MCUR1 is an Essential Component of Mitochondrial Ca2+ Uptake that regulates Cellular Metabolism

Abstract

In dystrophic muscle, an increase in reactive oxygen species (ROS) production and sarcolemmal calcium (Ca 2þ) influx contributes to stretch-induced muscle damage however mechanistic insights into the activation of these pathways is lacking. In mdx myofibers (murine Duchenne muscular dystrophy), we have demonstrated that with mechanical stretch, the microtubule (MT) cytoskeleton is a critical mechano-transduction element for the activation of NADPH oxi-dase2 (Nox2) derived ROS production; a pathway we term X-ROS signaling [1]. Downstream, we showed that X-ROS sensitized stretch activated channels (SACs) to increase sarcolemmal Ca 2þ influx during stretch. The significance of the MT cytoskeleton activation of X-ROS in mdx was revealed when the acute targeting of MT density proffered protection from contraction induced damage. In mammalian cells, the MT network is a dynamic structure in which MT density is determined by the stability of MT filaments. Our initial studies used acute pharmacological stabilization (taxol) or destabilization (colchicine) to establish MT network density as critical for the mechano-activation of X-ROS. We now interrogate critical upstream pathways and use new pharmacological and molecular approaches to explore the role of endogenous modulators of MT stability and how they may contribute to the enhanced X-ROS in dystrophic skeletal muscle.

Overexpression of ryanodine receptor type 1 enhances mitochondrial fragmentation and Ca2+-induced ATP production in cardiac H9c2 myoblasts

“…Although in these studies MCU was confirmed as the most dominant Ca 2ϩ influx mechanism (see also Ref. 42), interestingly, mitochondrial morphology, respiration, and cell viability remain normal in MCU knockout or MCU-overexpressing cells (4,17,52,67) even though Ca 2ϩ influx is critical in the regulation of these main mitochondrial functions. In addition, recent reports using mathematical analysis (81) and electrophysiological experiments (21) have suggested that cardiac mitochondria Ca 2ϩ influx through MCU might be slow and small under the physiological range of cytosolic Ca 2ϩ concentrations ([Ca 2ϩ ] c ; i.e., 0.1-20 M) compared with other cytosolic Ca 2ϩ fluxes such as sarco(endo)plasmic reticulum Ca 2ϩ -ATPase (SERCA).…”

Modulation of Autophagy by Calcium Signalosome in Human Disease

“…VDAC1, a Ca 21 channel located at the mitochondrial outer membrane, allows the transfer of Ca 21 from the ER to the intermembrane space through a direct interaction with IP3-R. Subsequently, mitochondrial Ca 21 uptake 1 (MICU1) and MCUR1 transport Ca 21 from the intermembrane space to the lumen of mitochondria (Mallilankaraman et al, 2012a;Williams et al, 2013a). Inside the organelle, Ca 21 regulates the activity of three key dehydrogenases from the Krebs cycle, thus allowing normal ATP production.…”

Role of Presenilin in Mitochondrial Oxidative Stress and Neurodegeneration in <em>Caenorhabditis elegans</em>

“…MICU modulates MCU function by physically interacting with it and serves as a gatekeeper in MCU-mediated mitochondrial calcium uptake. MICU ensures that mitochondria do not take up calcium into the mitochondria when cytoplasmic calcium levels are low (Csordas et al, 2013;Mallilankaraman et al, 2012). Unexpectedly, MCU-null mice do not exhibit any strikingly apparent phenotypes indicative of loss of mitochondrial calcium uptake (Herzig et al, 2013;Pan et al, 2013).…”