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Integrating cytosolic calcium signals into mitochondrial metabolic responses
Author(s) -
RobbGaspers Lawrence D.,
Burnett Paul,
Rutter Guy A.,
Denton Richard M.,
Rizzuto Rosario,
Thomas Andrew P.
Publication year - 1998
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1093/emboj/17.17.4987
Subject(s) - biology , cytosol , mitochondrion , nad+ kinase , calcium , oxidative phosphorylation , microbiology and biotechnology , respiratory chain , vasopressin , calcium signaling , stimulation , membrane potential , biochemistry , electrochemical gradient , signal transduction , medicine , endocrinology , enzyme , membrane
Stimulation of hepatocytes with vasopressin evokes increases in cytosolic free Ca 2+ ([Ca 2+ ] c ) that are relayed into the mitochondria, where the resulting mitochondrial Ca 2+ ([Ca 2+ ] m ) increase regulates intramitochondrial Ca 2+ ‐sensitive targets. To understand how mitochondria integrate the [Ca 2+ ] c signals into a final metabolic response, we stimulated hepatocytes with high vasopressin doses that generate a sustained increase in [Ca 2+ ] c . This elicited a synchronous, single spike of [Ca 2+ ] m and consequent NAD(P)H formation, which could be related to changes in the activity state of pyruvate dehydrogenase (PDH) measured in parallel. The vasopressin‐induced [Ca 2+ ] m spike evoked a transient increase in NAD(P)H that persisted longer than the [Ca 2+ ] m increase. In contrast, PDH activity increased biphasically, with an initial rapid phase accompanying the rise in [Ca 2+ ] m , followed by a sustained secondary activation phase associated with a decline in cellular ATP. The decline of NAD(P)H in the face of elevated PDH activity occurred as a result of respiratory chain activation, which was also manifest in a calcium‐dependent increase in the membrane potential and pH gradient components of the proton motive force (PMF). This is the first direct demonstration that Ca 2+ ‐mobilizing hormones increase the PMF in intact cells. Thus, Ca 2+ plays an important role in signal transduction from cytosol to mitochondria, with a single [Ca 2+ ] m spike evoking a complex series of changes to activate mitochondrial oxidative metabolism.