Figure 1.

Mitochondrial functions susceptible to affect neurotransmission. Schematic representation of a mitochondrion illustrating the different mitochondrial functions discussed in the text. (1) Mitochondria are dynamic organelles, able to move bidirectionally along microtubules tracts with the help of motor proteins (kinesin for anterograde and dynein for retrograde axonal transport, respectively) and adaptor proteins (e.g., Milton and the associated Rho-GTPase Miro or syntabulin). Short-distance transport along actin filaments is mediated by myosin motors (not shown). (2) The Krebs cycle takes place in the mitochondrial matrix, generating α-ketoglutarate and electron donors (NADH and succinate). (3) Transamination of α-ketoglutarate yields the neurotransmitter glutamate, which can also be formed by glutamine hydrolysis. Glutamate can be further decarboxylated to yield GABA, another neurotransmitter. (4) The electron transport chain (ETC), consisting of 4 multiprotein complexes, mediates electron transfer (blue arrow) from NADH and succinate to the electron acceptor O₂. Numerous drugs target components of the ETC, for example MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) and rotenone affect complex I while antimycin A1 inhibits complex III. Electron transfer is coupled with proton extrusion out of the matrix toward the intermembrane space, producing an electrochemical gradient across the inner membrane (about – 200 mV). (5) Protons ultimately return to the matrix through the ATP synthase, using the free energy produced by the ETC to drive ATP synthesis. Oligomycin is an inhibitor of the ATP synthase. (6) Mitochondria are also involved in calcium homeostasis, and Ca²⁺ ions can be sequestered in the matrix under the form of a reversible phosphate complex. While the outer mitochondrial membrane is rather permeable to calcium, Ca²⁺ entry across the inner mitochondrial membrane is mediated by a uniporter, and its extrusion largely relies on a sodium/calcium exchanger. Mitochondrial calcium transport can be inhibited by TPP⁺ (tetraphenylphosphonium).