The debate continues - What is the role of MCU and mitochondrial calcium uptake in the heart?

Abstract

Since the identification of the mitochondrial calcium uniporter (MCU) in 2011, several studies utilizing genetic models have attempted to decipher the role of mitochondrial calcium uptake in cardiac physiology. Confounding results in various mutant mouse models have led to an ongoing debate regarding the function of MCU in the heart. In this review, we evaluate and discuss the totality of evidence for mitochondrial calcium uptake in the cardiac stress response and highlight recent reports that implicate MCU in the control of homeostatic cardiac metabolism and function. This review concludes with a discussion of current gaps in knowledge and remaining experiments to define how MCU contributes to contractile function, cell death, metabolic regulation, and heart failure progression.

Keywords: Calcium; Cardiac function; Energetics; Ischemia reperfusion; MCU; MICU1; Mitochondria; NCLX; Permeability transition.

Figure 1–. MCU is required for the heart to rapidly increase work output in response to an acute physiological increase in demand.

Homeostatic _mCa²⁺ cycling maintains sufficient ATP production to match basal rates of ATP consumption. Recent data suggest that the mtCU may be required for such basal _mCa²⁺ flux to support cardiac metabolism. In response to exercise or sympathetic stimulation, cytosolic Ca²⁺ concentration rises. In the wild-type heart, this increase in cytosolic Ca²⁺ concentration is rapidly communicated to the mitochondria via acute Ca²⁺ uptake through MCU, the pore-forming subunit of the mitochondrial calcium uniporter complex (mtCU). The subsequent increase in matrix Ca²⁺ concentration stimulates TCA cycle dehydrogenases and ATP synthase in order to increase OXPHOS and the rate of mitochondrial ATP production. This rapid increase in the rate of ATP production is required to fuel increased crossbridge cycling and SERCA activity to allow for an increase in heart rate and contractility. In the absence of MCU, rapid _mCa²⁺ uptake is abolished and the heart cannot quickly increase its mitochondrial metabolism in order to fuel a rapid increase in cardiac work rate.

Figure 2–. Perinatal deletion of cardiomyocyte MCU does not alter IR-injury.

A-B) There is no difference in infarct size as quantified by TTC and Evan’s blue staining (A), or in serum concentration of cardiac troponin-I (cTnI, B) between control (MCU^fl/fl) and MCU^fl/fl × αMHC-Cre mice subjected to 40 minutes of in vivo LCA ischemia and 24 hours of reperfusion. (n=9–11 mice / group). C-E) There is no difference in left ventricular end-diastolic dimension (LVEDD), end systolic dimension (LVESD), or percent fractional shortening (FS) between control and cardiac MCU-null mice as measured by echocardiography after 24 hours of reperfusion (n=11–14 mice / group). F-G) There is no difference in longitudinal or radial strain rates between control and cardiac MCU-null mice as measured by 2D echo after 24 hours of reperfusion (n=14–16 mice / group). Data are presented as mean ± S.E.M. All mouse models and experimental details for I/R are as previously reported in Luongo et al. (81). All animal experiments were approved by Temple University’s IACUC and followed AAALAC guidelines.

Figure 3–. MCU mediates acute _mCa²⁺ overload in the face of cytosolic Ca²⁺ overload, and triggers permeability transition and cardiomyocyte death in IR-injury.

_mCa²⁺ uptake through MCU can trigger mitochondrial permeability transition, leading to mitochondrial swelling, membrane rupture, and the initiation of necrotic cell death. This pathway is largely responsible for cardiomyocyte death in myocardial IR-injury and heart failure. Acute inhibition or genetic disruption of MCU function can prevent excessive _mCa²⁺ uptake, mPTP opening, and necrosis during IR-injury. With chronic, sustained MCU disruption, cardiomyocytes can remodel such that the protective effects against acute injury are lost. The mPTP may be sensitized to low levels of _mCa²⁺, and thus open even in the absence of rapid _mCa²⁺ uptake, perhaps in response to smaller, more gradual increases in _mCa²⁺ mediated by MCU-independent _mCa²⁺ uptake pathways. Chronic MCU disruption also causes upregulation of additional cell death pathways that may allow for cardiomyocyte death during IR-injury, even in the context of reduced _mCa²⁺ uptake.