7 results on '"Seelam, Ajay"'
Search Results
2. MIRO-1 Determines Mitochondrial Shape Transition upon GPCR Activation and Ca2+ Stress
- Author
-
Nemani, Neeharika, primary, Carvalho, Edmund, additional, Tomar, Dhanendra, additional, Dong, Zhiwei, additional, Ketschek, Andrea, additional, Breves, Sarah L., additional, Jaña, Fabián, additional, Worth, Alison M., additional, Heffler, Julie, additional, Palaniappan, Palaniappan, additional, Tripathi, Aparna, additional, Subbiah, Ramasamy, additional, Riitano, Massimo F., additional, Seelam, Ajay, additional, Manfred, Thomas, additional, Itoh, Kie, additional, Meng, Shuxia, additional, Sesaki, Hiromi, additional, Craigen, William J., additional, Rajan, Sudarsan, additional, Shanmughapriya, Santhanam, additional, Caplan, Jeffrey, additional, Prosser, Benjamin L., additional, Gill, Donald L., additional, Stathopulos, Peter B., additional, Gallo, Gianluca, additional, Chan, David C., additional, Mishra, Prashant, additional, and Madesh, Muniswamy, additional
- Published
- 2018
- Full Text
- View/download PDF
3. Mitochondrial Ca2+ Uniporter Is a Mitochondrial Luminal Redox Sensor that Augments MCU Channel Activity
- Author
-
Dong, Zhiwei, primary, Shanmughapriya, Santhanam, additional, Tomar, Dhanendra, additional, Siddiqui, Naveed, additional, Lynch, Solomon, additional, Nemani, Neeharika, additional, Breves, Sarah L., additional, Zhang, Xueqian, additional, Tripathi, Aparna, additional, Palaniappan, Palaniappan, additional, Riitano, Massimo F., additional, Worth, Alison M., additional, Seelam, Ajay, additional, Carvalho, Edmund, additional, Subbiah, Ramasamy, additional, Jaña, Fabián, additional, Soboloff, Jonathan, additional, Peng, Yizhi, additional, Cheung, Joseph Y., additional, Joseph, Suresh K., additional, Caplan, Jeffrey, additional, Rajan, Sudarsan, additional, Stathopulos, Peter B., additional, and Madesh, Muniswamy, additional
- Published
- 2017
- Full Text
- View/download PDF
4. Blockade of MCU-Mediated Ca2+Uptake Perturbs Lipid Metabolism via PP4-Dependent AMPK Dephosphorylation
- Author
-
Tomar, Dhanendra, Jaña, Fabián, Dong, Zhiwei, Quinn, William J., Jadiya, Pooja, Breves, Sarah L., Daw, Cassidy C., Srikantan, Subramanya, Shanmughapriya, Santhanam, Nemani, Neeharika, Carvalho, Edmund, Tripathi, Aparna, Worth, Alison M., Zhang, Xueqian, Razmpour, Roshanak, Seelam, Ajay, Rhode, Stephen, Mehta, Anuj V., Murray, Michael, Slade, Daniel, Ramirez, Servio H., Mishra, Prashant, Gerhard, Glenn S., Caplan, Jeffrey, Norton, Luke, Sharma, Kumar, Rajan, Sudarsan, Balciunas, Darius, Wijesinghe, Dayanjan S., Ahima, Rexford S., Baur, Joseph A., and Madesh, Muniswamy
- Abstract
Mitochondrial Ca2+uniporter (MCU)-mediated Ca2+uptake promotes the buildup of reducing equivalents that fuel oxidative phosphorylation for cellular metabolism. Although MCU modulates mitochondrial bioenergetics, its function in energy homeostasis in vivoremains elusive. Here we demonstrate that deletion of the Mcugene in mouse liver (MCUΔhep) and in Danio rerioby CRISPR/Cas9 inhibits mitochondrial Ca2+(mCa2+) uptake, delays cytosolic Ca2+(cCa2+) clearance, reduces oxidative phosphorylation, and leads to increased lipid accumulation. Elevated hepatic lipids in MCUΔhepwere a direct result of extramitochondrial Ca2+-dependent protein phosphatase-4 (PP4) activity, which dephosphorylates AMPK. Loss of AMPK recapitulates hepatic lipid accumulation without changes in MCU-mediated Ca2+uptake. Furthermore, reconstitution of active AMPK, or PP4 knockdown, enhances lipid clearance in MCUΔhephepatocytes. Conversely, gain-of-function MCU promotes rapid mCa2+uptake, decreases PP4 levels, and reduces hepatic lipid accumulation. Thus, our work uncovers an MCU/PP4/AMPK molecular cascade that links Ca2+dynamics to hepatic lipid metabolism.
- Published
- 2019
- Full Text
- View/download PDF
5. Blockade of MCU-Mediated Ca 2+ Uptake Perturbs Lipid Metabolism via PP4-Dependent AMPK Dephosphorylation.
- Author
-
Tomar D, Jaña F, Dong Z, Quinn WJ 3rd, Jadiya P, Breves SL, Daw CC, Srikantan S, Shanmughapriya S, Nemani N, Carvalho E, Tripathi A, Worth AM, Zhang X, Razmpour R, Seelam A, Rhode S, Mehta AV, Murray M, Slade D, Ramirez SH, Mishra P, Gerhard GS, Caplan J, Norton L, Sharma K, Rajan S, Balciunas D, Wijesinghe DS, Ahima RS, Baur JA, and Madesh M
- Subjects
- AMP-Activated Protein Kinase Kinases, Animals, Calcium Channels genetics, Cells, Cultured, Female, Hep G2 Cells, Humans, Male, Mice, Mice, Inbred C57BL, Mitochondria, Liver metabolism, Mitochondrial Proteins genetics, Phosphoprotein Phosphatases metabolism, Protein Kinases metabolism, Zebrafish, Calcium metabolism, Calcium Channels metabolism, Hepatocytes metabolism, Lipid Metabolism, Mitochondrial Proteins metabolism
- Abstract
Mitochondrial Ca
2+ uniporter (MCU)-mediated Ca2+ uptake promotes the buildup of reducing equivalents that fuel oxidative phosphorylation for cellular metabolism. Although MCU modulates mitochondrial bioenergetics, its function in energy homeostasis in vivo remains elusive. Here we demonstrate that deletion of the Mcu gene in mouse liver (MCUΔhep ) and in Danio rerio by CRISPR/Cas9 inhibits mitochondrial Ca2+ (m Ca2+ ) uptake, delays cytosolic Ca2+ (c Ca2+ ) clearance, reduces oxidative phosphorylation, and leads to increased lipid accumulation. Elevated hepatic lipids in MCUΔhep were a direct result of extramitochondrial Ca2+ -dependent protein phosphatase-4 (PP4) activity, which dephosphorylates AMPK. Loss of AMPK recapitulates hepatic lipid accumulation without changes in MCU-mediated Ca2+ uptake. Furthermore, reconstitution of active AMPK, or PP4 knockdown, enhances lipid clearance in MCUΔhep hepatocytes. Conversely, gain-of-function MCU promotes rapidm Ca2+ uptake, decreases PP4 levels, and reduces hepatic lipid accumulation. Thus, our work uncovers an MCU/PP4/AMPK molecular cascade that links Ca2+ dynamics to hepatic lipid metabolism., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2019
- Full Text
- View/download PDF
6. MIRO-1 Determines Mitochondrial Shape Transition upon GPCR Activation and Ca 2+ Stress.
- Author
-
Nemani N, Carvalho E, Tomar D, Dong Z, Ketschek A, Breves SL, Jaña F, Worth AM, Heffler J, Palaniappan P, Tripathi A, Subbiah R, Riitano MF, Seelam A, Manfred T, Itoh K, Meng S, Sesaki H, Craigen WJ, Rajan S, Shanmughapriya S, Caplan J, Prosser BL, Gill DL, Stathopulos PB, Gallo G, Chan DC, Mishra P, and Madesh M
- Subjects
- Animals, HeLa Cells, Humans, Mice, Mice, Mutant Strains, Mitochondria genetics, Receptors, G-Protein-Coupled genetics, rho GTP-Binding Proteins genetics, Calcium metabolism, Mitochondria metabolism, Mitochondrial Dynamics, Receptors, G-Protein-Coupled metabolism, Stress, Physiological, rho GTP-Binding Proteins metabolism
- Abstract
Mitochondria shape cytosolic calcium ([Ca
2+ ]c ) transients and utilize the mitochondrial Ca2+ ([Ca2+ ]m ) in exchange for bioenergetics output. Conversely, dysregulated [Ca2+ ]c causes [Ca2+ ]m overload and induces permeability transition pore and cell death. Ablation of MCU-mediated Ca2+ uptake exhibited elevated [Ca2+ ]c and failed to prevent stress-induced cell death. The mechanisms for these effects remain elusive. Here, we report that mitochondria undergo a cytosolic Ca2+ -induced shape change that is distinct from mitochondrial fission and swelling. [Ca2+ ]c elevation, but not MCU-mediated Ca2+ uptake, appears to be essential for the process we term mitochondrial shape transition (MiST). MiST is mediated by the mitochondrial protein Miro1 through its EF-hand domain 1 in multiple cell types. Moreover, Ca2+ -dependent disruption of Miro1/KIF5B/tubulin complex is determined by Miro1 EF1 domain. Functionally, Miro1-dependent MiST is essential for autophagy/mitophagy that is attenuated in Miro1 EF1 mutants. Thus, Miro1 is a cytosolic Ca2+ sensor that decodes metazoan Ca2+ signals as MiST., (Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.)- Published
- 2018
- Full Text
- View/download PDF
7. Mitochondrial Ca 2+ Uniporter Is a Mitochondrial Luminal Redox Sensor that Augments MCU Channel Activity.
- Author
-
Dong Z, Shanmughapriya S, Tomar D, Siddiqui N, Lynch S, Nemani N, Breves SL, Zhang X, Tripathi A, Palaniappan P, Riitano MF, Worth AM, Seelam A, Carvalho E, Subbiah R, Jaña F, Soboloff J, Peng Y, Cheung JY, Joseph SK, Caplan J, Rajan S, Stathopulos PB, and Madesh M
- Subjects
- Animals, COS Cells, Calcium Channels chemistry, Calcium Channels genetics, Cell Death, Cell Hypoxia, Chlorocebus aethiops, Cysteine, Endothelial Cells drug effects, Endothelial Cells pathology, Energy Metabolism, Glutathione metabolism, HEK293 Cells, HeLa Cells, Humans, Lipopolysaccharides pharmacology, Mice, Mice, Inbred C57BL, Mice, Knockout, Mitochondria drug effects, Mitochondria pathology, Mitochondrial Membranes drug effects, Mitochondrial Membranes pathology, Mutation, Oxidation-Reduction, Protein Multimerization, Protein Processing, Post-Translational, Protein Structure, Quaternary, Structure-Activity Relationship, Thrombin pharmacology, Time Factors, Transfection, Calcium metabolism, Calcium Channels metabolism, Calcium Signaling drug effects, Endothelial Cells metabolism, Ion Channel Gating drug effects, Mitochondria metabolism, Mitochondrial Membranes metabolism, Reactive Oxygen Species metabolism
- Abstract
Ca
2+ dynamics and oxidative signaling are fundamental mechanisms for mitochondrial bioenergetics and cell function. The MCU complex is the major pathway by which these signals are integrated in mitochondria. Whether and how these coactive elements interact with MCU have not been established. As an approach toward understanding the regulation of MCU channel by oxidative milieu, we adapted inflammatory and hypoxia models. We identified the conserved cysteine 97 (Cys-97) to be the only reactive thiol in human MCU that undergoes S-glutathionylation. Furthermore, biochemical, structural, and superresolution imaging analysis revealed that MCU oxidation promotes MCU higher order oligomer formation. Both oxidation and mutation of MCU Cys-97 exhibited persistent MCU channel activity with higher [Ca2+ ]m uptake rate, elevated mROS, and enhanced [Ca2+ ]m overload-induced cell death. In contrast, these effects were largely independent of MCU interaction with its regulators. These findings reveal a distinct functional role for Cys-97 in ROS sensing and regulation of MCU activity., (Copyright © 2017 Elsevier Inc. All rights reserved.)- Published
- 2017
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.