Dataset Information

Adrenergic signaling regulates mitochondrial Ca2+ uptake through Pyk2-dependent tyrosine phosphorylation of the mitochondrial Ca2+ uniporter.

ABSTRACT:

Aims

Mitochondrial Ca2+ homeostasis is crucial for balancing cell survival and death. The recent discovery of the molecular identity of the mitochondrial Ca2+ uniporter pore (MCU) opens new possibilities for applying genetic approaches to study mitochondrial Ca2+ regulation in various cell types, including cardiac myocytes. Basal tyrosine phosphorylation of MCU was reported from mass spectroscopy of human and mouse tissues, but the signaling pathways that regulate mitochondrial Ca2+ entry through posttranslational modifications of MCU are completely unknown. Therefore, we investigated α1-adrenergic-mediated signal transduction of MCU posttranslational modification and function in cardiac cells.

Results

α1-adrenoceptor (α1-AR) signaling translocated activated proline-rich tyrosine kinase 2 (Pyk2) from the cytosol to mitochondrial matrix and accelerates mitochondrial Ca2+ uptake via Pyk2-dependent MCU phosphorylation and tetrametric MCU channel pore formation. Moreover, we found that α1-AR stimulation increases reactive oxygen species production at mitochondria, mitochondrial permeability transition pore activity, and initiates apoptotic signaling via Pyk2-dependent MCU activation and mitochondrial Ca2+ overload.

Innovation

Our data indicate that inhibition of α1-AR-Pyk2-MCU signaling represents a potential novel therapeutic target to limit or prevent mitochondrial Ca2+ overload, oxidative stress, mitochondrial injury, and myocardial death during pathophysiological conditions, where chronic adrenergic stimulation is present.

Conclusion

The α1-AR-Pyk2-dependent tyrosine phosphorylation of the MCU regulates mitochondrial Ca2+ entry and apoptosis in cardiac cells.

SUBMITTER: O-Uchi J

PROVIDER: S-EPMC4116095 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Mitochondrial Ca(2+) uniporter is the primary influx pathway for Ca(2+) into respiring mitochondria, and hence plays a key role in mitochondrial Ca(2+) homeostasis. Though the mechanism of extra-matrix Ca(2+) dependency of mitochondrial Ca(2+) uptake has been well characterized both experimentally and mathematically, the mechanism of membrane potential (??) dependency of mitochondrial Ca(2+) uptake has not been completely characterized. In this paper, we perform a quantitative reevaluation of a previous biophysical model of mitochondrial Ca(2+) uniporter that characterized the possible mechanism of ?? dependency of mitochondrial Ca(2+) uptake. Based on a model simulation analysis, we show that model predictions with a variant assumption (Case 2: external and internal Ca(2+) binding constants for the uniporter are distinct), that provides the best possible description of the ?? dependency, are highly sensitive to variation in matrix [Ca(2+)], indicating limitations in the variant assumption (Case 2) in providing physiologically plausible description of the observed ?? dependency. This sensitivity is attributed to negative estimate of a biophysical parameter that characterizes binding of internal Ca(2+) to the uniporter. Reparameterization of the model with additional nonnengativity constraints on the biophysical parameters showed that the two variant assumptions (Case 1 and Case 2) are indistinguishable, indicating that the external and internal Ca(2+) binding constants for the uniporter may be equal (Case 1). The model predictions in this case are insensitive to variation in matrix [Ca(2+)] but do not match the ?? dependent data in the domain ???120 mV. To effectively characterize this ?? dependency, we reformulate the ?? dependencies of the rate constants of Ca(2+) translocation via the uniporter by exclusively redefining the biophysical parameters associated with the free-energy barrier of Ca(2+) translocation based on a generalized, non-linear Goldman-Hodgkin-Katz formulation. This alternate uniporter model has all the characteristics of the previous uniporter model and is also able to characterize the possible mechanisms of both the extra-matrix Ca(2+) and ?? dependencies of mitochondrial Ca(2+) uptake. In addition, the model is insensitive to variation in matrix [Ca(2+)], predicting relatively stable physiological operation. The model is critical in developing mechanistic, integrated models of mitochondrial bioenergetics and Ca(2+) handling.