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Unraveling the roles of SLC25A22 and SLC25A46 in mitochondrial metabolism and neurological disorders

Award Number: R03NS147002
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: 09/11/2026
PERIOD OF PERFORMANCE END DATE: 08/31/2027

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Unraveling the roles of SLC25A22 and SLC25A46 in mitochondrial metabolism and neurological disorders - PROJECT SUMMARY/ABSTRACT Mitochondrial solute carriers (SLC25A family) are crucial for transporting metabolites across the mitochondrial membrane, a process essential for cellular metabolism. Of the 53 known SLC25 family members, 16 have been linked to human Mendelian disorders, many of which present as neuro-metabolic abnormalities affecting brain development and function. Despite well-established genetic associations, the mechanisms by which SLC25A gene loss leads to disease remain largely unknown, partly due to the lack of robust in vivo models. This proposal aims to address these gaps by developing and characterizing Drosophila models of SLC25A46 (an orphan mitochondrial carrier) and SLC25A22 (a glutamate carrier), both strongly associated with human neurological disorders and highly conserved in Drosophila. Using advanced Drosophila genetic tools, we generated a T2A-Gal4 knock-in fly for Slc25a46a, the Drosophila homolog of human SLC25A46, whose loss-of-function variants cause Charcot-Marie-Tooth type 2- like neurodevelopmental disorder. Our studies revealed that Slc25a46a is highly expressed in neurons, and null mutant flies exhibit locomotion defects and hyperfused mitochondria, consistent with human SLC25A46-deficient cells. Metabolic profiling further identified accumulation of branched-chain amino acids (BCAAs) in mutant brains, suggesting a role for SLC25A46 in mitochondrial BCAA import and catabolism. We hypothesize that SLC25A46 mutations cause neurological dysfunction by disrupting mitochondrial fission, impairing BCAA metabolism, and dysregulating mTORC1 signaling, which we will investigate in Aim 1. In Aim 2, we will develop and characterize a Drosophila model of SLC25A22-associated neonatal epileptic encephalopathy. Given that SLC25A22 deficiency in human cells impairs mitochondrial glutamate transport and reduces glutathione (GSH) levels, we hypothesize that mutations in SLC25A22 contribute to epileptic encephalopathy by impairing mitochondrial glutamate metabolism and increasing oxidative stress in neurons and glial cells, which we will test in Aim 2. This work leverages Drosophila models to investigate SLC25A46- and SLC25A22-associated disorders, providing critical mechanistic insights and potential therapeutic strategies. The findings will significantly impact our understanding of mitochondrial metabolism and dynamics, with broad implications for neurodevelopmental and neurodegenerative 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: 2026 ( Subtotal = $170,500 )
2026	2026	OKLAHOMA MEDICAL RESEARCH FOUNDATION	825 NE 13TH ST	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	9/11/2026	NEW	$170,500
														Subtotal = $170,500

Grand Total All Awards = $170,500

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Unraveling the roles of SLC25A22 and SLC25A46 in mitochondrial metabolism and neurological disorders

Award Number: R03NS147002

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: 09/11/2026

PERIOD OF PERFORMANCE END DATE: 08/31/2027

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