Matrix alkalinization: A novel mitochondrial signal for sustained pancreatic β-cell activation

Andreas Wiederkehr, Kyu Sang Park, Olivier Dupont, Nicolas Demaurex, Tullio Pozzan, Gary W. Cline, Claes B. Wollheim

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Abstract

Nutrient secretagogues activate mitochondria of the pancreatic β-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 β-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 31P-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 β-cells. As cytosolic alkalinisation to the nutrient was of much smaller amplitude, the matrix alkalinisation was accompanied by a pronounced increase of the ΔpH 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 ΔpH increases in permeabilised cells abrogated substrate-driven ATP synthesis. We propose that the mitochondrial pH and ΔpH are key determinants of mitochondrial energy metabolism and metabolite transport important for cell activation.

Original languageEnglish
Pages (from-to)417-428
Number of pages12
JournalEMBO Journal
Volume28
Issue number4
DOIs
Publication statusPublished - 2009 Feb 18

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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    Wiederkehr, A., Park, K. S., Dupont, O., Demaurex, N., Pozzan, T., Cline, G. W., & Wollheim, C. B. (2009). Matrix alkalinization: A novel mitochondrial signal for sustained pancreatic β-cell activation. EMBO Journal, 28(4), 417-428. https://doi.org/10.1038/emboj.2008.302