Electrical control of the cell energy metabolism at the level of mitochondrial outer membrane.

Energy, generated by the mitochondrial oxidative phosphorylation system, is transferred to the cytosol across the mitochondrial outer membrane (MOM), through the voltage-dependent anion channels (VDACs). The role of the VDAC's voltage-gating process to control the transfer of ATP, creatine phosphate and other negatively charged metabolites across MOM might be crucial for the cell energy metabolism regulation. However, it depends on the probability of the outer membrane potential (OMP) generation by a currently undefined mechanism that has usually been considered doubtful, based on the assumption that VDACs always stay in the electrically open state. Nevertheless, computational analysis of various possible metabolically-dependent mechanisms of OMP generation suggests that MOM is not a "coarse sieve", but in fact it functions as an electrical gatekeeper of cell energy metabolism, due to a probable OMP-dependent VDAC's gating. OMP generation could also be involved in the control of cell death resistance and mechanisms of various diseases.

Mitochondrial Nicotinic Acetylcholine Receptors Support Liver Cells Viability After Partial Hepatectomy.

Nicotinic acetylcholine receptors (nAChRs) expressed on the cell plasma membrane are ligand-gated ion channels mediating fast synaptic transmission, regulating neurotransmitter and cytokine release and supporting the viability of many cell types. The nAChRs expressed in mitochondria regulate the release of pro-apoptotic factors, like cytochrome c, in ion channel-independent manner. Here we show that α3ß2, α7ß2, and α9α10 nAChR subtypes are up-regulated in rat liver mitochondria 3-6 h after partial hepatectomy resulting in increased sustainability of mitochondria to apoptogenic effects of Ca2+ and H2O2. In contrast, laparotomy resulted in down-regulation of all nAChR subunits, except α9, and decreased mitochondria sustainability to apoptogenic effects of Ca2+ and H2O2. Experiments performed in liver mitochondria from α3+/-, α7-/-, ß4-/-, α7ß2-/-, or wild-type C57Bl/6J mice demonstrated that the decrease of α3 or absence of α7 or α7/ß2 subunits in mitochondria is compensated with ß4 and α9 subunits, which could be found in α3ß4, α4ß4, α9ß4, and α9α10 combinations. Mitochondria from knockout mice maintained their sustainability to Ca2+ but were differently regulated by nAChR subtype-specific ligands: PNU-282987, methyllycaconitine, dihydro-ß-erythroidine, α-conotoxin MII, and α-conotoxin PeIA. It is concluded that mitochondrial nAChRs play an important role in supporting the viability of hepatic cells and, therefore, may be a pharmacological target for pro-survival therapy. The concerted action of multiple nAChR subtypes controlling either CaKMII- or Src-dependent signaling pathways in mitochondria ensures a reliable protection against apoptogenic factors of different nature.

Multiple functions of syncytiotrophoblast mitochondria.

The human placenta plays a central role in pregnancy, and the syncytiotrophoblast cells are the main components of the placenta that support the relationship between the mother and fetus, in apart through the production of progesterone. In this review, the metabolic processes performed by syncytiotrophoblast mitochondria associated with placental steroidogenesis are described. The metabolism of cholesterol, specifically how this steroid hormone precursor reaches the mitochondria, and its transformation into progesterone are reviewed. The role of nucleotides in steroidogenesis, as well as the mechanisms associated with signal transduction through protein phosphorylation and dephosphorylation of proteins is discussed. Finally, topics that require further research are identified, including the need for new techniques to study the syncytiotrophoblast in situ using non-invasive methods.

Mitochondria express several nicotinic acetylcholine receptor subtypes to control various pathways of apoptosis induction.

Nicotinic acetylcholine receptors control survival, proliferation and cytokine release in non-excitable cells. Previously we reported that α7 nicotinic receptors were present in the outer membranes of mouse liver mitochondria to regulate mitochondrial pore formation and cytochrome c release. Here we used a wide spectrum of nicotinic receptor subunit-specific antibodies to show that mitochondria express several nicotinic receptor subtypes in a tissue-specific manner: brain and liver mitochondria contain α7ß2, α4ß2 and less α3ß2 nicotinic receptors, while mitochondria from the lung express preferentially α3ß4 receptor subtype; all of them are non-covalently connected to voltage-dependent anion channels and control cytochrome c release. By using selective ligands of different nicotinic receptor subtypes (acetylcholine (1 µM) or dihydro-ß-erythroidine (1 µM) for α4ß2), conotoxin MII (1 nM) for α3ß2, MLA (50 nM) for α7ß2 and acetylcholine (10 µM) for all subtypes) and apoptogenic agents triggering different mitochondrial signaling pathways (1 µM wortmannin, 90 µM Ca(2+) or 0.5 mM H2O2) it was found that α7ß2 receptors affect mainly PI3K/Akt pathway, while α3ß2 and α4ß2 nAChRs also significantly influence CaKMII- and Src-dependent pathways. It is concluded that cholinergic regulation in mitochondria is realized through multiple nicotinic receptor subtypes, which control various pathways inducing mitochondrial type of apoptosis.