Damage of presynaptic mitochondria could result in release of proapoptotic factors that threaten the integrity of the entire neuron. We discovered that ␣-synuclein (Syn) forms a triple complex with anionic lipids (such as cardiolipin) and cytochrome c, which exerts a peroxidase activity. The latter catalyzes covalent hetero-oligomerization of Syn with cytochrome c into high molecular weight aggregates. Syn is a preferred substrate of this reaction and is oxidized more readily than cardiolipin, dopamine, and other phenolic substrates. Lewy bodies (LBs), 3 mitochondrial impairment, and oxidative stress are cardinal features of Parkinson disease (PD) and several related neurodegenerative disorders (1, 2). Aggregation of ␣-synuclein (Syn), an abundant protein in synaptic terminals, plays a major role in the formation of LBs (3, 4). Neither the mechanisms of LB production nor their pathogenic or protective roles in neurodegeneration are well understood.In nigrostriatal dopaminergic synaptic terminals, mitochondria, harboring a host of death-initiating factors, are in peril of damage by reactive oxygen species generated by disrupted electron transport and/or oxidative metabolism of dopamine (DA). Because cytochrome c (cyt c)-dependent formation of apoptosomes and activation of caspases designates a point of no return in the apoptotic program, release of proapoptotic factors from synaptic mitochondria could threaten the integrity of the entire neuron. How neurons protect themselves against inadvertent release of death signals from damaged synaptic mitochondria is not known.The N-terminal fragment of Syn contains six variants of an 11-amino acid consensus motif that include an apolipoprotein-like class A2 helix participating in binding of different lipids, particularly anionic phospholipids (5). This domain is believed to be important for Syn functions in regulation of neuronal lipid metabolism, particularly turnover of a mitochondria-specific phospholipid, cardiolipin (CL) (6). However, the relevance of the Syn lipid binding capacity in regulating neuronal injury (apoptotic) responses has not been established.