A common feature in the early stages of many neurodegenerative diseases lies in mitochondrial dysfunction, oxidative stress, and reduced levels of synaptic transmission. Many genes associated with neurodegenerative diseases are now known to regulate either mitochondrial function, redox state, or the exocytosis of neurotransmitters. Mitochondria are the primary source of reactive oxygen species and ATP and control apoptosis. Mitochondria are concentrated in synapses and significant alterations to synaptic mitochondrial localization, number, morphology, or function can be detrimental to synaptic transmission. Mitochondrial by-products are capable of regulating various steps of neurotransmission and mitochondrial dysfunction and oxidative stress occur in the early stages of many neurodegenerative diseases. This mini-review will highlight the prospect that mitochondria regulates synaptic exocytosis by controlling synaptic ATP and reactive oxygen species levels and that dysfunctional exocytosis caused by mitochondrial abnormalities may be a common underlying phenomenon in the initial stages of some human neurodegenerative diseases.