# Investigating Citric Acid Cycle Perturbations in Complex I Deficient Mitochondrial Encephalopathy > **NIH NIH R01** · UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA · 2024 · $361,325 ## Abstract 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. ## Key facts - **NIH application ID:** 10842429 - **Project number:** 5R01NS126851-03 - **Recipient organization:** UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA - **Principal Investigator:** Norma Frizzell - **Activity code:** R01 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2024 - **Award amount:** $361,325 - **Award type:** 5 - **Project period:** 2022-05-01 → 2026-04-30 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10842429 ## Citation > US National Institutes of Health, RePORTER application 10842429, Investigating Citric Acid Cycle Perturbations in Complex I Deficient Mitochondrial Encephalopathy (5R01NS126851-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10842429. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*