Investigating Citric Acid Cycle Perturbations in Complex I Deficient Mitochondrial Encephalopathy

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Principal Investigator: Norma  Frizzell
Organization: UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
Fiscal Year: 2024
Award: $361,325
Funding agency: National Institute of Neurological Disorders and Stroke

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.

Terms: <2-Keto-4-Hydroxyglutarate Dehydrogenase><2-Oxoglutarate Dehydrogenase><2-Oxoglutarate Dehydrogenase Complex><2-ketoglutarate><2-oxoglutarate><Acceleration><Address><Affect><Anti-Inflammatories><Anti-Inflammatory Agents><Anti-inflammatory><Ataxia><Ataxy><Basal Ganglia><Basal Nuclei><Biochemical><Bioenergetics><Brain><Brain Nervous System><Brain Stem><Brainstem><Bypass><Cell Body><Cells><Chemicals><Citric Acid Cycle><Clinical><Complex><Coordination Impairment><Cysteine><Data><Defect><Developmental Delay><Developmental Delay Disorders><Disease><Disorder><Dysfunction><Dyssynergia><Encephalon><Encephalopathies><Engineering><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Esters><Exhibits><Fumarates><Functional disorder><GTP><Generations><Genes><Genetic><Genetic Alteration><Genetic Change><Genetic defect><Glia><Glial Cells><Gliosis><Guanosine Triphosphate><Half-Cystine><Histone H3><Hortega cell><Human><Impairment><Infiltration><Inflammation><Inflammatory><Intermediary Metabolism><KO mice><Ketoglutarate Dehydrogenase Complex><Knock-out><Knock-out Mice><Knockout><Knockout Mice><Kolliker's reticulum><Krebs Cycle><L-Cysteine><L-Lysine><Lactic Acidosis><Leigh Disease><Leigh Syndrome><Lesion><Life><Link><Live Birth><Lysine><Malate Dehydrogenase><Malic Dehydrogenase><Mediating><Metabolic Processes><Metabolic acidosis><Metabolism><Microglia><Mitochondria><Mitochondrial Diseases><Mitochondrial Disorders><Mitochondrial complex I deficiency><Modeling><Modern Man><Modification><Mutation><NAD-Malate Dehydrogenase><Nerve Cells><Nerve Unit><Neural Cell><Neurocyte><Neuroglia><Neuroglial Cells><Neurons><Non-neuronal cell><Nonneuronal cell><Null Mouse><Oxidative Phosphorylation><Oxidative Phosphorylation Pathway><Oxoglutarate Dehydrogenase><Pathologic><Pathology><Peptides><Permeability><Phagocytes><Phagocytic Cell><Phenotype><Phosphorylation><Physiopathology><Post-Translational Modification Protein/Amino Acid Biochemistry><Post-Translational Modifications><Post-Translational Protein Modification><Post-Translational Protein Processing><Posttranslational Modifications><Posttranslational Protein Processing><Production><Protein Modification><Protein Phosphorylation><Proteins><Reaction><Reporting><Resolution><Respiratory Chain><Role><Seizures><Severities><Site><Specific Child Development Disorders><Subacute Necrotizing Encephalomyelitis><Subacute Necrotizing Encephalomyelopathy><Subacute Necrotizing Encephalopathy><TCA cycle><Therapeutic><Tricarboxylic Acid Cycle><alpha ketoglutarate><alpha-Ketoglutarate Dehydrogenase><alpha-Ketoglutarate Dehydrogenase Complex><alpha-oxoglutarate><amebocyte><customized therapy><customized treatment><demethylation><design><designing><effective therapy><effective treatment><epigenetically><genome mutation><gitter cell><histone demethylase><histone methylation><individualized medicine><individualized patient treatment><individualized therapeutic strategy><individualized therapy><individualized treatment><insight><mesoglia><microglial cell><microgliocyte><mitochondrial><mouse model><murine model><nerve cell death><nerve cell loss><nerve cement><neural inflammation><neuroinflammation><neuroinflammatory><neuron cell death><neuron cell loss><neuron death><neuron loss><neuronal><neuronal cell death><neuronal cell loss><neuronal death><neuronal loss><neuropathologic><neuropathological><neuropathology><novel><olfactory bulb><pathophysiology><patient specific therapies><patient specific treatment><perivascular glial cell><prevent><preventing><resolutions><respiratory><social role><succinyl-CoA><succinyl-coenzyme A><tailored medical treatment><tailored therapy><tailored treatment><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><transcription regulatory network><unique treatment><α-ketoglutarate><α-oxoglutarate><αKG>