Mitochondrial calcium and the regulation of metabolism in the heart

Abstract

Consumption of adenosine triphosphate (ATP) by the heart can change dramatically as the energetic demands increase from a period of rest to strenuous activity. Mitochondrial ATP production is central to this metabolic response since the heart relies largely on oxidative phosphorylation as its source of intracellular ATP. Significant evidence has been acquired indicating that Ca(2+) plays a critical role in regulating ATP production by the mitochondria. Here the evidence that the Ca(2+) concentration in the mitochondrial matrix ([Ca(2+)]m) plays a pivotal role in regulating ATP production by the mitochondria is critically reviewed and aspects of this process that are under current active investigation are highlighted. Importantly, current quantitative information on the bidirectional Ca(2+) movement across the inner mitochondrial membrane (IMM) is examined in two parts. First, we review how Ca(2+) influx into the mitochondrial matrix depends on the mitochondrial Ca(2+) channel (i.e., the mitochondrial calcium uniporter or MCU). This discussion includes how the MCU open probability (PO) depends on the cytosolic Ca(2+) concentration ([Ca(2+)]i) and on the mitochondrial membrane potential (ΔΨm). Second, we discuss how steady-state [Ca(2+)]m is determined by the dynamic balance between this MCU-based Ca(2+) influx and mitochondrial Na(+)/Ca(2+) exchanger (NCLX) based Ca(2+) efflux. These steady-state [Ca(2+)]m levels are suggested to regulate the metabolic energy supply due to Ca(2+)-dependent regulation of mitochondrial enzymes of the tricarboxylic acid cycle (TCA), the proteins of the electron transport chain (ETC), and the F1F0 ATP synthase itself. We conclude by discussing the roles played by [Ca(2+)]m in influencing mitochondrial responses under pathological conditions. This article is part of a Special Issue entitled "Mitochondria: From BasicMitochondrial Biology to Cardiovascular Disease."

Keywords: ATP; Calcium; Metabolism; Mitochondria; mPTP.

Figure 1.. Cardiac Mitochondria and Mitochondrial Ca²⁺ signaling.

A) Electron micrograph (EM) of a single cardiac sarcomere showing the location of the transverse tubule (TT), junctional SR compartment (jsr), and intermyofibrillar mitochondrion (IFM). Modified from [15]. B) spatial representation showing the Ca²⁺ release unit (CRU) located between the transverse-tubule (TT) and junctional SR (JSR) membranes relative to an IFM. C) During a Ca²⁺ spark, [Ca²⁺]_i briefly bathes the mitochondrion with levels indicated by the blue line and [Ca²⁺]_m rises to levels roughly similar to the red line. Modified from [8]. Note that the left y-axis is log scale.

Figure 2.. Ca²⁺ sensitivity of the MCU complex.

This diagram shows the four known transmembrane components (and regulators) of the MCU complex (MCU,MCUb,EMRE, and MCUR1). Also shown are the known regulators present in the intermembrane space which includes MICU1, MICU2, and SLC25A23. Ca²⁺ sensitivities are indicated by the red arrows. Black arrow indicates inhibition of MCU by Ru360.

Figure 3.. Diagram of Mitochondrial Metabolism Components.

Enzymes with known Ca²⁺ sensitivities are indicated by red arrow labels with a plus (+) while Ca²⁺-insensitives ones are indicated by blue labels. The five complexes responsible for oxidative phosphorylation are light blue ovals and labeled with their respective Roman numerals (i.e., I,II,..,V). The TCA cycle is responsible for converting Acetyl-CoA into NADH and is indicated with curved black arrows. Red arrows indicate Ca²⁺ interactions/pathways. Protein and enzyme abbreviations: pyruvate dehydrogenase (PDH); citrate synthase (CS); aconitase (A); isocitrate dehydrogenase (ICD); a-ketoglutarate dehydrogenase (KDH); succinyl CoA synthetase (SCS); succinate dehydrogenase (SDH); fumarase (F); malate dehydrogenase (MDH); mitochondrial Ca²⁺ uniporter (MCU); mitochondrial Na⁺/Ca²⁺ exchanger (NCLX); Leucine zipper-EF-hand containing transmembrane protein 1 (Letm1); cytochrome C (C); ubiquinone (Q); voltage-dependent anion channel (VDAC); ATP/ADP translocase (ANT); inorganic phosphate carrier (PiC); and the mitochondrial Na⁺/H⁺ exchanger (NHE).

Figure 4.. Calcium sensitivities of Mitochondrial Enzymes/Proteins.

Colored bars indicate ranges of Ca²⁺ sensitivity. Red bars indicate Ca²⁺-dependent sensitivities likely to increase ATP production while blue bars indicate likely Ca²⁺-dependent decreases in ATP production. Asterices (*) indicate entities which sense [Ca²⁺]_ims and not [Ca²⁺]_m (e.g., GPDH, aralar1, and citrin).