PGAM5 tethers a ternary complex containing Keap1 and Nrf2 to mitochondria

Lo, Shih-Ching; Hannink, Mark

doi:10.1016/j.yexcr.2008.02.014

Cited by 300Genomics, phytochemicals, and oxidative stressRedox biology and oxidative stressGlutathione Transferases and Polymorphisms

PGAM5 tethers a ternary complex containing Keap1 and Nrf2 to mitochondria

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Lo, Shih-Ching, Hannink, Mark·2008·Experimental Cell Research

DOI 10.1016/j.yexcr.2008.02.014PMC PMC2409987

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Abstract

Eukaryote cells balance production of reactive oxygen species (ROS) with levels of anti-oxidant enzyme activity to maintain cellular redox homeostasis. Mitochondria are a major source of ROS, while many anti-oxidant genes are regulated by the Nrf2 transcription factor. Keap1, a redox-regulated substrate adaptor for a cullin-based ubiquitin ligase, targets Nrf2 for proteosome-mediated degradation and represses Nrf2-dependent gene expression. We have previously identified a member of the phosphoglycerate mutase family, PGAM5, as a Keap1-binding protein. In this report, we demonstrate that PGAM5 is targeted to the outer membrane of mitochondria by an N-terminal mitochondrial-localization sequence. Furthermore, we provide evidence that PGAM5 forms a ternary complex containing both Keap1 and Nrf2, in which the dimeric Keap1 protein simultaneously binds both PGAM5 and Nrf2 through their conserved E(S/T)GE motifs. Knockdown of either Keap1 or PGAM5 activates Nrf2-dependent gene expression. We suggest that this ternary complex provides a molecular framework for understanding how nuclear anti-oxidant gene expression is regulated in response to changes in mitochondrial function(s).

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PGAM5 can recruit both Keap1 and Nrf2 to the outer mitochondrial membrane to form a ternary Keap1-PGAM5-Nrf2 complex, resulting in stress-induced Keap1-mediated ubiquitination and degradation of Miro2 rather than Nrf2.
“Interestingly, PGAM5 can recruit both Keap1 and Nrf2 to the outer mitochondrial membrane by binding to one molecule of a Keap1 dimer while simultaneously binding Nrf2 to form a ternary Keap1-PGAM5-Nrf2 complex [102,103]. Interestingly, this results in the stress-induced Keap1-mediated ubiquitination and degradation of not Nrf2, but of mitochondrial Rho GTPase 2 (Miro2), a mitochondrial GTPase inv”
From Nrf2 and Oxidative Stress: A General Overview of Mechanisms and Implications in Human Disease (2022) · cites this paper as [102]

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Strachan, G. D., Morgan, K. L., Otis, L. L., Caltagarone, J., Gittis, A. H., Bowser, R. P., & Jordan‐Sciutto, K. L. (2004) · Biochemistry · doi:10.1021/bi0494166 · Cited by 34 · see citing works
An unsuspected ecdysteroid/steroid phosphatase activity in the key T‐cell regulator, Sts‐1: Surprising relationship to insect ecdysteroid phosphate phosphatase
Davies, L., Anderson, I., Turner, P., Shirras, A. D., Rees, H. H., & Rigden, D. J. (2007) · Proteins Structure Function and Bioinformatics · doi:10.1002/prot.21357 · Cited by 25 · see citing works
Keap1 in adhesion complexes
Velichkova, M., & Hasson, T. (2003) · Cell Motility and the Cytoskeleton · doi:10.1002/cm.10138 · Cited by 24 · see citing works

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Role of nrf2 in oxidative stress and toxicity
Ma, Q. (2013) · Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev-pharmtox-011112-140320 · Cited by 4,903 · see citing works
Transcriptional Regulation by Nrf2
Tonelli, C., Chio, I. I. C., & Tuveson, D. A. (2017) · Antioxidants and Redox Signaling · doi:10.1089/ars.2017.7342 · Cited by 2,206 · see citing works
The Nrf2 regulatory network provides an interface between redox and intermediary metabolism
Hayes, J. D., & Dinkova‐Kostova, A. T. (2014) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2014.02.002 · Cited by 2,158 · see citing works
Reactive oxygen species and mitochondria: A nexus of cellular homeostasis
Dunn, J. D., Álvarez, L., Zhang, X., & Soldati, T. (2015) · Redox Biology · doi:10.1016/j.redox.2015.09.005 · Cited by 1,199 · see citing works
Proteasomal and Autophagic Degradation Systems
Đikić, I. (2017) · Annual Review of Biochemistry · doi:10.1146/annurev-biochem-061516-044908 · Cited by 1,165 · see citing works
Nrf2 and Oxidative Stress: A General Overview of Mechanisms and Implications in Human Disease
Ngo, V., & Duennwald, M. L. (2022) · Antioxidants · doi:10.3390/antiox11122345 · Cited by 1,130 · see citing works
The cytoprotective role of the Keap1–Nrf2 pathway
Baird, L., & Dinkova‐Kostova, A. T. (2011) · Archives of Toxicology · doi:10.1007/s00204-011-0674-5 · Cited by 1,029 · see citing works
The Mitochondrial Phosphatase PGAM5 Functions at the Convergence Point of Multiple Necrotic Death Pathways
Wang, Z., Jiang, H., Chen, S., Du, F., & Wang, X. (2012) · Cell · doi:10.1016/j.cell.2011.11.030 · Cited by 949 · see citing works
NRF2 and KEAP1 mutations: permanent activation of an adaptive response in cancer
Hayes, J. D., & McMahon, M. J. (2009) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2008.12.008 · Cited by 870 · see citing works
Mechanisms of activation of the transcription factor Nrf2 by redox stressors, nutrient cues, and energy status and the pathways through which it attenuates degenerative disease
Tebay, L. E., Robertson, H., Durant, S. T., Vitale, S. R., Penning, T. M., Dinkova-Kostova, A. T., & Hayes, J. D. (2015) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2015.06.021 · Cited by 837 · see citing works
Stress-activated cap’n’collar transcription factors in aging and human disease
Sykiotis, G. P., & Bohmann, D. (2010) · Science Signaling · doi:10.1126/scisignal.3112re3 · Cited by 776 · see citing works
SKN-1/Nrf, stress responses, and aging in Caenorhabditis elegans
Blackwell, T. K., Steinbaugh, M. J., Hourihan, J. M., Ewald, C. Y., & Isik, M. (2015) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2015.06.008 · Cited by 622 · see citing works
A Regulatory Signaling Loop Comprising the PGAM5 Phosphatase and CK2 Controls Receptor-Mediated Mitophagy
Chen, G., Han, Z., Feng, D., Chen, Y., Chen, L., Wu, H., Huang, L., Zhou, C., Cai, X., Fu, C., et al. (2014) · Molecular Cell · doi:10.1016/j.molcel.2014.02.034 · Cited by 600 · see citing works
Regulation of Nrf2 by Mitochondrial Reactive Oxygen Species in Physiology and Pathology
Kasai, S., Shimizu, S., Tatara, Y., Mimura, J., & Itoh, K. (2020) · Biomolecules · doi:10.3390/biom10020320 · Cited by 572 · see citing works
Nrf2/Keap1/ARE signaling: Towards specific regulation
Ulasov, A. V., Rosenkranz, A. A., Georgiev, G. P., & Sobolev, A. S. (2021) · Life Sciences · doi:10.1016/j.lfs.2021.120111 · Cited by 520 · see citing works
Nrf2 at the heart of oxidative stress and cardiac protection
Chen, Q. M., & Maltagliati, A. J. (2017) · Physiological Genomics · doi:10.1152/physiolgenomics.00041.2017 · Cited by 474 · see citing works
Regulation of proteasome activity in health and disease
Schmidt, M., & Finley, D. J. (2013) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2013.08.012 · Cited by 461 · see citing works
Oxeiptosis, a ROS-induced caspase-independent apoptosis-like cell-death pathway
Holze, C., Michaudel, C., Mackowiak, C., Haas, D. A., Benda, C., Hubel, P., Pennemann, F. L., Schnepf, D., Wettmarshausen, J., Braun, M., et al. (2017) · Nature Immunology · doi:10.1038/s41590-017-0013-y · Cited by 459 · see citing works
Targeting Nrf2 to Suppress Ferroptosis and Mitochondrial Dysfunction in Neurodegeneration
Abdalkader, M., Lampinen, R., Kanninen, K. M., Malm, T., & Liddell, J. R. (2018) · Frontiers in Neuroscience · doi:10.3389/fnins.2018.00466 · Cited by 421 · see citing works
PHB2 (prohibitin 2) promotes PINK1-PRKN/Parkin-dependent mitophagy by the PARL-PGAM5-PINK1 axis
Yan, C., Gong, L., Chen, L., Xu, M., Abou‐Hamdan, H., Tang, M., Désaubry, L., & Song, Z. (2019) · Autophagy · doi:10.1080/15548627.2019.1628520 · Cited by 416 · see citing works
The role of Nrf2 in oxidative stress-induced endothelial injuries
Chen, B., Lu, Y., Chen, Y., & Cheng, J. (2015) · Journal of Endocrinology · doi:10.1530/joe-14-0662 · Cited by 400 · see citing works
Canonical and non-canonical mechanisms of Nrf2 activation
Silva‐Islas, C. A., & Maldonado, P. D. (2018) · Pharmacological Research · doi:10.1016/j.phrs.2018.06.013 · Cited by 393 · see citing works
The crosstalk between ferroptosis and mitochondrial dynamic regulatory networks
Li, J., Jia, Y., Ding, Y.-X., Bai, J., Cao, F., & Li, F. (2023) · International Journal of Biological Sciences · doi:10.7150/ijbs.83348 · Cited by 393 · see citing works
Oxidative Stress: Signaling Pathways, Biological Functions, and Disease
Liu, S., Liu, J., Wang, Y., Deng, F., & Deng, Z. (2025) · MedComm · doi:10.1002/mco2.70268 · Cited by 435 · see citing works
Proteasome Structure and Assembly
Budenholzer, L., Cheng, C. L., Li, Y., & Hochstrasser, M. (2017) · Journal of Molecular Biology · doi:10.1016/j.jmb.2017.05.027 · Cited by 369 · see citing works
The multifaceted role of Nrf2 in mitochondrial function
Holmström, K. M., Kostov, R. V., & Dinkova-Kostova, A. T. (2016) · Current Opinion in Toxicology · doi:10.1016/j.cotox.2016.10.002 · Cited by 368 · see citing works
Fumarate Is Cardioprotective via Activation of the Nrf2 Antioxidant Pathway
Ashrafian, H., Czibik, G., Bellahcene, M., Aksentijević, D., Smith, A. C., Mitchell, S. J., Dodd, M. S., Kirwan, J., Byrne, J. J., Ludwig, C., et al. (2012) · Cell Metabolism · doi:10.1016/j.cmet.2012.01.017 · Cited by 303 · see citing works
The Role of Nrf2 in Cardiovascular Function and Disease
Satta, S., Mahmoud, A. M., Wilkinson, F. L., Alexander, M. Y., & White, S. J. (2017) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2017/9237263 · Cited by 299 · see citing works
The Nrf2-antioxidant response element pathway: a target for regulating energy metabolism
Vomhof‐DeKrey, E. E., & Picklo, M. J. (2012) · The Journal of Nutritional Biochemistry · doi:10.1016/j.jnutbio.2012.03.005 · Cited by 283 · see citing works
Universal Features of Post-Transcriptional Gene Regulation Are Critical for Plasmodium Zygote Development
Mair, G. R., Lasonder, E., Garver, L. S., Franke-Fayard, B. M. D., Carret, C., Wiegant, J. C. A. G., Dirks, R. W., Dimopoulos, G., Janse, C. J., & Waters, A. P. (2010) · PLoS Pathogens · doi:10.1371/journal.ppat.1000767 · Cited by 278 · see citing works
Nrf2 for protection against oxidant generation and mitochondrial damage in cardiac injury
Chen, Q. M. (2021) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2021.12.001 · Cited by 269 · see citing works
Balancing mitochondrial biogenesis and mitophagy to maintain energy metabolism homeostasis
Palikaras, K., Lionaki, E., & Tavernarakis, N. (2015) · Cell Death and Differentiation · doi:10.1038/cdd.2015.86 · Cited by 268 · see citing works
Beyond repression of Nrf2: An update on Keap1
Kopacz, A., Klóska, D., Forman, H. J., Józkowicz, A., & Grochot‐Przeczek, A. (2020) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2020.03.023 · Cited by 262 · see citing works
Mitochondrial phosphatase PGAM5 modulates cellular senescence by regulating mitochondrial dynamics
Yu, B., Ma, J., Li, J., Wang, D., Wang, Z., & Wang, S. (2020) · Nature Communications · doi:10.1038/s41467-020-16312-7 · Cited by 266 · see citing works
Physical and functional interaction of sequestosome 1 with Keap1 regulates the Keap1-Nrf2 cell defense pathway
Copple, I. M., Lister, A., Obeng, A. D., Kitteringham, N. R., Jenkins, R. E., Layfield, R., Foster, B. J., Goldring, C. E., & Park, B. K. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.096545 · Cited by 260 · see citing works
Involvement of Nrf2 in myocardial ischemia and reperfusion injury
Shen, Y., Liu, X., Shi, J., & Xiang, W. (2018) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2018.11.190 · Cited by 257 · see citing works
The Crosstalk between Nrf2 and Inflammasomes
Hennig, P., Garstkiewicz, M., Grossi, S., Filippo, M. D., French, L. E., & Beer, H. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19020562 · Cited by 256 · see citing works
Review of Molecular Mechanisms Involved in the Activation of the Nrf2-ARE Signaling Pathway by Chemopreventive Agents
Giudice, A., Arra, C., & Turco, M. C. (2010) · Methods in molecular biology · doi:10.1007/978-1-60761-738-9_3 · Cited by 254 · see citing works
Computational classification of mitochondrial shapes reflects stress and redox state
Ahmad, T., Aggarwal, K., Pattnaik, B., Mukherjee, S., Sethi, T., Tiwari, B. K., Kumar, M., Micheal, A., Mabalirajan, U., Ghosh, B., et al. (2013) · Cell Death & Disease · doi:10.1038/cddis.2012.213 · Cited by 233 · see citing works
Mechanism of the Nrf2/Keap1/ARE signaling system
Tkachev, V., Брониславовна, М. Е., & Зенков, Н. К. (2011) · Biochemistry (Moscow) · doi:10.1134/s0006297911040031 · Cited by 228 · see citing works
Regulatory crosstalk between the oxidative stress-related transcription factor Nfe2l2/Nrf2 and mitochondria
Ryoo, I.-G., & Kwak, M. (2018) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2018.09.014 · Cited by 221 · see citing works
Effects of Glucagon-Like Peptide-1 on Oxidative Stress and Nrf2 Signaling
Oh, Y., & Jun, H.-S. (2017) · International Journal of Molecular Sciences · doi:10.3390/ijms19010026 · Cited by 217 · see citing works
“In addition to their location in the cytoskeleton, Nrf2 and Keap1 have also been detected at the outer mitochondrial membrane, binding to mitochondrial phosphatase phosphoglycerate mutase (PGAM) family member 5 [46] and affecting mitochondrial function.”
Background
Impaired Nuclear Nrf2 Translocation Undermines the Oxidative Stress Response in Friedreich Ataxia
Paupe, V., Dassa, E. P., Gonçalves, S., Auchère, F., Lönn, M. E., Holmgren, A., & Rustin, P. (2009) · PLoS ONE · doi:10.1371/journal.pone.0004253 · Cited by 218 · see citing works
Nrf2 as a regulator of mitochondrial function: Energy metabolism and beyond
Esteras, N., & Abramov, A. Y. (2022) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2022.07.013 · Cited by 214 · see citing works
Molecular cross-talk between the NRF2/KEAP1 signaling pathway, autophagy, and apoptosis
Stępkowski, T. M., & Kruszewski, M. K. (2011) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2011.01.033 · Cited by 212 · see citing works
Effects of 4-hydroxynonenal on vascular endothelial and smooth muscle cell redox signaling and function in health and disease
Chapple, S., Cheng, X.-H., & Mann, G. (2013) · Redox Biology · doi:10.1016/j.redox.2013.04.001 · Cited by 183 · see citing works
The membrane scaffold SLP2 anchors a proteolytic hub in mitochondria containing PARL and the i‐AAA protease YME1L
Wai, T., Saita, S., Nolte, H., Müller, S., König, T., Richter‐Dennerlein, R., Sprenger, H., Madrenas, J., Mühlmeister, M., Brandt, U., et al. (2016) · EMBO Reports · doi:10.15252/embr.201642698 · Cited by 188 · see citing works
Rhomboid Protease PARL Mediates the Mitochondrial Membrane Potential Loss-induced Cleavage of PGAM5
Sekine, S., Kanamaru, Y., Koike, M., Nishihara, A., Okada, M., Kinoshita, H., Kamiyama, M., Maruyama, J., Uchiyama, Y., Ishihara, N., et al. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.357509 · Cited by 187 · see citing works
Phosphoglycerate mutase 5 exacerbates cardiac ischemia-reperfusion injury through disrupting mitochondrial quality control
Zhu, H., Tan, Y., Du, W., Li, Y., Toan, S., Mui, D., Tian, F., & Zhou, H. (2020) · Redox Biology · doi:10.1016/j.redox.2020.101777 · Cited by 188 · see citing works
The BCL2L1 and PGAM5 axis defines hypoxia-induced receptor-mediated mitophagy
Wu, H., Xue, D., Chen, G., Han, Z., Huang, L., Zhu, C., Wang, X., Jin, H., Wang, J., Zhu, Y., et al. (2014) · Autophagy · doi:10.4161/auto.29568 · Cited by 183 · see citing works
Activation of Mitochondrial Biogenesis by Heme Oxygenase-1–mediated NF-E2–related Factor-2 Induction Rescues Mice from Lethal Staphylococcus aureus Sepsis
MacGarvey, N. C., Suliman, H. B., Bartz, R. R., Fu, P. P., Withers, C. M., Welty‐Wolf, K. E., & Piantadosi, C. A. (2012) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.201106-1152oc · Cited by 184 · see citing works
Impaired Redox Signaling and Antioxidant Gene Expression in Endothelial Cells in Diabetes: A Role for Mitochondria and the Nuclear Factor-E2-Related Factor 2-Kelch-Like ECH-Associated Protein 1 Defense Pathway
Cheng, X., Siow, R. C. M., & Mann, G. E. (2010) · Antioxidants and Redox Signaling · doi:10.1089/ars.2010.3283 · Cited by 181 · see citing works
Redox regulation of mitochondrial biogenesis
Piantadosi, C. A., & Suliman, H. B. (2012) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2012.09.014 · Cited by 178 · see citing works
Increased Nrf2 Activation in Livers from Keap1-Knockdown Mice Increases Expression of Cytoprotective Genes that Detoxify Electrophiles more than those that Detoxify Reactive Oxygen Species
Reisman, S. A., Yeager, R. L., Yamamoto, M. P., & Klaassen, C. D. (2009) · Toxicological Sciences · doi:10.1093/toxsci/kfn267 · Cited by 174 · see citing works
The Keap1–Nrf2 Cell Defense Pathway – A Promising Therapeutic Target?
Copple, I. M. (2012) · Advances in pharmacology · doi:10.1016/b978-0-12-398339-8.00002-1 · Cited by 172 · see citing works
Monitoring Keap1–Nrf2 interactions in single live cells
Baird, L., Swift, S., Llères, D., & Dinkova‐Kostova, A. T. (2014) · Biotechnology Advances · doi:10.1016/j.biotechadv.2014.03.004 · Cited by 171 · see citing works
Genetic deficiency of the mitochondrial protein PGAM5 causes a Parkinson’s-like movement disorder
Lü, W., Karuppagounder, S. S., Springer, D., Allen, M. D., Zheng, L., Chao, B. N., Zhang, Y., Dawson, V. L., Dawson, T. M., & Lenardo, M. J. (2014) · Nature Communications · doi:10.1038/ncomms5930 · Cited by 161 · see citing works
PGAM5: A crucial role in mitochondrial dynamics and programmed cell death
Cheng, M., Lin, N., Dong, D., Ma, J., Su, J., & Sun, L. (2020) · European Journal of Cell Biology · doi:10.1016/j.ejcb.2020.151144 · Cited by 159 · see citing works
Mitochondrial Protein PGAM5 Regulates Mitophagic Protection against Cell Necroptosis
Lü, W., Sun, J., Yoon, J. S., Zhang, Y., Zheng, L., Murphy, E., Mattson, M. P., & Lenardo, M. J. (2016) · PLoS ONE · doi:10.1371/journal.pone.0147792 · Cited by 157 · see citing works
The Role of the Antioxidant Response in Mitochondrial Dysfunction in Degenerative Diseases: Cross-Talk between Antioxidant Defense, Autophagy, and Apoptosis
Huang, M., Chiang, S., Kalinowski, D. S., Bae, D.-H., Sahni, S., & Richardson, D. R. (2019) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2019/6392763 · Cited by 154 · see citing works
Mitochondrial phosphoglycerate mutase 5 uses alternate catalytic activity as a protein serine/threonine phosphatase to activate ASK1
Takeda, K., Komuro, Y., Hayakawa, T., Oguchi, H., Ishida, Y., Murakami, S., Noguchi, T., Kinoshita, H., Sekine, Y., Iemura, S.-I., et al. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0901823106 · Cited by 147 · see citing works
Nrf2 for cardiac protection: pharmacological options against oxidative stress
Chen, Q. M. (2021) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2021.06.005 · Cited by 145 · see citing works
Effects of ionizing radiation on the heart
Boerma, M., Sridharan, V., Mao, X. W., Nelson, G. A., Cheema, A. K., Koturbash, I., Singh, S. P., Tackett, A. J., & Hauer‐Jensen, M. (2016) · Mutation Research/Reviews in Mutation Research · doi:10.1016/j.mrrev.2016.07.003 · Cited by 142 · see citing works
Transcription factor NRF2 as a promising therapeutic target for Alzheimer’s disease
Qu, Z., Sun, J., Zhang, W., Yu, J., & Zhuang, C. (2020) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2020.06.028 · Cited by 140 · see citing works
Contribution of the Nrf2 Pathway on Oxidative Damage and Mitochondrial Failure in Parkinson and Alzheimer’s Disease
Villavicencio-Tejo, F., & Quintanilla, R. A. (2021) · Antioxidants · doi:10.3390/antiox10071069 · Cited by 135 · see citing works
Nuclear-Mitochondrial Interactions
Walker, B. R., & Moraes, C. T. (2022) · Biomolecules · doi:10.3390/biom12030427 · Cited by 136 · see citing works
MicroRNAs in the regulation of cellular redox status and its implications in myocardial ischemia-reperfusion injury
Carbonell, T., & Gomes, A. V. (2020) · Redox Biology · doi:10.1016/j.redox.2020.101607 · Cited by 132 · see citing works
Substrates of IAP Ubiquitin Ligases Identified with a Designed Orthogonal E3 Ligase, the NEDDylator
Zhuang, M., Guan, S., Wang, H., Burlingame, A. L., & Wells, J. A. (2012) · Molecular Cell · doi:10.1016/j.molcel.2012.10.022 · Cited by 125 · see citing works
Nrf2 protects mitochondrial decay by oxidative stress
Strom, J. G., Xu, B., Tian, X., & Chen, Q. M. (2015) · The FASEB Journal · doi:10.1096/fj.14-268904 · Cited by 125 · see citing works
Regulation of the Keap1/Nrf2 system by chemopreventive sulforaphane: implications of posttranslational modifications
Keum, Y. (2011) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2011.06092.x · Cited by 121 · see citing works
Molecular Mechanisms and Regulation of Mammalian Mitophagy
Choubey, V., Zeb, A., & Kaasik, A. (2021) · Cells · doi:10.3390/cells11010038 · Cited by 123 · see citing works
The regulation of cancer cell death and metabolism by extracellular matrix attachment
Buchheit, C. L., Rayavarapu, R. R., & Schafer, Z. T. (2012) · Seminars in Cell & Developmental Biology · doi:10.1016/j.semcdb.2012.04.007 · Cited by 115 · see citing works
Mitochondria as intracellular signaling platforms in health and disease
Tan, J. X., & Finkel, T. (2020) · The Journal of Cell Biology · doi:10.1083/jcb.202002179 · Cited by 119 · see citing works
The Mitochondrial Phosphatase PGAM5 Is Dispensable for Necroptosis but Promotes Inflammasome Activation in Macrophages
Moriwaki, K., Farias Luz, N., Balaji, S., De Rosa, M. J., O’Donnell, C. L., Gough, P. J., Bertin, J., Welsh, R. M., & Chan, F. K.-M. (2016) · The Journal of Immunology · doi:10.4049/jimmunol.1501662 · Cited by 116 · see citing works
Proteasome dysfunction inDrosophilasignals to an Nrf2-dependent regulatory circuit aiming to restore proteostasis and prevent premature aging
Tsakiri, E. N., Sykiotis, G. P., Papassideri, I. S., Terpos, E., Dimopoulos, M. A., Gorgoulis, V. G., Bohmann, D., & Trougakos, I. P. (2013) · Aging Cell · doi:10.1111/acel.12111 · Cited by 113 · see citing works
Bax-PGAM5L-Drp1 complex is required for intrinsic apoptosis execution
Wenjuan, X., Jing, L., Wang, Q., Lin, C., Chen, X., Diao, J., Liu, Y., & Sun, X. (2015) · Oncotarget · doi:10.18632/oncotarget.5013 · Cited by 110 · see citing works
Microtubules and cardiovascular diseases: insights into pathology and therapeutic strategies
Wu, Q., Wang, Y., Liu, J., Guan, X., Chang, X., Liu, Z., & Liu, R. (2024) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2024.106650 · Cited by 109 · see citing works
Mitochondrial Proteins Moonlighting in the Nucleus
Monaghan, R. M., & Whitmarsh, A. J. (2015) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2015.10.003 · Cited by 104 · see citing works
A PGAM5–KEAP1–Nrf2 complex is required for stress-induced mitochondrial retrograde trafficking
O'Mealey, G. B., Plafker, K. S., Berry, W. L., Janknecht, R., Chan, J. Y., & Plafker, S. M. (2017) · Journal of Cell Science · doi:10.1242/jcs.203216 · Cited by 99 · see citing works
NRF2, a Key Regulator of Antioxidants with Two Faces towards Cancer
Kim, J., & Keum, Y. (2016) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2016/2746457 · Cited by 100 · see citing works
Inonotus obliquus polysaccharides protect against Alzheimer's disease by regulating Nrf2 signaling and exerting antioxidative and antiapoptotic effects
Han, Y., Nan, S., Fan, J., Chen, Q., & Zhang, Y. (2019) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2019.03.033 · Cited by 99 · see citing works
Nrf2 activation induces mitophagy and reverses Parkin/Pink1 knock down-mediated neuronal and muscle degeneration phenotypes
Gumeni, S., Papanagnou, E., Manola, M. S., & Trougakos, I. P. (2021) · Cell Death and Disease · doi:10.1038/s41419-021-03952-w · Cited by 100 · see citing works
Pgam5 released from damaged mitochondria induces mitochondrial biogenesis via Wnt signaling
Bernkopf, D. B., Jalal, K., Brückner, M., Knaup, K. X., Gentzel, M., Schambony, A., & Behrens, J. (2018) · The Journal of Cell Biology · doi:10.1083/jcb.201708191 · Cited by 99 · see citing works
Transcriptional control of mitochondrial biogenesis and its interface with inflammatory processes
Piantadosi, C. A., & Suliman, H. B. (2012) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/j.bbagen.2012.01.003 · Cited by 98 · see citing works
How the Mitoprotein-Induced Stress Response Safeguards the Cytosol: A Unified View
Boos, F., Labbadia, J. P., & Herrmann, J. M. (2020) · Trends in Cell Biology · doi:10.1016/j.tcb.2019.12.003 · Cited by 90 · see citing works
Nrf2 deficiency impairs the barrier function of mouse oesophageal epithelium
Chen, H. H., Hu, Y., Fang, Y., Djukic, Z., Yamamoto, M. P., Shaheen, N. J., Orlando, R. C., & Chen, X. L. (2013) · Gut · doi:10.1136/gutjnl-2012-303731 · Cited by 96 · see citing works
The Loss of PGAM5 Suppresses the Mitochondrial Degeneration Caused by Inactivation of PINK1 in Drosophila
Imai, Y., Kanao, T., Sawada, T., Kobayashi, Y., Moriwaki, Y., Ishida, Y., Takeda, K., Ichijo, H., Lu, B., & Takahashi, R. (2010) · PLoS Genetics · doi:10.1371/journal.pgen.1001229 · Cited by 93 · see citing works
Crosstalk between endoplasmic reticulum stress and oxidative stress: a dynamic duo in multiple myeloma
Xiong, S., Chng, W. J., & Zhou, J. (2021) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-021-03756-3 · Cited by 95 · see citing works
A novel role of KEAP1/PGAM5 complex: ROS sensor for inducing mitophagy
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Mitochondrial proteins Anti-oxidant gene expression
Lo, S.-C., Hannink, M., Stress, O., & Ligases, U. (2008)
Self-citation
A PGAM5–KEAP1–Nrf2 complex is required for stress-induced mitochondrial retrograde trafficking
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PGAM5, a Bcl-X L-interacting Protein, Is a Novel Substrate for the Redox-regulated Keap1-dependent
Complex, U. L., Lo, S.-C., & Hannink, M. (2013)
Self-citation
PGAM5, a Bcl‐XL‐interacting protein, is a novel substrate for the redox‐regulated Keap1‐dependent ubiquitin ligase complex.
Lo, S., & Hannink, M. (2007) · The FASEB Journal · doi:10.1096/fasebj.21.6.a1022 · Cited by 1 · see citing works
Self-citation
The spatiotemporal regulation of the Keap1–Nrf2 pathway and its importance in cellular bioenergetics
Dinkova‐Kostova, A. T., Baird, L., Holmström, K. M., Meyer, C. J., & Abramov, A. Y. (2015) · Biochemical Society Transactions · doi:10.1042/bst20150003 · Cited by 86 · see citing works

Authors: Lo, S.-C., & Hannink, M.
Affiliations: University of Missouri (US)
Corresponding author: Hannink, Mark
ORCID: Lo, Shih-Ching
Hannink, Mark
Venue: Experimental Cell Research
Publisher: Elsevier BV
Published: 2008-05
Volume: 314
Issue: 8
Pages: 1789-1803
ISSN: 0014-4827 (ISSN-L)
DOI: 10.1016/j.yexcr.2008.02.014
PMC: PMC2409987
OpenAlex: W1974124666
Cited by: 300
References: 82
Citations by year: 2026: 10 · 2025: 13 · 2024: 19 · 2023: 22 · 2022: 22 · 2021: 29 · 2020: 29 · 2019: 15 · 2018: 18 · 2017: 17 · 2016: 19 · 2015: 17 · 2014: 16 · 2013: 14 · 2012: 17
FWCI: 2.88
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
doi.org/10.15223/policy-017 (stm-asf)
doi.org/10.15223/policy-037 (stm-asf)
doi.org/10.15223/policy-012 (stm-asf)
doi.org/10.15223/policy-029 (stm-asf)
doi.org/10.15223/policy-004 (stm-asf)
Locations: Experimental Cell Research (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: National Institutes of Health (1 RO1 AT003389)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Glutathione Transferases and Polymorphisms
Keywords: PGAM5, Keap1, Nrf2, ternary complex, mitochondrial outer membrane, redox homeostasis, reactive oxygen species, antioxidant gene expression, proteasomal degradation
MeSH terms: Kelch-Like ECH-Associated Protein 1, Amino Acid Sequence, Animals, Carrier Proteins, Cell Line, Cell Nucleus, Gene Expression Regulation, Humans, Mitochondria, Molecular Sequence Data, Phosphoglycerate Mutase, Phosphoprotein Phosphatases, Protein Isoforms, Protein Sorting Signals, Mitochondrial Proteins, Intracellular Signaling Peptides and Proteins, NF-E2-Related Factor 2

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PGAM5 tethers a ternary complex containing Keap1 and Nrf2 to mitochondria

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