Nicotinic acetylcholine receptors in mitochondria: subunit composition, function and signaling

Nicotinic acetylcholine receptors (nAChRs) of neuronal type not only mediate the fast synaptic transmission, but also modulate proliferation, cytokine or transmitter release and survival in both excitable and non-excitable cells. Recent studies clearly indicate that these receptors can stimulate intracellular signaling in ion-independent manner. Classically, the nAChRs were attributed exclusively to the cell plasma membrane. The present review provides evidence for the expression and functioning of nAChRs in intracellular organelles, specifically mitochondria. It is shown that mitochondria can express a7b2, a3b2, a3b4 and a4b2 nAChRs in a tissue-specific manner. Mitochondrial nAChRs are found in the outer membrane in conjunction with voltage-dependent anion channels and regulate the formation of mitochondrial permeability transition pore releasing pro-apoptotic substances like cytochrome c or reactive oxygen species. The nAChR signaling in mitochondria does not require the ion flow through nAChR ion channels. Instead, it can be stimulated by the binding of agonists, antagonists or nAChR-specific antibodies and engages intramitochondrial kinases, similar to those activated by plasma membrane nAChRs. Mitochondrial nAChRs follow, similar to plasma membrane nAChRs, biosynthetic post-translational pathways. In particular, one of the signals targeting them to mitochondria might be extra sialiation and fucosylation. Mitochondrial nAChRs form an additional line of defense for the cell survival, and their therapeutic targeting may be important for treating cancer and neurodegenerative diseases.