Mechanism of neurodegeneration of neurons with mitochondrial DNA mutations

Andrey Y. Abramov, Tora K. Smulders-Srinivasan, Denise M. Kirby, Rebeca Acin-Perez, José Antonio Enriquez, Robert N. Lightowlers, Michael R. Duchen, Douglass M. Turnbull

    Research output: Contribution to journalArticle

    69 Citations (Scopus)

    Abstract

    Mutations of mitochondrial DNA are associated with a wide spectrum of disorders, primarily affecting the central nervous system and muscle function. The specific consequences of mitochondrial DNA mutations for neuronal pathophysiology are not understood. In order to explore the impact of mitochondrial mutations on neuronal biochemistry and physiology, we have used fluorescence imaging techniques to examine changes in mitochondrial function in neurons differentiated from mouse embryonic stem-cell cybrids containing mitochondrial DNA polymorphic variants or mutations. Surprisingly, in neurons carrying a severe mutation in respiratory complex I (<10 residual complex I activity) the mitochondrial membrane potential was significantly increased, but collapsed in response to oligomycin, suggesting that the mitochondrial membrane potential was maintained by the F1Fo ATPase operating in 'reverse' mode. In cells with a mutation in complex IV causing ∼40 residual complex IV activity, the mitochondrial membrane potential was not significantly different from controls. The rate of generation of mitochondrial reactive oxygen species, measured using hydroethidium and signals from the mitochondrially targeted hydroethidine, was increased in neurons with both the complex I and complex IV mutations. Glutathione was depleted, suggesting significant oxidative stress in neurons with a complex I deficiency, but not in those with a complex IV defect. In the neurons with complex I deficiency but not the complex IV defect, neuronal death was increased and was attenuated by reactive oxygen species scavengers. Thus, in neurons with a severe mutation of complex I, the maintenance of a high potential by F1Fo ATPase activity combined with an impaired respiratory chain causes oxidative stress which promotes cell death.

    Original languageEnglish
    Pages (from-to)797-807
    Number of pages11
    JournalBrain
    Volume133
    Issue number3
    DOIs
    Publication statusPublished - 1 Mar 2010

    Fingerprint Dive into the research topics of 'Mechanism of neurodegeneration of neurons with mitochondrial DNA mutations'. Together they form a unique fingerprint.

  • Cite this

    Abramov, A. Y., Smulders-Srinivasan, T. K., Kirby, D. M., Acin-Perez, R., Enriquez, J. A., Lightowlers, R. N., Duchen, M. R., & Turnbull, D. M. (2010). Mechanism of neurodegeneration of neurons with mitochondrial DNA mutations. Brain, 133(3), 797-807. https://doi.org/10.1093/brain/awq015