The ubiquitous mitochondrial protein unfoldase CLPX regulates erythroid heme synthesis by control of iron utilization and heme synthesis enzyme activation and turnover
| Autor: | Laurie K. Jackson, Samantha Gillis, Aidan Danoff, Leah O'Neill, Hector A. Bergonia, Gaël Nicolas, Hervé Puy, Mark Perfetto, Catherine M. Rondelli, John D. Phillips, Richard West, Yvette Y. Yien |
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| Rok vydání: | 2021 |
| Předmět: |
ferrochelatase
Accelerated Communication Iron EPP erythropoietic protoporphyria Heme Protein degradation Mitochondrion Biochemistry porphyria Gene Knockout Techniques Mice Enzyme activator chemistry.chemical_compound FECH ferrochelatase Cell Line Tumor CLPX caseinolytic mitochondrial matrix peptidase chaperone subunit X Animals Molecular Biology Zebrafish ALAS aminolevulinate synthase PPIX protoporphyrin IX AAA+ ATPases associated with various cellular activities biology ATP synthase 5-aminolevulinate synthase Endopeptidase Clp Cell Biology Ferrochelatase ALAS2 Mitochondria Cell biology Enzyme Activation PPOX protoporphyrinogen IX oxidase chemistry protoporphyrinogen IX oxidase MEL mouse erythroleukemia Chaperone (protein) Models Animal Proteolysis protein degradation CLPP caseinolytic protease proteolytic subunit biology.protein ATP-dependent protease Leukemia Erythroblastic Acute 5-Aminolevulinate Synthetase |
| Zdroj: | The Journal of Biological Chemistry |
| ISSN: | 0021-9258 |
| Popis: | Heme plays a critical role in catalyzing life-essential redox reactions in all cells, and its synthesis must be tightly balanced with cellular requirements. Heme synthesis in eukaryotes is tightly regulated by the mitochondrial AAA+ unfoldase CLPX (caseinolytic mitochondrial matrix peptidase chaperone subunit X), which promotes heme synthesis by activation of δ-aminolevulinate synthase (ALAS/Hem1) in yeast and regulates turnover of ALAS1 in human cells. However, the specific mechanisms by which CLPX regulates heme synthesis are unclear. In this study, we interrogated the mechanisms by which CLPX regulates heme synthesis in erythroid cells. Quantitation of enzyme activity and protein degradation showed that ALAS2 stability and activity were both increased in the absence of CLPX, suggesting that CLPX primarily regulates ALAS2 by control of its turnover, rather than its activation. However, we also showed that CLPX is required for PPOX (protoporphyrinogen IX oxidase) activity and maintenance of FECH (ferrochelatase) levels, which are the terminal enzymes in heme synthesis, likely accounting for the heme deficiency and porphyrin accumulation observed in Clpx−/− cells. Lastly, CLPX is required for iron utilization for hemoglobin synthesis during erythroid differentiation. Collectively, our data show that the role of CLPX in yeast ALAS/Hem1 activation is not conserved in vertebrates as vertebrates rely on CLPX to regulate ALAS turnover as well as PPOX and FECH activity. Our studies reveal that CLPX mutations may cause anemia and porphyria via dysregulation of ALAS, FECH, and PPOX activities, as well as of iron metabolism. |
| Databáze: | OpenAIRE |
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