The inner mitochondrial membrane is famously impermeable to solutes not provided with a specific carrier. When this impermeability is lost, either in a developmental context or under stress, the consequences for the cell can be far-reaching. Permeabilization of isolated mitochondria, studied since the early days of the field, is often discussed as if it were a biochemically well-defined phenomenon, occurring by a unique mechanism. On the contrary, evidence has been accumulating that it may be the common outcome of several distinct processes, involving different proteins or protein complexes, depending on circumstances. A clear definition of this putative variety is a prerequisite for an understanding of mitochondrial permeabilization within cells, of its roles in the life of organisms, and of the possibilities for pharmacological intervention.

Medium-chain triglycerides have been used as part of a ketogenic diet effective in reducing epileptic episodes. The health benefits of the derived medium-chain fatty acids (MCFAs) are thought to result from the stimulation of liver ketogenesis providing fuel for the brain. We tested whether MCFAs have direct effects on energy metabolism in induced pluripotent stem cell-derived human astrocytes and neurons. Using single-cell imaging, we observed an acute pronounced reduction of the mitochondrial electrical potential and a concomitant drop of the NAD(P)H signal in astrocytes, but not in neurons. Despite the observed effects on mitochondrial function, MCFAs did not lower intracellular ATP levels or activate the energy sensor AMP-activated protein kinase. ATP concentrations in astrocytes were unaltered, even when blocking the respiratory chain, suggesting compensation through accelerated glycolysis. The MCFA decanoic acid (300 μM) promoted glycolysis and augmented lactate formation by 49.6%. The shorter fatty acid octanoic acid (300 μM) did not affect glycolysis but increased the rates of astrocyte ketogenesis 2.17-fold compared with that of control cells. MCFAs may have brain health benefits through the modulation of astrocyte metabolism leading to activation of shuttle systems that provide fuel to neighboring neurons in the form of lactate and ketone bodies.-Thevenet, J., De Marchi, U., Santo Domingo, J., Christinat, N., Bultot, L., Lefebvre, G., Sakamoto, K., Descombes, P., Masoodi, M., Wiederkehr, A. Medium-chain fatty acids inhibit mitochondrial metabolism in astrocytes promoting astrocyte-neuron lactate and ketone body shuttle systems.

Background: Whether mitochondrial Ca 2ϩ extrusion is mediated by NCLX (mitochondrial sodium/calcium exchanger) or LETM1 (leucine zipper-EF-hand-containing transmembrane protein 1) and controls matrix redox state is unknown. Results: NCLX, but not LETM1, increases Ca 2ϩ extrusion, limits NAD(P)H production, and promotes matrix oxidation. Conclusion: NCLX controls the duration of matrix Ca 2ϩ elevations and their impact on redox signaling. Significance: NCLX is a potential target for the treatment of redox-dependent diseases.

Background: Nutrients stimulate calcium dependent activation of energy metabolism, in pancreatic beta cells.Results: Glucose-induced ATP synthase-dependent respiration is strictly calcium-dependent, with little or no effect of calcium on the NAD(P)H response.Conclusion: Calcium coordinates oxidative metabolism and respiration in pancreatic beta cells.Significance: Calcium has novel mitochondrial targets downstream of mitochondrial dehydrogenases.