Dopamine metabolism by a monoamine oxidase mitochondrial shuttle activates the electron transport chain

Monoamine oxidase (MAO) metabolizes cytosolic dopamine (DA), thereby limiting auto-oxidation, but is also thought to generate cytosolic hydrogen peroxide (H2O2). We show that MAO metabolism of DA does not increase cytosolic H2O2 but leads to mitochondrial electron transport chain (ETC) activity. This is dependent upon MAO anchoring to the outer mitochondrial membrane and shuttling electrons through the intermembrane space to support the bioenergetic demands of phasic DA release. Graves et al. demonstrate that as the neurotransmitter dopamine cycles through the cytosol at release sites, it can be metabolized by a mitochondrial enzyme to help generate the energy necessary to sustain synaptic function.