Mitochondrial dysfunction and dendritic beading during neuronal toxicity

Sam M. Greenwood, Sarah M. Mizielinska, Bruno G. Frenguelli, Jenni Harvey, Christopher N. Connolly

    Research output: Contribution to journalArticle

    72 Citations (Scopus)

    Abstract

    Mitochondrial dysfunction ( depolarization and structural collapse), cytosolic ATP depletion, and neuritic beading are early hallmarks of neuronal toxicity induced in a variety of pathological conditions. We show that, following global exposure to glutamate, mitochondrial changes are spatially and temporally coincident with dendritic bead formation. During oxygen-glucose deprivation, mitochondrial depolarization precedes mitochondrial collapse, which in turn is followed by dendritic beading. These events travel as a wave of activity from distal dendrites toward the neuronal cell body. Despite the spatiotemporal relationship between dysfunctional mitochondria and dendritic beads, mitochondrial depolarization and cytoplasmic ATP depletion do not trigger these events. However, mitochondrial dysfunction increases neuronal vulnerability to these morphological changes during normal physiological activity. Our findings support a mechanism whereby, during glutamate excitotoxicity, Ca2+ influx leads to mitochondrial depolarization, whereas Na+ influx leads to an unsustainable increase in ATP demand (Na+, K+ -ATPase activity). This leads to a drop in ATP levels, an accumulation of intracellular Na+ ions, and the subsequent influx of water, leading to microtubule depolymerization, mitochondrial collapse, and dendritic beading. Following the removal of a glutamate challenge, dendritic recovery is dependent upon the integrity of the mitochondrial membrane potential, but not on a resumption of ATP synthesis or Na+, K+ -ATPase activity. Thus, dendritic recovery is not a passive reversal of the events that induce dendritic beading. These findings suggest that the degree of calcium influx and mitochondrial depolarization inflicted by a neurotoxic challenge, determines the ability of the neuron to recover its normal morphology.

    Original languageEnglish
    Pages (from-to)26235-26244
    Number of pages10
    JournalJournal of Biological Chemistry
    Volume282
    Issue number36
    DOIs
    Publication statusPublished - 7 Sep 2007

    Cite this

    Greenwood, Sam M. ; Mizielinska, Sarah M. ; Frenguelli, Bruno G. ; Harvey, Jenni ; Connolly, Christopher N. / Mitochondrial dysfunction and dendritic beading during neuronal toxicity. In: Journal of Biological Chemistry. 2007 ; Vol. 282, No. 36. pp. 26235-26244.
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    Mitochondrial dysfunction and dendritic beading during neuronal toxicity. / Greenwood, Sam M.; Mizielinska, Sarah M.; Frenguelli, Bruno G.; Harvey, Jenni; Connolly, Christopher N.

    In: Journal of Biological Chemistry, Vol. 282, No. 36, 07.09.2007, p. 26235-26244.

    Research output: Contribution to journalArticle

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    AU - Mizielinska, Sarah M.

    AU - Frenguelli, Bruno G.

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