Regulation of mitochondrial ATP synthesis by calcium: evidence for a long-term metabolic priming.
In recent years, mitochondria have emerged as important targets of agonist-dependent increases in cytosolic Ca(2+) concentration. Here, we analyzed the significance of Ca(2+) signals for the modulation of organelle function by directly measuring mitochondrial and cytosolic ATP levels ([ATP](m) and [ATP](c), respectively) with specifically targeted chimeras of the ATP-dependent photoprotein luciferase. In both HeLa cells and primary cultures of skeletal myotubes, stimulation with agonists evoking cytosolic and mitochondrial Ca(2+) signals caused increases in [ATP](m) and [ATP](c) that depended on two parameters: (i) the amplitude of the Ca(2+) rise in the mitochondrial matrix, and (ii) the availability of mitochondrial substrates. Moreover, the Ca(2+) elevation induced a long-lasting priming that persisted long after agonist washout and caused a major increase in [ATP](m) upon addition of oxidative substrates. These results demonstrate a direct role of mitochondrial Ca(2+) in driving ATP production and unravel a form of cellular memory that allows a prolonged metabolic activation in stimulated cells.
Jouaville
L S
LS
Department of Biomedical Sciences, Consiglio Nazionale delle Ricerche Center for Study of Biomembranes, University of Padova, 35131 Padova, Italy.
Pinton
P
P
Bastianutto
C
C
Rutter
G A
GA
Rizzuto
R
R
D000255:Adenosine Triphosphate / Q000096:biosynthesis*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D006367:HeLa Cells; D006632:Histamine / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000166:cytology; D051381:Rats; D013997:Time Factors
D006632:Histamine; D000255:Adenosine Triphosphate; D005947:Glucose; D002118:Calcium