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Modes of metabolic compensation during mitochondrial disease using the drosophila model of ATP6 dysfunction

Celotto, AM and Chiu, WK and van Voorhies, W and Palladino, MJ (2011) Modes of metabolic compensation during mitochondrial disease using the drosophila model of ATP6 dysfunction. PLoS ONE, 6 (10).

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Numerous mitochondrial DNA mutations cause mitochondrial encephalomyopathy: a collection of related diseases for which there exists no effective treatment. Mitochondrial encephalomyopathies are complex multisystem diseases that exhibit a relentless progression of severity, making them both difficult to treat and study. The pathogenic and compensatory metabolic changes that are associated with chronic mitochondrial dysfunction are not well understood. The Drosophila ATP6 1 mutant models human mitochondrial encephalomyopathy and allows the study of metabolic changes and compensation that occur throughout the lifetime of an affected animal. ATP6 1animals have a nearly complete loss of ATP synthase activity and an acute bioenergetic deficit when they are asymptomatic, but surprisingly we discovered no chronic bioenergetic deficit in these animals during their symptomatic period. Our data demonstrate dynamic metabolic compensatory mechanisms that sustain normal energy availability and activity despite chronic mitochondrial complex V dysfunction resulting from an endogenous mutation in the mitochondrial DNA. ATP6 1animals compensate for their loss of oxidative phosphorylation through increases in glycolytic flux, ketogenesis and Kreb's cycle activity early during pathogenesis. However, succinate dehydrogenase activity is reduced and mitochondrial supercomplex formation is severely disrupted contributing to the pathogenesis seen in ATP6 1 animals. These studies demonstrate the dynamic nature of metabolic compensatory mechanisms and emphasize the need for time course studies in tractable animal systems to elucidate disease pathogenesis and novel therapeutic avenues. &Copy; 2011 Celotto et al.


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Item Type: Article
Status: Published
CreatorsEmailPitt UsernameORCID
Celotto, AM
Chiu, WKwac18@pitt.eduWAC18
van Voorhies, W
Palladino, MJmjp44@pitt.eduMJP44
ContributionContributors NameEmailPitt UsernameORCID
Date: 3 October 2011
Date Type: Publication
Journal or Publication Title: PLoS ONE
Volume: 6
Number: 10
DOI or Unique Handle: 10.1371/journal.pone.0025823
Schools and Programs: School of Medicine > Pharmacology and Chemical Biology
Refereed: Yes
MeSH Headings: Animals; Behavior, Animal; Cell Respiration; Citric Acid Cycle; Disease Models, Animal; Disease Progression; Drosophila--metabolism; Drosophila Proteins--metabolism; Electron Transport; Energy Metabolism; Glycolysis; Humans; Longevity; Mitochondrial Diseases--metabolism; Mitochondrial Diseases--pathology; Mitochondrial Diseases--physiopathology; Mitochondrial Proton-Translocating ATPases--metabolism; Models, Biological; Phenotype; Protein Multimerization; Survival Analysis; Time Factors
Other ID: NLM PMC3185040
PubMed Central ID: PMC3185040
PubMed ID: 21991365
Date Deposited: 10 Sep 2012 14:40
Last Modified: 22 Jun 2021 13:55


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