Matrix alkalinization: a novel mitochondrial signal for sustained pancreatic beta-cell activation.
Nutrient secretagogues activate mitochondria of the pancreatic beta-cell through the provision of substrate, hyperpolarisation of the inner mitochondrial membrane and mitochondrial calcium rises. We report that mitochondrial matrix pH, a parameter not previously studied in the beta-cell, also exerts an important control function in mitochondrial metabolism. During nutrient stimulation matrix pH alkalinises, monitored by the mitochondrial targeted fluorescent pH-sensitive protein mtAlpHi or (31)P-NMR inorganic phosphate chemical shifts following saturation transfer. Compared with other cell types, the resting mitochondrial pH was surprisingly low, rising from pH 7.25 to 7.7 during nutrient stimulation of rat beta-cells. As cytosolic alkalinisation to the nutrient was of much smaller amplitude, the matrix alkalinisation was accompanied by a pronounced increase of the DeltapH across the inner mitochondrial membrane. Furthermore, matrix alkalinisation closely correlates with the cytosolic ATP net increase, which is also associated with elevated ATP synthesis rates in mitochondria. Preventing DeltapH increases in permeabilised cells abrogated substrate-driven ATP synthesis. We propose that the mitochondrial pH and DeltapH are key determinants of mitochondrial energy metabolism and metabolite transport important for cell activation.
Wiederkehr
Andreas
A
Department of Cell Physiology and Metabolism, University of Geneva, Geneva, Switzerland. andreas.wiederkehr@unige.ch
Park
Kyu-Sang
KS
Dupont
Olivier
O
Demaurex
Nicolas
N
Pozzan
Tullio
T
Cline
Gary W
GW
Wollheim
Claes B
CB
D000255:Adenosine Triphosphate / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D003600:Cytosol / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D005973:Glutamine / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D007700:Kinetics; D007930:Leucine / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008928:Mitochondria / Q000378:metabolism*; D008954:Models, Biological; D010710:Phosphates / Q000737:chemistry; D051381:Rats
D007328:Insulin; D010710:Phosphates; D005973:Glutamine; D000255:Adenosine Triphosphate; D007930:Leucine; D005947:Glucose