Abstract
Mitochondrial Ca2+ uptake (mCa2+ uptake) is thought to be mediated by the mitochondrial Ca2+ uniporter (MCU). UCP2 and UCP3 belong to a superfamily of mitochondrial ion transporters. Both proteins are expressed in the inner mitochondrial membrane of the heart. Recently, UCP2 was reported to modulate the function of the cardiac MCU related channel mCa1. However, the possible role of UCP3 in modulating cardiac mCa2+ uptake via the MCU remains inconclusive. To understand the role of UCP3, we analyzed cardiac mCa1 single-channel activity in mitoplast-attached single-channel recordings from isolated murine cardiac mitoplasts, from adult wild-type controls (WT), and from UCP3 knockout mice (UCP3–/–). Single-channel registrations in UCP3−/− confirmed a murine voltage-gated Ca2+ channel, i.e., mCa1, which was inhibited by Ru360. Compared to WT, mCa1 in UCP3−/− revealed similar single-channel characteristics. However, in UCP3−/− the channel exhibited decreased single-channel activity, which was insensitive to adenosine triphosphate (ATP) inhibition. Our results suggest that beyond UCP2, UCP3 also exhibits regulatory effects on cardiac mCa1/MCU function. Furthermore, we speculate that UCP3 might modulate previously described inhibitory effects of ATP on mCa1/MCU activity as well.
Highlights
Mitochondrial Ca2? handling is involved in several major cellular processes
The MCU was identified as a highly Ca2?-selective protein complex that consists of the poreforming mitochondrial Ca2? uniporter protein (MCU) (Baughman et al 2011; Chaudhuri et al 2013; De Stefani et al 2011), the essential MCU regulator (EMRE), and the mitochondrial calcium uptake 1 and 2 (MICU1/2) (Ahuja and Muallem 2014; Mallilankaraman et al 2012; Perocchi et al 2010; Plovanich et al 2013)
By patch-clamping the inner membrane of subsarcolemmal mitoplasts prepared from isolated cardiomyocytes from UCP3-/, we verified the existence of murine mitochondrial mCa1 channels in 29 % of total patches
Summary
Mitochondrial Ca2? handling is involved in several major cellular processes. It is known to regulate the rate of mitochondrial energy adenosine triphosphate (ATP) production (Jouaville et al 1999; Territo et al 2000), to control mitochondrial reactive oxygen species (ROS) generation (Kohlhaas et al.), and to supervise the initiation of cell death (Bernardi and Rasola 2007; Hoppe; O’Rourke 2007). Uptake) is mainly mediated by the mitochondrial calcium uniporter (MCU) (Kirichok et al 2004; Maack et al 2006; Michels et al 2009) which is highly sensitive to Ruthenium Red or to its more specific derivate Ruthenium360 (Ru360) (Brookes et al 2008; Kirichok et al 2004; Michels et al 2009; Zazueta et al 1999). Uniporter protein (MCU) (Baughman et al 2011; Chaudhuri et al 2013; De Stefani et al 2011), the essential MCU regulator (EMRE), and the mitochondrial calcium uptake 1 and 2 (MICU1/2) (Ahuja and Muallem 2014; Mallilankaraman et al 2012; Perocchi et al 2010; Plovanich et al 2013). The function and regulatory mechanisms of MCU have not been fully understood yet
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