Mitochondrial free calcium regulation during sarcoplasmic reticulum calcium release in rat cardiac myocytes

Andrienko, Tatyana N; Picht, Eckard; Bers, Donald M.

doi:10.1016/j.yjmcc.2009.03.015

Cited by 78 publications

(76 citation statements)

References 44 publications

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“…2, 4, and 5). Due to the central role of mitochondria in controlling cell metabolism and cell death, many studies have been conducted in cardiac muscle to examine the role of mitochondria in shaping cytosolic Ca 2ϩ transients in both physiological and pathophysiological conditions (23,(37)(38)(39)(40) release from the SR. Although our data support the idea that compromised mitochondrial function could be a principal factor contributing to the augmented Ca 2ϩ release activity in the ALS muscle, it is also possible that the enhanced Ca 2ϩ transient includes contributions from increased SR Ca 2ϩ release in the defective fiber segment due to a greater activity of ryanodine receptor/Ca 2ϩ release channels (RyR).…”

Section: Discussionmentioning

confidence: 99%

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Mitochondrial Calcium Uptake Regulates Rapid Calcium Transients in Skeletal Muscle during Excitation-Contraction (E-C) Coupling

Yan

et al. 2011

Journal of Biological Chemistry

109

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Defective coupling between sarcoplasmic reticulum and mitochondria during control of intracellular Ca 2؉ signaling has been implicated in the progression of neuromuscular diseases. Our previous study showed that skeletal muscles derived from an amyotrophic lateral sclerosis (ALS) mouse model displayed segmental loss of mitochondrial function that was coupled with elevated and uncontrolled sarcoplasmic reticulum Ca 2؉ release activity. The localized mitochondrial defect in the ALS muscle allows for examination of the mitochondrial contribution to Ca 2؉ removal during excitation-contraction coupling by comparing Ca 2؉ transients in regions with normal and defective mitochondria in the same muscle fiber. Here we show that Ca 2؉ transients elicited by membrane depolarization in fiber segments with defective mitochondria display an ϳ10% increased amplitude. These regional differences in Ca 2؉ transients were abolished by the application of 1,2-bis(O-aminophenoxy)ethane-N,N,N,N-tetraacetic acid, a fast Ca 2؉ chelator that reduces mitochondrial Ca 2؉ uptake. Using a mitochondria-targeted Ca 2؉ biosensor (mt11-YC3.6) expressed in ALS muscle fibers, we monitored the dynamic change of mitochondrial Ca 2؉ levels during voltage-induced Ca 2؉ release and detected a reduced Ca 2؉ uptake by mitochondria in the fiber segment with defective mitochondria, which mirrored the elevated Ca 2؉ transients in the cytosol. Our study constitutes a direct demonstration of the importance of mitochondria in shaping the cytosolic Ca 2؉ signaling in skeletal muscle during excitation-contraction coupling and establishes that malfunction of this mechanism may contribute to neuromuscular degeneration in ALS.

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Section: Discussionmentioning

confidence: 99%

“…The data shown in Fig. 2 (22)(23)(24)(25). Interpretation of rhod-2 results in intact cells can be difficult because a portion of the dye remains in the cytosol or enters other organelles.…”

Section: Inhibition Of the Mitochondrial Uniporter Promotes Propagatimentioning

confidence: 99%

Mitochondrial Calcium Uptake Regulates Rapid Calcium Transients in Skeletal Muscle during Excitation-Contraction (E-C) Coupling

Yan

et al. 2011

Journal of Biological Chemistry

109

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“…When ⌬⌿ m is fully polarized, the energetic cost of removing excess Ca 2ϩ from the matrix against a Ϫ180 mV driving force is huge, and both sodium-calcium exchange and hydrogen-calcium exchange are kinetically slower than Ca 2ϩ uptake via the Ca 2ϩ uniporter (26). Complete ⌬⌿ m dissipation by a transient mPTP opening allows accumulated matrix Ca 2ϩ to flow rapidly out of the matrix down its concentration gradient and equilibrate with cytoplasmic free [Ca 2ϩ ] (27) at a much faster rate than possible via sodium-calcium or hydrogen-calcium exchange.…”

Section: Discussionmentioning

confidence: 99%

Protective Role of Transient Pore Openings in Calcium Handling by Cardiac Mitochondria

Kôrge

Yang

et al. 2011

Journal of Biological Chemistry

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Long-lasting mitochondrial permeability transition pore (mPTP) openings damage mitochondria, but transient mPTP openings protect against chronic cardiac stress. To probe the mechanism, we subjected isolated cardiac mitochondria to gradual Ca 2؉ loading, which, in the absence of BSA, induced long-lasting mPTP opening, causing matrix depolarization. However, with BSA present to mimic cytoplasmic fatty acidbinding proteins, the mitochondrial population remained polarized and functional, even after matrix Ca 2؉ release caused an extramitochondrial free [Ca 2؉ ] increase to >10 M, unless mPTP openings were inhibited. These findings could be explained by asynchronous transient mPTP openings allowing individual mitochondria to depolarize long enough to flush accumulated matrix Ca 2؉ and then to repolarize rapidly after pore closure. Because subsequent matrix Ca 2؉ reuptake via the Ca 2؉ uniporter is estimated to be >100-fold slower than matrix Ca 2؉ release via mPTP, only a tiny fraction of mitochondria (<1%) are depolarized at any given time. Our results show that transient mPTP openings allow cardiac mitochondria to defend themselves collectively against elevated cytoplasmic Ca 2؉ levels as long as respiratory chain activity is able to balance proton influx with proton pumping. We found that transient mPTP openings also stimulated reactive oxygen species production, which may engage reactive oxygen species-dependent cardioprotective signaling.

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“…There is a controversial issue on the possibility that [Ca 2＋ ]m changes in a beat-to-beat manner. Beat-to-beat mitochondrial Ca 2＋ transients have been identified on adult rabbit cardiac myocytes [8] and on rat cardiac myocytes [9]. In contrast, beat-to-beat change in [Ca 2＋ ]m was not identified on cat ventricular myocytes [10].…”

Section: ＋mentioning

confidence: 92%

“…JB Youm, et al rabbit cardiac myocytes [8] and on rat cardiac myocytes [9]. In contrast, beat-to-beat change in [Ca 2＋ ]m was not identified on cat ventricular myocytes [10].…”

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confidence: 97%

A Computational Model of Cytosolic and Mitochondrial [Ca2+] in Paced Rat Ventricular Myocytes

Youm

Choi

Jang

et al. 2011

Korean J Physiol Pharmacol

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INTRODUCTIONThe major role of ventricular myocardium is to contract regularly in response to electrical excitation in order to pump oxygenated blood out of ventricle. Two key elements are directly involved in the normal cycle of contractile activity in ventricular myocytes. One is intracellular Ca 2＋ -cycling and the other is ATP synthesis by mitochondria. Upon release from sarcoplasmic reticulum (SR), Ca 2＋ binds to troponin C to move the tropomyosin away exposing the myosin-binding site of actin filament. If ATP and Ca 2＋ are high enough near the contractile apparatus, the cross bridge cycle continues and muscle would contract. In the end of contraction, majority of Ca 2＋ is pumped back into the Ca 2＋ store by SR Ca 2＋ pump then muscle relaxes.Therefore, disruption of either Ca 2＋-cycling or ATP synthesis can disturb normal cycle of ventricular contraction. ATP synthesis by mitochondria can directly or indirectly affect the Ca 2＋ -cycling by regulating the ATP-driven SR Ca 2＋ pump [1,2] and sarcolemmal Na ＋ /K ＋ pump [1].Metabolic inhibitors are supposed to suppress the normal cycle of contraction via this mechanism. There has been evidence that Ca 2＋-cycling affects the ATP synthesis in mitochondria. Increased mitochondrial Ca 2＋ influx across the inner mitochondrial membrane has been known to stimulate F0F1-ATPase activity [3,4]. Increase in mitochondrial [Ca 2＋ ] ([Ca 2＋ ]m) has also been known to stimulate tricarboxylic acid (TCA) cycle dehydrogenases [5,6]. The resultant increase in NADH could affect the ATP synthesis of mitochondria. This is supposed to be the control mechanism that matches energy demand for bigger contraction induced by higher cytosolic (or intracellular) [Ca 2＋ ] ( [Ca 2＋ ]i) [7]. There is a controversial issue on the possibility that [Ca 2＋ ]m changes in a beat-to-beat manner. Beat-to-beat mitochondrial Ca 2＋ transients have been identified on adult 218JB Youm, et al rabbit cardiac myocytes [8] and on rat cardiac myocytes [9]. In contrast, beat-to-beat change in [Ca 2＋ ]m was not identified on cat ventricular myocytes [10]. Further complicating thing is that the ATP depletion can affect action potential (AP) waveform by stimulating ATP sensitive K ＋ channel.Reduced action potential duration (APD) by activation of ATP sensitive K ＋ channel can reduce the energy demand during contraction. All above observations demonstrate how complex the interaction among Ca 2＋-cycling, ATP production, and electrical excitation could be. If all those elements are properly modeled, an integrated mathematical model could be developed and utilized to investigate those complex interactions.Recently, cardiac models integrating electrophysiology, Ca 2＋ cycling, and energy metabolism have emerged based on experimental results from guinea pig ventricular myocytes [11,12]. Although they were able to couple mitochondrial energetics to excitation-contraction coupling, the description of mitochondrial ion transport is limited and the modeling of pHm and pHi is lacking which is a key elem...

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Mitochondrial free calcium regulation during sarcoplasmic reticulum calcium release in rat cardiac myocytes

Abstract: Abstract

Cited by 78 publications

References 44 publications

Mitochondrial Calcium Uptake Regulates Rapid Calcium Transients in Skeletal Muscle during Excitation-Contraction (E-C) Coupling

Mitochondrial Calcium Uptake Regulates Rapid Calcium Transients in Skeletal Muscle during Excitation-Contraction (E-C) Coupling

Protective Role of Transient Pore Openings in Calcium Handling by Cardiac Mitochondria

A Computational Model of Cytosolic and Mitochondrial [Ca2+] in Paced Rat Ventricular Myocytes

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