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  • Title: Human NARP mitochondrial mutation metabolism corrected with alpha-ketoglutarate/aspartate: a potential new therapy.
    Author: Sgarbi G, Casalena GA, Baracca A, Lenaz G, DiMauro S, Solaini G.
    Journal: Arch Neurol; 2009 Aug; 66(8):951-7. PubMed ID: 19667215.
    Abstract:
    OBJECTIVE: To verify whether enhanced substrate-level phosphorylation increases viability and adenosine 5'-triphosphate (ATP) content of cells with neuropathy, ataxia, and retinitis pigmentosa/maternally inherited Leigh syndrome (NARP/MILS) mitochondrial DNA mutations and ATP synthase dysfunction. DESIGN: We used cell lines "poisoned" with oligomycin, the specific inhibitor of ATP synthase, and "natural" models, including transmitochondrial human cell lines (cybrids) harboring 2 different pathogenic mutations associated with the NARP/MILS phenotypes. MAIN OUTCOME MEASURES: Cell survival, morphology, and ATP content. RESULTS: When normal human fibroblasts cultured in glucose-free medium were forced to increase energy consumption by exposure to the ionophore gramicidin or were energy challenged by oligomycin inhibition, their survival at 72 hours was 5%, but this increased to 70% when the medium was supplemented with alpha-ketoglutarate/aspartate to boost mitochondrial substrate-level phosphorylation. Homoplasmic cybrids harboring the 8993T-->G NARP mutation were also protected from death (75% vs 15% survival at 72 hours) by the supplemented medium and their ATP content was similar to controls. CONCLUSIONS: These results show that ATP synthase-deficient cells can be rescued by increasing mitochondrial substrate-level phosphorylation and suggest potential dietary or pharmacological therapeutic approaches based on the supplementation of alpha-ketoglutarate/aspartate to patients with impaired ATP synthase activity.
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