $53,974 )
2024	2024	UNIVERSITY OF MIAMI	1320 S DIXIE HWY STE 1200	CORAL GABLES	FL	33146	MIAMI-DADE	USA	Child Health and Human Development Extramural Research	001	3	4/24/2024	NON-COMPETING CONTINUATION	$1,280
2024	2024	UNIVERSITY OF MIAMI	1320 S DIXIE HWY STE 1200	CORAL GABLES	FL	33146	MIAMI-DADE	USA	Child Health and Human Development Extramural Research	000	3	12/28/2023	NON-COMPETING CONTINUATION	$52,694
														Subtotal = $53,974

Issue Date FY: 2023 ( Subtotal = $52,694 )
2023	2023	UNIVERSITY OF MIAMI	1400 NW 10TH AVE	MIAMI	FL	33136	MIAMI-DADE	USA	Child Health and Human Development Extramural Research	001	2	2/7/2023	NON-COMPETING CONTINUATION	$942
2023	2023	UNIVERSITY OF MIAMI	1600 NW 10 AVE	MIAMI	FL	33136	MIAMI-DADE	USA	Child Health and Human Development Extramural Research	000	2	12/6/2022	NON-COMPETING CONTINUATION	$51,752
														Subtotal = $52,694

Issue Date FY: 2022 ( Subtotal = $51,752 )
2022	2022	UNIVERSITY OF MIAMI	1600 NW 10 AVE	MIAMI	FL	33136	MIAMI-DADE	USA	Child Health and Human Development Extramural Research	002	1	2/28/2022	NEW	$0
2022	2022	UNIVERSITY OF MIAMI	1600 NW 10 AVE	MIAMI	FL	33136	MIAMI-DADE	USA	Child Health and Human Development Extramural Research	000	1	12/30/2021	NEW	$51,036
2022	2022	UNIVERSITY OF MIAMI	1600 NW 10 AVE	MIAMI	FL	33136	MIAMI-DADE	USA	Child Health and Human Development Extramural Research	003	1	5/3/2022	NEW	$717
2022	2022	UNIVERSITY OF MIAMI	1600 NW 10 AVE	MIAMI	FL	33136	MIAMI-DADE	USA	Child Health and Human Development Extramural Research	001	1	12/30/2021	NEW	$0
2022	2022	UNIVERSITY OF MIAMI	1600 NW 10 AVE	MIAMI	FL	33136	MIAMI-DADE	USA	Child Health and Human Development Extramural Research	004	1	5/25/2022	NEW	-$1
														Subtotal = $51,752

Grand Total All Awards = $193,555

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Mitochondrial mRNA structure as a driver of Leigh Syndrome

Award Number: F30HD107939

ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 01/01/2022

PERIOD OF PERFORMANCE END DATE: 05/31/2025

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