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Investigating Citric Acid Cycle Perturbations in Complex I Deficient Mitochondrial Encephalopathy

Award Number: R01NS126851
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: 05/01/2022
PERIOD OF PERFORMANCE END DATE: 04/30/2026

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Investigating Citric Acid Cycle Perturbations in Complex I Deficient Mitochondrial Encephalopathy - ABSTRACT Mitochondrial diseases are respiratory chain disorders in which the mitochondria are no longer operating efficiently to produce ATP, usually due to a problem with one or more components of the oxidative phosphorylation machinery. Mitochondrial diseases manifesting as encephalopathies occur at a rate of 1 in 5000 live births and are often fatal in the first few years of life. The genetic cause and clinical course of these encephalopathies, e.g., Complex I deficient Leigh Syndrome, are well-described. The effective treatment of these diseases is limited by our lack of mechanistic understanding of pathomechanisms that drive neuronal decline, beyond the known Complex-I bioenergetic deficit. We have previously described the reaction of the citric acid cycle metabolite fumarate with protein cysteine residues to generate an irreversible modification, 2-succinocysteine (2SC), also known as protein succination. Fumarate and protein succination increase in the Ndufs4 knockout mouse model of mitochondrial Complex I deficiency. We demonstrate that the succination of a component of the α-ketoglutarate dehydrogenase (α- KGDH) complex impairs the enzymatic activity of this complex. This results in decreased succinyl CoA production, and impaired substrate level phosphorylation to produce much needed GTP/ATP. We hypothesize that metabolic acidosis derived from the Complex I loss redirects α-KG toward 2-hydroxyglutarate production. We predict that this influences the epigenetic landscape in the affected neurons. The citric acid cycle of other non-neuronal cells are also impacted in the Ndufs4 knockout mouse. We show preliminary data to demonstrate an impaired ability to produce itaconate, an important anti-inflammatory metabolite. This is significant given the accumulation of microglia in the center of neuropathological lesions. Our novel hypotheses link specific citric acid cycle perturbations to the chemical modifications of proteins that may accelerate the biochemical damage within the regions most affected by pathology. To address these specific pathomechanisms we outline targeted therapeutic approaches that should reduce the drivers of neuropathology.


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 = $372,500 )
2025	2025	UNIVERSITY OF SOUTH CAROLINA	1600 HAMPTON ST	COLUMBIA	SC	29208	RICHLAND	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	6/2/2025	NON-COMPETING CONTINUATION	$372,500
														Subtotal = $372,500

Issue Date FY: 2024 ( Subtotal = $361,325 )
2024	2024	UNIVERSITY OF SOUTH CAROLINA	1600 HAMPTON ST	COLUMBIA	SC	29208	RICHLAND	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	5/22/2024	NON-COMPETING CONTINUATION	$361,325
														Subtotal = $361,325

Issue Date FY: 2023 ( Subtotal = $372,500 )
2023	2023	UNIVERSITY OF SOUTH CAROLINA	1600 HAMPTON ST # 414	COLUMBIA	SC	29208	RICHLAND	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	5/16/2023	NON-COMPETING CONTINUATION	$372,500
														Subtotal = $372,500

Issue Date FY: 2022 ( Subtotal = $372,500 )
2022	2022	UNIVERSITY OF SOUTH CAROLINA	1600 HAMPTON ST # 414	COLUMBIA	SC	29208	RICHLAND	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	4/13/2022	NEW	$372,500
														Subtotal = $372,500

Grand Total All Awards = $1,478,825

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Investigating Citric Acid Cycle Perturbations in Complex I Deficient Mitochondrial Encephalopathy

Award Number: R01NS126851

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: 05/01/2022

PERIOD OF PERFORMANCE END DATE: 04/30/2026

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