The Na+‐independent Ca2+ efflux system in mitochondria is a Ca2+/2H+ exchange system

Rottenberg, Hagai; Marbach, Miriam

doi:10.1016/0014-5793(90)81330-q

Cited by 25 publications

(4 citation statements)

References 20 publications

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“…Cation exchangers fulfill this need. Unlike mCa 2+ uptake via MCU, which is dependent on ΔΨ m and on the chemical gradient, exchange of Ca 2+ and H + via CHE m may or may not be dependent on ΔΨ m (Rottenberg and Marbach, 1990; Gunter et al, 1991). But the direction of Ca 2+ and H + flux mediated solely by CHE m is dependent on a large IMM [H + ] or [Ca 2+ ] gradient to shuttle Ca 2+ or H + across the IMM.…”

Section: Discussionmentioning

confidence: 99%

“…A primary mCa 2+ efflux pathway is the Na + /Ca 2+ exchanger (NCE m ) (Boyman et al, 2013). In unicellular organisms and in some non-cardiac tissues there is firm evidence (Azzone et al, 1977; Pozzan et al, 1977; Wingrove et al, 1984; Brand, 1985; Rottenberg and Marbach, 1990; Gunter et al, 1991, 1994; Bernardi, 1999; Demaurex et al, 2009; Nishizawa et al, 2013) for slow homeostatic mCa 2+ efflux through a Na + -independent Ca 2+ exchanger (NICE), i.e., a non-electrogenic Ca 2+ /H + exchanger (CHE) that might be activated when the ΔpH m gradient across the IMM is altered. The amount of free (ionized) [Ca 2+ ] m available for exchange depends on the extent of dynamic mCa 2+ buffering (Bazil et al, 2013; Blomeyer et al, 2013; Tewari et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

“…mCa 2+ influx via the MCU and efflux via the NCE m are largely voltage (ΔΨ m ) dependent, whereas Ca 2+ transport via the CHE m , while pH-dependent, may be electrogenic (1 H + for 1 Ca 2+ ) or non-electrogenic (2 H + for 1 Ca 2+ ). However, CHE m can be indirectly dependent on the full IMM electrochemical gradient if there is a decrease in the IMM ΔpH m gradient (Rottenberg and Marbach, 1990; Dash and Beard, 2008; Dash et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

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Slow Ca2+ Efflux by Ca2+/H+ Exchange in Cardiac Mitochondria Is Modulated by Ca2+ Re-uptake via MCU, Extra-Mitochondrial pH, and H+ Pumping by FOF1-ATPase

et al. 2019

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Mitochondrial (m) Ca2+ influx is largely dependent on membrane potential (ΔΨm), whereas mCa2+ efflux occurs primarily via Ca2+ ion exchangers. We probed the kinetics of Ca2+/H+ exchange (CHEm) in guinea pig cardiac muscle mitochondria. We tested if net mCa2+ flux is altered during a matrix inward H+ leak that is dependent on matrix H+ pumping by ATPm hydrolysis at complex V (FOF1-ATPase). We measured [Ca2+]m, extra-mitochondrial (e) [Ca2+]e, ΔΨm, pHm, pHe, NADH, respiration, ADP/ATP ratios, and total [ATP]m in the presence or absence of protonophore dinitrophenol (DNP), mitochondrial uniporter (MCU) blocker Ru360, and complex V blocker oligomycin (OMN). We proposed that net slow influx/efflux of Ca2+ after adding DNP and CaCl2 is dependent on whether the ΔpHm gradient is/is not maintained by reciprocal outward H+ pumping by complex V. We found that adding CaCl2 enhanced DNP-induced increases in respiration and decreases in ΔΨm while [ATP]m decreased, ΔpHm gradient was maintained, and [Ca2+]m continued to increase slowly, indicating net mCa2+ influx via MCU. In contrast, with complex V blocked by OMN, adding DNP and CaCl2 caused larger declines in ΔΨm as well as a slow fall in pHm to near pHe while [Ca2+]m continued to decrease slowly, indicating net mCa2+ efflux in exchange for H+ influx (CHEm) until the ΔpHm gradient was abolished. The kinetics of slow mCa2+ efflux with slow H+ influx via CHEm was also observed at pHe 6.9 vs. 7.6 by the slow fall in pHm until ΔpHm was abolished; if Ca2+ reuptake via the MCU was also blocked, mCa2+ efflux via CHEm became more evident. Of the two components of the proton electrochemical gradient, our results indicate that CHEm activity is driven largely by the ΔpHm chemical gradient with H+ leak, while mCa2+ entry via MCU depends largely on the charge gradient ΔΨm. A fall in ΔΨm with excess mCa2+ loading can occur during cardiac cell stress. Cardiac cell injury due to mCa2+ overload may be reduced by temporarily inhibiting FOF1-ATPase from pumping H+ due to ΔΨm depolarization. This action would prevent additional slow mCa2+ loading via MCU and permit activation of CHEm to mediate efflux of mCa2+.HIGHLIGHTS We examined how slow mitochondrial (m) Ca2+ efflux via Ca2+/H+ exchange (CHEm) is triggered by matrix acidity after a rapid increase in [Ca2+]m by adding CaCl2 in the presence of dinitrophenol (DNP) to permit H+ influx, and oligomycin (OMN) to block H+ pumping via FOF1-ATP synthase/ase (complex V).Declines in ΔΨm and pHm after DNP and added CaCl2 were larger when complex V was blocked.[Ca2+]m slowly increased despite a fall in ΔΨm but maintained pHm when H+ pumping by complex V was permitted.[Ca2+]m slowly decreased and external [Ca2+]e increased with declines in both ΔΨm and pHm when complex V was blocked.ATPm hydrolysis supports a falling pHm and redox state and promotes a slow increase in [Ca2+]m.After rapid Ca2+ influx due to a bolus of CaCl2, slow mCa2+ efflux by CHEm occurs directly if pHe is low.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Slow Ca2+ Efflux by Ca2+/H+ Exchange in Cardiac Mitochondria Is Modulated by Ca2+ Re-uptake via MCU, Extra-Mitochondrial pH, and H+ Pumping by FOF1-ATPase

et al. 2019

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“…To accommodate mitochondrial Ca 2+ in response to changes in cytosolic Ca 2+ levels, an Ca 2+ ions are extruded from the mitochondrial matrix. Two major pathways are identified to counter the MCU complex and trigger Ca 2+ efflux from mitochondria, namely, the Na + /Ca 2+ /Li + permeable exchanger (NCLX) [ 69 , 70 ] and the H + /Ca 2+ exchanger (HCX) [ 71 ].…”

Section: Maintenance Of Mitochondrial Ca 2+ Homeosmentioning

confidence: 99%

Mitochondrial Ca2+ regulation in the etiology of heart failure: physiological and pathophysiological implications

Cui

Zhang

et al. 2020

Acta Pharmacol Sin

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Heart failure (HF) represents one of the leading causes of cardiovascular diseases with high rates of hospitalization, morbidity and mortality worldwide. Ample evidence has consolidated a crucial role for mitochondrial injury in the progression of HF. It is well established that mitochondrial Ca 2+ participates in the regulation of a wide variety of biological processes, including oxidative phosphorylation, ATP synthesis, reactive oxygen species (ROS) generation, mitochondrial dynamics and mitophagy. Nonetheless, mitochondrial Ca 2+ overload stimulates mitochondrial permeability transition pore (mPTP) opening and mitochondrial swelling, resulting in mitochondrial injury, apoptosis, cardiac remodeling, and ultimately development of HF. Moreover, mitochondria possess a series of Ca 2+ transport influx and efflux channels, to buffer Ca 2+ in the cytoplasm. Interaction at mitochondria-associated endoplasmic reticulum membranes (MAMs) may also participate in the regulation of mitochondrial Ca 2+ homeostasis and plays an essential role in the progression of HF. Here, we provide an overview of regulation of mitochondrial Ca 2+ homeostasis in maintenance of cardiac function, in an effort to identify novel therapeutic strategies for the management of HF.

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Transport of calcium by mitochondria

Gunter

1994

J Bioenerg Biomembr

254

139

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The identification of intramitochondrial free calcium ([Ca2+]m) as a primary metabolic mediator [see Hansford (this volume) and Gunter, T. E., Gunter, K. K., Sheu, S.-S., and Gavin, C. E. (1994) Am. J. Physiol. 267, C313-C339, for reviews] has emphasized the importance of understanding the characteristics of those mechanisms that control [Ca2+]m. In this review, we attempt to update the descriptions of the mechanisms that mediate the transport of Ca2+ across the mitochondrial inner membrane, emphasizing the energetics of each mechanism. New concepts within this field are reviewed and some older concepts are discussed more completely than in earlier reviews. The mathematical forms of the membrane potential dependence and concentration dependence of the uniporter are interpolated in such a way as to display the convenience of considering Vmax to be an explicit function of the membrane potential. Recent evidence for a transient rapid conductance state of the uniporter is discussed. New evidence concerning the energetics and stoichiometries of both Na(+)-dependent and Na(+)-independent efflux mechanisms is reviewed. Explicit mathematical expressions are used to describe the energetics of the system and the kinetics of transport via each Ca2+ transport mechanism.

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The Na⁺‐independent Ca²⁺ efflux system in mitochondria is a Ca²⁺/2H⁺ exchange system

Cited by 25 publications

References 20 publications

Slow Ca2+ Efflux by Ca2+/H+ Exchange in Cardiac Mitochondria Is Modulated by Ca2+ Re-uptake via MCU, Extra-Mitochondrial pH, and H+ Pumping by FOF1-ATPase

Slow Ca2+ Efflux by Ca2+/H+ Exchange in Cardiac Mitochondria Is Modulated by Ca2+ Re-uptake via MCU, Extra-Mitochondrial pH, and H+ Pumping by FOF1-ATPase

Mitochondrial Ca2+ regulation in the etiology of heart failure: physiological and pathophysiological implications

Transport of calcium by mitochondria

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