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Mitochondrial Methionyl-tRNA Formyltransferase (MTFMT) Mouse Model to elucidate Mitochondrial Translation initiation Defect and Disease Mechanisms in Leigh Syndrome

Award Number: R21NS145159
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2025
PERIOD OF PERFORMANCE END DATE: 12/31/2025

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Mitochondrial Methionyl-tRNA Formyltransferase (MTFMT) Mouse Model to elucidate Mitochondrial Translation initiation Defect and Disease Mechanisms in Leigh Syndrome - Project Summary Mutations in genes that constitute the mitochondrial translational machinery cause various mitochondrial disorders. These disorders lead to a wide range of clinical manifestations, including but not limited to Leigh syndrome, (LS) mitochondrial encephalopathy, and myopathy. LS is a severe mitochondrial disorder caused by mitochondrial and nuclear DNA mutations. Biallelic mutations in MTFMT (OMIM 611766), a nuclear gene that encodes mitochondrial methionyl-tRNA formyltransferase, lead to combined oxidative phosphorylation (OXPHOS) deficiency and LS. MTFMT catalyzes the synthesis of N-formylmethionine-tRNAMet (fMet- tRNAMet or tRNAfMet), a crucial step in mitochondrial translation initiation and protein synthesis. Despite the established role of MTFMT mutations in LS, the precise mechanisms by which these mutations disrupt mitochondrial translation and cause LS remain unclear. The most common MTFMT mutation is c.626C>T, which generates a splicing suppressor resulting in exon 4 skipping and protein truncation (p. R181SfsX5). The lack of appropriate animal models has been a significant barrier in understanding the disease's pathogenesis. To bridge this knowledge gap, we have developed a novel transgenic mouse model, replacing murine exon 4 with either wild-type (WT) or mutant human exon 4 harboring the c.626C>T mutation. Preliminary data show that this model mimics exon 4 skipping, Mtfmt protein reduction, and decreased OXPHOS subunit levels, closely replicating the human molecular phenotype. This proposal seeks to utilize this innovative model to investigate the molecular and biochemical pathways disrupted by the MTFMT mutation. We aim to achieve the following: (1) Characterize the neurological and behavioral phenotypes of the Mtfmt murine model, focusing on motor function, anxiety-like behaviors, and disease progression, and (2) Define the molecular and biochemical mechanisms underlying mitochondrial dysfunction, with emphasis on mitochondrial translation fidelity, neuronal dysfunction, and gene expression. Our study will provide a novel platform for understanding LS pathogenesis and for developing potential therapies.


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 = $0 )
2026	2025	TRANSLATIONAL GENOMICS RESEARCH INSTITUTE	445 N 5TH ST	PHOENIX	AZ	85004	MARICOPA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	5/12/2026	NEW	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $543,351 )
2025	2025	TRANSLATIONAL GENOMICS RESEARCH INSTITUTE	445 N 5TH ST	PHOENIX	AZ	85004	MARICOPA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	7/31/2025	NEW	$543,351
														Subtotal = $543,351

Grand Total All Awards = $543,351

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Mitochondrial Methionyl-tRNA Formyltransferase (MTFMT) Mouse Model to elucidate Mitochondrial Translation initiation Defect and Disease Mechanisms in Leigh Syndrome

Award Number: R21NS145159

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/2025

PERIOD OF PERFORMANCE END DATE: 12/31/2025

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