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Human NARP Mitochondrial Mutation Metabolism Corrected With -Ketoglutarate/Aspartate

A Potential New Therapy

Gianluca Sgarbi, PhD; Gabriella A. Casalena, PhD; Alessandra Baracca, PhD; Giorgio Lenaz, MD, PhD; Salvatore DiMauro, MD; Giancarlo Solaini, PhD

Arch Neurol. 2009;66(8):951-957.

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 -ketoglutarate/aspartate to boost mitochondrial substrate-level phosphorylation. Homoplasmic cybrids harboring the 8993TG 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 -ketoglutarate/aspartate to patients with impaired ATP synthase activity.

Author Affiliations: Dipartimento di Biochimica "G. Moruzzi," Università di Bologna, Bologna, Italy (Drs Sgarbi, Casalena, Baracca, Lenaz, and Solaini); and Department of Neurology, Columbia University Medical Center, New York, New York (Dr DiMauro).

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