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. 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. The clinical course of these encephalopathies, e.g. Leigh Syndrome, are well-described, the precise biochemical alterations that contribute to neuropathology, beyond the ATP defect, are less understood. 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). We have described increased 2SC in several models, including the Ndufs4 knockout mouse model of mitochondrial Complex I deficiency. Preliminary data shown in this proposal links the succination of a component of the ?-ketoglutarate dehydrogenase (?-KGDH) complex to the defective function of this enzyme complex. This results in decreased succinyl CoA production, and impaired substrate level phosphorylation to produce much needed GTP. We hypothesize that the ?-KG is instead converted to 2-hydroxyglutarate under acidic conditions, i.e. lactic acidosis. We predict that this influences the epigenetic landscape in the affected neurons. Further, we note that metabolic acidosis combined with Ndufs4 bioenergetic defect also impacts the activated microglia in the affected regions of the brain, by suppressing production of an anti-inflammatory metabolite. We hypothesize that this leads to unresolved inflammation that may further exacerbate neuronal cell death. Our novel data suggests that citric acid cycle dysfunction plays a key role in mediating the biochemical damage within the regions most affected by pathology. In this proposal we outline several targeted anaplerotic therapies, and an improved delivery method, that should ameliorate some of these biochemical defects. Importantly, since these compounds are non-toxic fuels, they can be combined with existing vitamin/antioxidants to support neuronal health.
Mitochondrial diseases e.g. Leigh Syndrome affect 1 in 5000 live births. This work will directly assess how a deficiency in a component of the electron transport chain leads to the direct dysfunction of other pathways including the citric acid cycle. We will determine if the accumulation of alternative metabolites contributes to the neuropathology. Our understanding of these metabolic alterations has led us to propose a series of tailored therapies that could be combined with existing vitamin/antioxidant cocktails to alleviate the energy deficit.
