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Cited by 70Mitochondrial Function and PathologyATP Synthase and ATPases ResearchMetabolism and Genetic Disorders

Modes of Metabolic Compensation during Mitochondrial Disease Using the Drosophila Model of ATP6 Dysfunction

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Celotto, Alicia M., Chiu, Wai Kan, Van Voorhies, Wayne, Palladino, Michael J.·2011·PLoS ONE
DOI 10.1371/journal.pone.0025823PMC PMC3185040
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Abstract

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(1)animals 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(1)animals 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.

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  • APOE4 astrocytes exhibit lower medium pH.

    “the APOE4 astrocytes also exhibit lower medium pH, suggestive of increased compensatory glycolysis39 (Fig. 5e)”

    From Altered mitochondrial dynamics and function in APOE4-expressing astrocytes (2020) · cites this paper as [39]

    The Results section, “Metabolic compensation: glycolysis” (page unavailable), reports increased lactic acid in young ATP6-mutant Drosophila and identifies increased glycolysis as an early compensatory mechanism. That supports the cited interpretation, but the paper does not report APOE4 astrocytes or lower medium pH; the citing sentence points to its own Fig. 5e for that observation. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • Lower medium pH in APOE4 astrocytes is suggestive of increased compensatory glycolysis.

    “suggestive of increased compensatory glycolysis39 (Fig. 5e)”

    From Altered mitochondrial dynamics and function in APOE4-expressing astrocytes (2020) · cites this paper as [39]

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Authors
Celotto, A. M., Chiu, W. K., Van Voorhies, W., & Palladino, M. J.
Affiliations
University of Pittsburgh (US)
Corresponding author
Celotto, Alicia M.
ORCID
Palladino, Michael J.
Venue
PLoS ONE
Publisher
Public Library of Science (PLoS)
Published
2011-10-03
Volume
6
Issue
10
Pages
e25823
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0025823
PMC
PMC3185040
OpenAlex
W2077266294
Cited by
70
References
1
Citations by year
2026: 7 · 2025: 3 · 2024: 4 · 2023: 7 · 2022: 1 · 2021: 3 · 2020: 4 · 2019: 8 · 2018: 5 · 2017: 4 · 2016: 7 · 2015: 3 · 2014: 7 · 2013: 5 · 2012: 2
FWCI
1.71
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • D-Scholarship@Pitt (University of Pittsburgh) (acceptedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Figshare (submittedVersion, cc-by)
Funders
  • National Institutes of Health
  • National Institute on Aging (AG027453, R01AG027453, R01AG025046)
  • National Cancer Institute (U56CA096286, CA96286, U54CA132383)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › ATP Synthase and ATPases Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
Keywords
mitochondrial encephalomyopathy, Drosophila model, metabolic compensation, oxidative phosphorylation, glycolytic flux, ketogenesis, succinate dehydrogenase, mitochondrial supercomplexes, mitochondrial DNA mutations, pathogenesis
MeSH terms
Animals, Behavior, Animal, Citric Acid Cycle, Disease Models, Animal, Drosophila, Electron Transport, Energy Metabolism, Glycolysis, Humans, Longevity, Models, Biological, Phenotype, Time Factors, Survival Analysis, Disease Progression, Cell Respiration, Mitochondrial Proton-Translocating ATPases, Mitochondrial Diseases, Drosophila Proteins, Protein Multimerization

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