Mitochondrial Calcium Regulation of Cardiac Metabolism in Health and Disease

Abstract

Oxidative phosphorylation is regulated by mitochondrial calcium (Ca²⁺) in health and disease. In physiological states, Ca²⁺ enters via the mitochondrial Ca²⁺ uniporter and rapidly enhances NADH and ATP production. However, maintaining Ca²⁺ homeostasis is critical: insufficient Ca²⁺ impairs stress adaptation, and Ca²⁺ overload can trigger cell death. In this review, we delve into recent insights further defining the relationship between mitochondrial Ca²⁺ dynamics and oxidative phosphorylation. Our focus is on how such regulation affects cardiac function in health and disease, including heart failure, ischemia-reperfusion, arrhythmias, catecholaminergic polymorphic ventricular tachycardia, mitochondrial cardiomyopathies, Barth syndrome, and Friedreich's ataxia. Several themes emerge from recent data. First, mitochondrial Ca²⁺ regulation is critical for fuel substrate selection, metabolite import, and matching of ATP supply to demand. Second, mitochondrial Ca²⁺ regulates both the production and response to reactive oxygen species (ROS), and the balance between its pro- and antioxidant effects is key to how it contributes to physiological and pathological states. Third, Ca²⁺ exerts localized effects on the electron transport chain (ETC), not through traditional allosteric mechanisms but rather indirectly. These effects hinge on specific transporters, such as the uniporter or the Na⁺/Ca²⁺ exchanger, and may not be noticeable acutely, contributing differently to phenotypes depending on whether Ca²⁺ transporters are acutely or chronically modified. Perturbations in these novel relationships during disease states may either serve as compensatory mechanisms or exacerbate impairments in oxidative phosphorylation. Consequently, targeting mitochondrial Ca²⁺ holds promise as a therapeutic strategy for a variety of cardiac diseases characterized by contractile failure or arrhythmias.

Keywords: MCU; heart failure; ischemia-reperfusion injury; mitochondrial calcium transport; mitochondrial cardiomyopathy.

FIGURE 1.

The localized nature of mitochondrial Ca²⁺ signaling In the heart, Ca²⁺ transfer from sarcoplasmic reticulum (SR) to mitochondria occurs at sites of close contact between the SR and mitochondria, allowing rapid transport through RyR2 (cardiac ryanodine receptor), voltage-dependent anion channel (VDAC), and MCU [mitochondrial Ca²⁺ uniporter (pore-forming subunit)] into the mitochondrial matrix. Ca²⁺ export back to the SR occurs in a more distal location, with Ca²⁺ exchange for Na⁺ via NCLX (Na⁺/Ca²⁺ exchanger) and finally uptake back into the SR via sarco(endo)plasmic reticulum Ca²⁺ ATPase (SERCA) pumps. IMM, inner mitochondrial membrane; IMS, intermembrane space; MICU1/2, mitochondrial Ca²⁺ uptake (gating subunit); OMM, outer mitochondrial membrane.

FIGURE 2.

Overview of established and novel forms of mitochondrial metabolism regulation by Ca²⁺ MCU [mitochondrial Ca²⁺ uniporter (pore-forming subunit)] imports Ca²⁺ into the matrix, whereas export mechanisms include Ca²⁺/H⁺ exchange via LETM1/TMBIM5 and Na⁺/Ca²⁺ exchange via NCLX/TMEM65. Well-established mechanisms of Ca²⁺ regulation are shown with solid red arrows and include allosteric regulation of aspartate-glutamate carriers (AGC), glycerol-3-phosphate dehydrogenase 2 (GPD2), isocitrate dehydrogenase (IDH), α-ketoglutarate dehydrogenase (αKDH), pyruvate dehydrogenase (PDH) phosphatase, and short Ca²⁺-binding mitochondrial carriers (SCaMC). Newer indirect mechanisms are shown as dashed red arrows and involve regulation of Complex I, coenzyme Q (CoQ), Complex IV, and ATP synthase. Cyt c, cytochrome c; IMM, inner mitochondrial membrane; IMS, intermembrane space; MCU, mitochondrial Ca²⁺ uniporter (pore-forming subunit); MPC, mitochondrial pyruvate carrier; OMM, outer mitochondrial membrane.

FIGURE 3.

New mechanisms involving mitochondrial Ca²⁺ A: Complex I interacts with MCU [mitochondrial Ca²⁺ uniporter (pore-forming subunit)] and increases its turnover because of reactive oxygen species (ROS) leak (CLIPT), which helps protect Complex I from oxidation. B: matrix acidification during ischemic injury solubilizes Ca²⁺ from Ca²⁺ phosphate precipitates. The increased matrix Ca²⁺ via NCLX boosts matrix Na⁺, thereby decreasing inner mitochondrial membrane (IM) fluidity and slowing coenzyme Q (CoQ) diffusion and the activity of Complexes II + III. C: excess Ca²⁺ may trigger rearrangement of the F1 domain of the ATP synthase to produce a channel in the membrane. IMS, intermembrane space; NTD, NH₂-terminal domain of MCU.

FIGURE 4.

Mitochondrial Ca²⁺ pathways involved in health and disease A: by regulating multiple enzymes involved in metabolite transport, the tricarboxylic acid (TCA) cycle, and the electron transport chain (ETC), Ca²⁺ allows rapid matching of ATP supply to demand. B: Ca²⁺ overload produces permeability transition, in which the ATP synthase, ATP/ADP translocase (ANT), and mitochondrial Ca²⁺ uniporter (MCU) regulator 1 (MCUR1) are implicated. C: by boosting flux through the TCA cycle, Ca²⁺ can produce both prooxidant effects [via NADH oxidation and reactive oxygen species (ROS) leak through Complex I] and antioxidant effects [enhancing the supply of NADPH by indirectly increasing substrates to malic enzyme 3 (ME3), IDH2 (isocitrate dehydrogenase 2), and nicotinamide nucleotide transhydrogenase (NNT)]. The balance of these effects determines the ultimate consequence of Ca²⁺ on oxidative stress. D: metabolism can be altered differently depending on the chronicity of uniporter inhibition. Acute inhibition abrogates supply-demand matching and Ca²⁺ overload during ischemia-reperfusion injury. However, chronic inhibition can potentially activate other cell death pathways, cause compensation of Ca²⁺ influx by reversing the direction of Ca²⁺/H⁺ and Na⁺/Ca²⁺ exchangers, or cause the loss of protective uniporter functions such as its interaction with Complex I. All of these chronic mechanisms can offset the benefit on Ca²⁺ overload of uniporter inhibition and may underlie the benefits of boosting uniporter activity in chronic cardiac disease. GSSH, reduced glutathione.

FIGURE 5.

Mitochondrial Ca²⁺ alterations involved in cardiac disease A and B: contributions to arrhythmogenesis after cardiac injury. A: depletion of mitochondrial Ca²⁺ by excessive Na⁺/Ca²⁺ exchange can lead to energetic impairment via insufficient NADH production and promote arrhythmias. B: Ca²⁺ overload in states of overnutrition promotes the production of mitochondrial reactive oxygen species (mROS), promoting oxidative injury to ryanodine receptor (RyR)2, diastolic Ca²⁺ leak, action potential (AP) lengthening, and consequent arrhythmias. C: the balance between the effects described in A and B may also determine whether mitochondrial Ca²⁺ promotes or inhibits arrhythmias in CPVT. D: in mitochondrial cardiomyopathies, injury to Complex I prevents interaction and oxidation of MCU (mitochondrial Ca²⁺ uniporter), leading to buildup in uniporter levels and subsequent energetic compensation. E: cardiolipin (blue) can bind within a fenestration between the MCU transmembrane domains. Loss of cardiolipin in Barth syndrome may alter MCU structure to inhibit interaction with accessory subunits and prevent Ca²⁺ influx. IM, inner mitochondrial membrane; IMS, intermembrane space.