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Interactions with and Membrane Permeabilization of Brain Mitochondria by Amyloid Fibrils
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Soluble, prefibrillar α-synuclein oligomers promote complex I-dependent, Ca2+-induced mitochondrial dysfunction
Eric S Luth1, Irina G Stavrovskaya2, Tim Bartels1
1From the Center for Neurologic Diseases, Department of Neurology, and.
The Journal of Biological Chemistry
|June 20, 2014
Summary
Soluble, prefibrillar alpha-synuclein (αSyn) oligomers, not monomers or fibrils, impair mitochondrial function in Parkinson disease models. These toxic oligomers disrupt calcium handling and accelerate cell death, highlighting a key mechanism in PD pathogenesis.
Area of Science:
- Neuroscience
- Biochemistry
- Cell Biology
Background:
- Alpha-synuclein (αSyn) aggregation and mitochondrial dysfunction are key contributors to Parkinson disease (PD) pathogenesis.
- The specific aggregation state of αSyn most detrimental to mitochondria and the conditions influencing this toxicity remain unclear.
Purpose of the Study:
- To investigate the impact of different αSyn aggregation states on mitochondrial calcium (Ca2+) stress.
- To elucidate the mechanisms by which αSyn affects mitochondrial function, particularly in neurons with high Ca2+ loads.
Main Methods:
- Utilized an in vitro system with isolated mitochondria and purified recombinant human αSyn in various aggregation states.
- Employed fluorimetry to simultaneously measure mitochondrial Ca2+ retention, swelling, membrane potential, and cytochrome c release.
- Assessed the role of the permeability transition pore, electron transport chain complex I, and Ca2+ uptake in αSyn-induced mitochondrial dysfunction.
Main Results:
- Soluble, prefibrillar αSyn oligomers, but not monomeric or fibrillar forms, significantly impaired mitochondrial Ca2+ retention and promoted Ca2+-induced swelling and depolarization.
- Oligomeric αSyn accelerated cytochrome c release, indicating mitochondrial outer membrane permeabilization.
- These toxic effects were dependent on electron flow through complex I and mitochondrial Ca2+ uptake, and were rescued by inhibiting the permeability transition pore.
Conclusions:
- Soluble prefibrillar αSyn oligomers induce mitochondrial phenotypes relevant to Parkinson disease, including complex I dysfunction, altered membrane potential, and disrupted Ca2+ homeostasis.
- The detrimental effects of αSyn on mitochondria are linked to its oligomeric state and occur under conditions of high cellular Ca2+ demand.
- These findings reveal a specific mechanism by which αSyn oligomers contribute to neurodegeneration in PD.
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