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Mitochondrial matrix pH controls oxidative phosphorylation and metabolism‐secretion coupling in INS‐1E clonal β cells
Author(s) -
Akhmedov Dmitry,
Braun Matthias,
Mataki Chikage,
Park KyuSang,
Pozzan Tullio,
Schoonjans Kristina,
Rorsman Patrik,
Wollheim Claes B.,
Wiederkehr Andreas
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.10-162222
Subject(s) - exocytosis , oxidative phosphorylation , mitochondrial matrix , microbiology and biotechnology , mitochondrion , cytosol , chemistry , insulin , adenosine triphosphate , phosphorylation , biochemistry , biology , secretion , endocrinology , enzyme
Glucose‐evoked mitochondrial signals augment ATP synthesis in the pancreatic β cell. This activation of energy metabolism increases the cytosolic ATP/ADP ratio, which stimulates plasma membrane electrical activity and insulin granule exocytosis. We have recently demonstrated that matrix pH increases during nutrient stimulation of the pancreatic β cell. Here, we have tested whether mitochondrial matrix pH controls oxidative phosphorylation and metabolism‐secretion coupling in the rat β‐cell line INS‐1E. Acidification of the mitochondrial matrix pH by nigericin blunted nutrient‐dependent respiratory and ATP responses (continuously monitored in intact cells). Using electrophysiology and single cell imaging, we find that the associated defects in energy metabolism suppress glucose‐stimulated plasma membrane electrical activity and cytosolic calcium transients. The same parameters were unaffected after direct stimulation of electrical activity with tolbutamide, which bypasses mitochondrial function. Furthermore, lowered matrix pH strongly inhibited sustained, but not first‐phase, insulin secretion. Our results demonstrate that the matrix pH exerts a control function on oxidative phosphorylation in intact cells and that this mode of regulation is of physiological relevance for the generation of downstream signals leading to insulin granule exocytosis. We propose that matrix pH serves a novel signaling role in sustained cell activation.—Akhmedov, D., Braun, M., Mataki, C., Park, K.‐S., Pozzan, T., Schoonjans, K., Rorsman, P., Wollheim, C. B., Wiederkehr, A. Mitochondrial matrix pH controls oxidative phosphorylation and metabolism‐secretion coupling in INS‐1E clonal β cells. FASEB J . 24, 4613–4626 (2010). www.fasebj.org