The mitochondrial Na+/Ca2+ exchanger is essential for Ca2+ homeostasis and viability

Luongo, Timothy S.; Lambert, Jonathan P; Gross, Polina; Nwokedi, Mary; Lombardi, Alyssa A.; Shanmughapriya, Santhanam; Carpenter, April C.; Kolmetzky, Devin W.; Gao, Erhe; Berlo, Jop H. van; Tsai, Emily J.; Molkentin, Jeffery D.; Chen, Xiongwen; Madesh, Muniswamy; Houser, Steven R.; Elrod, John W.

doi:10.1038/nature22082

Cited by 329 publications

(316 citation statements)

References 38 publications

Supporting

Mentioning

298

Contrasting

Unclassified

Order By: Relevance

“…The reduction in Ca 2+ efflux appears mediated by a reduction in Nclx transcription, which leads to consequent reduction in Na + -Ca 2+ exchanger protein levels. Such a reduction may ultimately predispose to sudden death via mitochondrial Ca 2+ overload, as seen in other forms of heart failure [62]. The situation for the mitochondrial Ca 2+ uniporter is more complicated, since we find decreased transcripts but increased protein expression of channel subunits.…”

Section: Discussionmentioning

confidence: 75%

Mitochondrial cardiomyopathies feature increased uptake and diminished efflux of mitochondrial calcium

Sommakia

Houlihan

Deane

et al. 2017

Journal of Molecular and Cellular Cardiology

View full text Add to dashboard Cite

Calcium (Ca2+) influx into the mitochondrial matrix stimulates ATP synthesis. Here, we investigate whether mitochondrial Ca2+ transport pathways are altered in the setting of deficient mitochondrial energy synthesis, as increased matrix Ca2+ may provide a stimulatory boost. We focused on mitochondrial cardiomyopathies, which feature such dysfunction of oxidative phosphorylation. We study a mouse model where the main transcription factor for mitochondrial DNA (transcription factor A, mitochondrial, Tfam) has been disrupted selectively in cardiomyocytes. By the second postnatal week (10–15 day old mice), these mice have developed a dilated cardiomyopathy associated with impaired oxidative phosphorylation. We find evidence of increased mitochondrial Ca2+ during this period using imaging, electrophysiology, and biochemistry. The mitochondrial Ca2+ uniporter, the main portal for Ca2+ entry, displays enhanced activity, whereas the mitochondrial sodium-calcium (Na+-Ca2+) exchanger, the main portal for Ca2+ efflux, is inhibited. These changes in activity reflect changes in protein expression of the corresponding transporter subunits. While decreased transcription of Nclx, the gene encoding the Na+-Ca2+ exchanger, explains diminished Na+-Ca2+ exchange, the mechanism for enhanced uniporter expression appears to be post-transcriptional. Notably, such changes allow cardiac mitochondria from Tfam knockout animals to be far more sensitive to Ca2+-induced increases in respiration. In the absence of Ca2+, oxygen consumption declines to less than half of control values in these animals, but rebounds to control levels when incubated with Ca2+. Thus, we demonstrate a phenotype of enhanced mitochondrial Ca2+ in a mitochondrial cardiomyopathy model, and show that such Ca2+ accumulation is capable of rescuing deficits in energy synthesis capacity in vitro.

show abstract

Section: Discussionmentioning

confidence: 75%

Mitochondrial cardiomyopathies feature increased uptake and diminished efflux of mitochondrial calcium

Sommakia

Houlihan

Deane

et al. 2017

Journal of Molecular and Cellular Cardiology

View full text Add to dashboard Cite

show abstract

“…More recently, severely compromised phenotypes at baseline were reported in an inducible cardiac‐specific NCLX‐KO mouse model (Luongo et al . ). This phenotype contrasted sharply to the functionally and energetically uncompromised phenotypes of three MCU‐deficient models.…”

Section: Potential Explanations On the Lack Of Energy Crisis In Mcu‐dmentioning

confidence: 97%

Why don't mice lacking the mitochondrial Ca²⁺ uniporter experience an energy crisis?

Wang

Fernandez-Sanz

Wang

et al. 2018

The Journal of Physiology

View full text Add to dashboard Cite

Current dogma holds that the heart balances energy demand and supply effectively and sustainably by sequestering enough Ca into mitochondria during heartbeats to stimulate metabolic enzymes in the tricarboxylic acid (TCA) cycle and electron transport chain (ETC). This process is called excitation-contraction-bioenergetics (ECB) coupling. Recent breakthroughs in identifying the mitochondrial Ca uniporter (MCU) and its associated proteins have opened up new windows for interrogating the molecular mechanisms of mitochondrial Ca homeostasis regulation and its role in ECB coupling. Despite remarkable progress made in the past 7 years, it has been surprising, almost disappointing, that germline MCU deficiency in mice with certain genetic background yields viable pups, and knockout of the MCU in adult heart does not cause lethality. Moreover, MCU deficiency results in few adverse phenotypes, normal performance, and preserved bioenergetics in the heart at baseline. In this review, we briefly assess the existing literature on mitochondrial Ca homeostasis regulation and then we consider possible explanations for why MCU-deficient mice are spared from energy crises under physiological conditions. We propose that MCU and/or mitochondrial Ca may have limited ability to set ECB coupling, that other mitochondrial Ca handling mechanisms may play a role, and that extra-mitochondrial Ca may regulate ECB coupling. Since the heart needs to regenerate a significant amount of ATP to assure the perpetuation of heartbeats, multiple mechanisms are likely to work in concert to match energy supply with demand.

show abstract

“…Although a number of candidate genes have been proposed in the past, including a Ca 2+ ‐ATPase (Huang et al ., ), a heavy‐metal ATPase (Moreno et al ., ) and a glutamate‐receptor‐like channel (Teardo et al ., ), none of them has been demonstrated to regulate [Ca 2+ ] stroma and to mediate Ca 2+ transport in intact chloroplasts. This situation is in stark contrast to our understanding of Ca 2+ transport across the mitochondrial membranes of animals and plants, the molecular basis of which has been resolved in recent years (Jiang et al ., ; Perocchi et al ., ; Baughman et al ., ; De Stefani et al ., ; Wagner et al ., ; Luongo et al ., ).…”

Section: Introductionmentioning

confidence: 97%

Chloroplast‐localized BICAT proteins shape stromal calcium signals and are required for efficient photosynthesis

et al. 2018

View full text Add to dashboard Cite

The photosynthetic machinery of plants must be regulated to maximize the efficiency of light reactions and CO fixation. Changes in free Ca in the stroma of chloroplasts have been observed at the transition between light and darkness, and also in response to stress stimuli. Such Ca dynamics have been proposed to regulate photosynthetic capacity. However, the molecular mechanisms of Ca fluxes in the chloroplasts have been unknown. By employing a Ca reporter-based approach, we identified two chloroplast-localized Ca transporters in Arabidopsis thaliana, BICAT1 and BICAT2, that determine the amplitude of the darkness-induced Ca signal in the chloroplast stroma. BICAT2 mediated Ca uptake across the chloroplast envelope, and its knockout mutation strongly dampened the dark-induced [Ca ] signal. Conversely, this Ca transient was increased in knockout mutants of BICAT1, which transports Ca into the thylakoid lumen. Knockout mutation of BICAT2 caused severe defects in chloroplast morphology, pigmentation and photosynthetic light reactions, rendering bicat2 mutants barely viable under autotrophic growth conditions, while bicat1 mutants were less affected. These results show that BICAT transporters play a role in chloroplast Ca homeostasis. They are also involved in the regulation of photosynthesis and plant productivity. Further work will be required to reveal whether the effect on photosynthesis is a direct result of their role as Ca transporters.

show abstract

The mitochondrial Na+/Ca2+ exchanger is essential for Ca2+ homeostasis and viability

Cited by 329 publications

References 38 publications

Mitochondrial cardiomyopathies feature increased uptake and diminished efflux of mitochondrial calcium

Mitochondrial cardiomyopathies feature increased uptake and diminished efflux of mitochondrial calcium

Why don't mice lacking the mitochondrial Ca²⁺ uniporter experience an energy crisis?

Chloroplast‐localized BICAT proteins shape stromal calcium signals and are required for efficient photosynthesis

Contact Info

Product

Resources

About

The mitochondrial Na+/Ca2+ exchanger is essential for Ca2+ homeostasis and viability

Cited by 329 publications

References 38 publications

Mitochondrial cardiomyopathies feature increased uptake and diminished efflux of mitochondrial calcium

Mitochondrial cardiomyopathies feature increased uptake and diminished efflux of mitochondrial calcium

Why don't mice lacking the mitochondrial Ca2+ uniporter experience an energy crisis?

Chloroplast‐localized BICAT proteins shape stromal calcium signals and are required for efficient photosynthesis

Contact Info

Product

Resources

About

Why don't mice lacking the mitochondrial Ca²⁺ uniporter experience an energy crisis?