Protein kinases reduce mitochondrial Ca2+ uptake through an action on the outer mitochondrial membrane

• Published in: Cell calcium (Edinburgh) 2010-08, Vol.48 (2), p.168-175
• Main Authors: Szanda, Gergö, Halász, Eszter, Spät, András
• Format: Article
• Language: English
• Subjects: Advanced Basic Science; Animals; Calcium - antagonists & inhibitors; Calcium - metabolism; Calcium Signaling - physiology; Cell Line; Down-Regulation - physiology; Enzyme Activation - physiology; Humans; Isoenzymes - physiology; MAP Kinase Signaling System - physiology; Membrane Potential, Mitochondrial - physiology; Mitochondria - enzymology; Mitochondria - metabolism; Mitochondrial Membranes - enzymology; Mitochondrial Membranes - metabolism; p38 Mitogen-Activated Protein Kinases - metabolism; p38 Mitogen-Activated Protein Kinases - physiology; Protein Kinase C - metabolism; Protein Kinase C - physiology
• ISSN: 0143-4160; 1532-1991
• DOI: 10.1016/j.ceca.2010.08.005

Abstract Cytosolic Ca2+ signal induces mitochondrial Ca2+ uptake that has far-reaching effect on several cellular functions. We have previously shown in H295R cells that the transfer of cytosolic Ca2+ signal into mitochondria is attenuated by the simultaneous activation of p38 MAPK and novel-type PKC isoforms (Szanda et al. (2008) [1] , Koncz et al. (2009) [2] ). In the present study we show that (i) kinase-mediated inhibition of mitochondrial Ca2+ uptake persists after clamping or dissipation of the mitochondrial membrane potential; (ii) kinase activation increases the [Ca2+ ] required for half-maximal Ca2+ uptake rate in permeabilized cells; (iii) inhibition of the Ca2+ uptake by the kinases is dependent on an intact mitochondrial outer membrane; (iv) when p38 MAPK and novel-type PKC isoforms are activated, the outer mitochondrial membrane may limit Ca2+ diffusion even in the low micromolar [Ca2+ ] range. These findings confirm the concept that the outer mitochondrial membrane impedes mitochondrial Ca2+ uptake by reducing the availability of Ca2+ at the transport sites (i.e. the inner mitochondrial membrane), and suggest that Ca2+ transport through the outer membrane is controlled by the activity of p38 MAPK and novel-type PKC isoforms.