Ca
 2+
 signals regulate mitochondrial metabolism by stimulating CREB-mediated expression of the mitochondrial Ca
 2+
 uniporter gene
 MCU

Shanmughapriya, Santhanam; Rajan, Sudarsan; Hoffman, Nicholas E.; Zhang, Xueqian; Guo, Shuchi; Kolesar, Jill E.; Hines, Kevin J.; Ragheb, Jonathan; Jog, Neelakshi R.; Caricchio, Roberto; Baba, Yoshifumi; Zhou, Yandong; Kaufman, Brett A.; Cheung, Joseph Y.; Kurosaki, Tomohiro; Gill, Donald L.; Madesh, Muniswamy

doi:10.1126/scisignal.2005673

Cited by 112 publications

(97 citation statements)

References 82 publications

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“…35 Therefore, we investigated whether CREB was involved in FUNDC1-induced Fis1 expression. First, we examined whether FUNDC1 regulates CREB phosphorylation in heart, and found that Fundc1 deletion resulted in decreased phosphorylation of CREB at Ser133 (Supplemental Figure 11B and 11C).…”

Section: Resultsmentioning

confidence: 99%

Binding of FUN14 Domain Containing 1 With Inositol 1,4,5-Trisphosphate Receptor in Mitochondria-Associated Endoplasmic Reticulum Membranes Maintains Mitochondrial Dynamics and Function in Hearts in Vivo

et al. 2017

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Background FUN14 domain containing 1 (FUNDC1) is a highly conserved outer mitochondrial membrane protein. The aim of this study is to examine if FUNDC1 modulates the mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs), mitochondrial morphology, and function in cardiomyocytes and in intact hearts. Methods The impacts of FUNDC1 on MAMs formation and cardiac functions were studied in mouse neonatal cardiomyocytes, in mice with cardiomyocyte-specific Fundc1 gene knockout (Fundc1f/Y/CreαMyHC+/−), and in the cardiac tissues of the patients with heart failure. Results In mouse neonatal cardiomyocytes and intact hearts, FUNDC1 was localized in MAMs by binding to ER-resided inositol 1,4,5-trisphosphate type 2 receptor (IP3R2). Fundc1 ablation disrupted MAMs, reduced the levels of IP3R2 and Ca2+ in both mitochondria and cytosol whereas overexpression of Fundc1 increased the levels of IP3R2 and Ca2+ in both mitochondria and cytosol. Consistently, Fundc1 ablation increased Ca2+ levels in ER whereas Fundc1 overexpression lowered ER Ca2+ levels. Further, Fundc1 ablation in cardiomyocytes elongated mitochondria, and compromised mitochondrial functions. Mechanistically, we found that Fundc1 ablation-induced reduction of intracellular Ca2+ levels suppressed mitochondrial fission 1 protein (Fis1) expression and mitochondrial fission by reducing the binding of the cAMP response element binding protein (CREB) in the Fis1 promoter. Fundc1f/Y/CreαMyHC+/− mice but not their littermate control mice (Fundc1wt/Y/CreαMyHC+/−) exhibited cardiac dysfunction. The ligation of the left ventricle artery of Fundc1f/Y/CreαMyHC+/− mice caused more severe cardiac dysfunction than those in sham-treated Fundc1f/Y/CreαMyHC+/− mice. Finally, we found that the FUNDC1/MAMs/CREB/Fis1 signaling axis was significantly suppressed in the patients with heart failure. Conclusions We conclude that FUNDC1 binds to IP3R2 to modulate ER Ca2+ release into mitochondria and cytosol and that a disruption of FUNDC1 and IP3R2 interaction lowers the levels of Ca2+ in mitochondria and cytosol, both of which instigate aberrant mitochondrial fission, mitochondrial dysfunction, cardiac dysfunction, and heart failure.

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Section: Resultsmentioning

confidence: 99%

Binding of FUN14 Domain Containing 1 With Inositol 1,4,5-Trisphosphate Receptor in Mitochondria-Associated Endoplasmic Reticulum Membranes Maintains Mitochondrial Dynamics and Function in Hearts in Vivo

et al. 2017

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“…Perturbation of [Ca 2+ ] m uptake may lead to cellular bioenergetic crisis (McCormack and Denton, 1990; Shanmughapriya et al, 2015b). To determine the effect of reduced [Ca 2+ ] m uptake, ATP levels in endothelial cells derived from MCUR1 ΔEC and MCU ΔEC mice were examined.…”

Section: Resultsmentioning

confidence: 99%

MCUR1 Is a Scaffold Factor for the MCU Complex Function and Promotes Mitochondrial Bioenergetics

et al. 2016

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SUMMARY Mitochondrial Ca2+ Uniporter (MCU)-dependent mitochondrial Ca2+ uptake is the primary mechanism for increasing matrix Ca2+ in most cell types. However, a limited understanding of the MCU complex assembly impedes the comprehension of the precise mechanisms underlying MCU activity. Here we report that mouse cardiomyocytes and endothelial cells lacking MCU regulator 1, MCUR1, have severely impaired [Ca2+]m uptake and IMCU current. MCUR1 binds to MCU and EMRE and function as a scaffold factor. Our protein binding analyses identified the minimal, highly conserved regions of coiled-coil domain of both MCU and MCUR1 that are necessary for heterooligomeric complex formation. Loss of MCUR1 perturbed MCU heterooligomeric complex and functions as a scaffold factor for the assembly of MCU complex. Vascular endothelial deletion of MCU and MCUR1 impaired mitochondrial bioenergetics, cell proliferation and migration but elicited autophagy. These studies establish the existence of a MCU complex which assembles at the mitochondrial integral membrane and regulates Ca2+-dependent mitochondrial metabolism.

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“…Transcriptional regulation has been shown to occur through the calcium-dependent transcription factor cAMP response-element binding protein, which binds to the MCU promoter 47 . Synaptic activity was shown to repress transcription of Mcu through a calmodulin kinase-dependent mechanism 48 .…”

Section: Additional Layers Of Regulationmentioning

confidence: 99%

The molecular era of the mitochondrial calcium uniporter

Kamer

Mootha

2015

Nat Rev Mol Cell Biol

298

237

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The mitochondrial calcium uniporter is an evolutionarily conserved calcium channel, and its biophysical properties and relevance to cell death, bioenergetics and signalling have been investigated for decades. However, the genes encoding this channel have only recently been discovered, opening up a new 'molecular era' in the study of its biology. We now know that the uniporter is not a single protein but rather a macromolecular complex consisting of pore-forming and regulatory subunits. We review recent studies that harnessed the power of molecular biology and genetics to characterize the mechanism of action of the uniporter, its evolution and its contribution to physiology and human disease.

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Ca ²⁺ signals regulate mitochondrial metabolism by stimulating CREB-mediated expression of the mitochondrial Ca ²⁺ uniporter gene MCU

Cited by 112 publications

References 82 publications

Binding of FUN14 Domain Containing 1 With Inositol 1,4,5-Trisphosphate Receptor in Mitochondria-Associated Endoplasmic Reticulum Membranes Maintains Mitochondrial Dynamics and Function in Hearts in Vivo

Binding of FUN14 Domain Containing 1 With Inositol 1,4,5-Trisphosphate Receptor in Mitochondria-Associated Endoplasmic Reticulum Membranes Maintains Mitochondrial Dynamics and Function in Hearts in Vivo

MCUR1 Is a Scaffold Factor for the MCU Complex Function and Promotes Mitochondrial Bioenergetics

The molecular era of the mitochondrial calcium uniporter

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Ca 2+ signals regulate mitochondrial metabolism by stimulating CREB-mediated expression of the mitochondrial Ca 2+ uniporter gene MCU

Cited by 112 publications

References 82 publications

Binding of FUN14 Domain Containing 1 With Inositol 1,4,5-Trisphosphate Receptor in Mitochondria-Associated Endoplasmic Reticulum Membranes Maintains Mitochondrial Dynamics and Function in Hearts in Vivo

Binding of FUN14 Domain Containing 1 With Inositol 1,4,5-Trisphosphate Receptor in Mitochondria-Associated Endoplasmic Reticulum Membranes Maintains Mitochondrial Dynamics and Function in Hearts in Vivo

MCUR1 Is a Scaffold Factor for the MCU Complex Function and Promotes Mitochondrial Bioenergetics

The molecular era of the mitochondrial calcium uniporter

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Ca ²⁺ signals regulate mitochondrial metabolism by stimulating CREB-mediated expression of the mitochondrial Ca ²⁺ uniporter gene MCU