The Critical Role Played by Mitochondrial MITF Serine 73 Phosphorylation in Immunologically Activated Mast Cells
In recent years, growing evidence has indicated the pivotal role of mitochondria in mast cell immunological activation. We have previously reported a decrease in degranulation and cytokine secretion following the inhibition of pyruvate dehydrogenase (PDH) either by CPI-613 (PDH inhibitor/anti-cancer...
| Main Authors: | , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2022-02-01
|
| Series: | Cells |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2073-4409/11/3/589 |
| _version_ | 1797488484628299776 |
|---|---|
| author | Lakshmi Bhargavi Paruchuru Sharmila Govindaraj Ehud Razin |
| author_facet | Lakshmi Bhargavi Paruchuru Sharmila Govindaraj Ehud Razin |
| author_sort | Lakshmi Bhargavi Paruchuru |
| collection | DOAJ |
| description | In recent years, growing evidence has indicated the pivotal role of mitochondria in mast cell immunological activation. We have previously reported a decrease in degranulation and cytokine secretion following the inhibition of pyruvate dehydrogenase (PDH) either by CPI-613 (PDH inhibitor/anti-cancer drug) or through its interaction with mitochondrial microphthalmia-associated transcription factor (MITF). In the present study, we further explored the role played by mitochondrial MITF in mast cell exocytosis using rat basophil leukemia cells [RBL], as well as mouse bone marrow-derived mast cells (BMMCs). Here, we report that mast cell degranulation, cytokine secretion and oxidative phosphorylation (OXPHOS) activities were associated with phosphorylation of Serine 73 of mitochondrial MITF, controlled by extracellular signals regulated by protein kinase (ERK1/2) activity. Also, we report here that decreased OXPHOS activity following ERK1/2 inhibition (U0126 treatment) during IgE-Ag activation was mediated by the dephosphorylation of Serine 73 mitochondrial MITF, which inhibited its association with PDH. This led to a reduction in mast cell reactivity. In addition, a phosphorylation-mimicking mitochondrial MITF-S73D positively regulated the mitochondrial activity, thereby supporting mast cell degranulation. Thus, the present research findings highlight the prominence of mitochondrial MITF Serine 73 phosphorylation in immunologically activated mast cells. |
| first_indexed | 2024-03-10T00:02:53Z |
| format | Article |
| id | doaj.art-fb80cf05d07148ff946d7c2c5d728e29 |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-10T00:02:53Z |
| publishDate | 2022-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-fb80cf05d07148ff946d7c2c5d728e292023-11-23T16:14:29ZengMDPI AGCells2073-44092022-02-0111358910.3390/cells11030589The Critical Role Played by Mitochondrial MITF Serine 73 Phosphorylation in Immunologically Activated Mast CellsLakshmi Bhargavi Paruchuru0Sharmila Govindaraj1Ehud Razin2Department of Biochemistry and Molecular Biology, Institute for Medical Research Israel-Canada, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem 91120, IsraelDepartment of Biochemistry and Molecular Biology, Institute for Medical Research Israel-Canada, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem 91120, IsraelDepartment of Biochemistry and Molecular Biology, Institute for Medical Research Israel-Canada, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem 91120, IsraelIn recent years, growing evidence has indicated the pivotal role of mitochondria in mast cell immunological activation. We have previously reported a decrease in degranulation and cytokine secretion following the inhibition of pyruvate dehydrogenase (PDH) either by CPI-613 (PDH inhibitor/anti-cancer drug) or through its interaction with mitochondrial microphthalmia-associated transcription factor (MITF). In the present study, we further explored the role played by mitochondrial MITF in mast cell exocytosis using rat basophil leukemia cells [RBL], as well as mouse bone marrow-derived mast cells (BMMCs). Here, we report that mast cell degranulation, cytokine secretion and oxidative phosphorylation (OXPHOS) activities were associated with phosphorylation of Serine 73 of mitochondrial MITF, controlled by extracellular signals regulated by protein kinase (ERK1/2) activity. Also, we report here that decreased OXPHOS activity following ERK1/2 inhibition (U0126 treatment) during IgE-Ag activation was mediated by the dephosphorylation of Serine 73 mitochondrial MITF, which inhibited its association with PDH. This led to a reduction in mast cell reactivity. In addition, a phosphorylation-mimicking mitochondrial MITF-S73D positively regulated the mitochondrial activity, thereby supporting mast cell degranulation. Thus, the present research findings highlight the prominence of mitochondrial MITF Serine 73 phosphorylation in immunologically activated mast cells.https://www.mdpi.com/2073-4409/11/3/589allergymast cellsmitochondriamicrophthalmia-associated transcription factorpyruvate dehydrogenaseextracellular signal-regulated kinase |
| spellingShingle | Lakshmi Bhargavi Paruchuru Sharmila Govindaraj Ehud Razin The Critical Role Played by Mitochondrial MITF Serine 73 Phosphorylation in Immunologically Activated Mast Cells Cells allergy mast cells mitochondria microphthalmia-associated transcription factor pyruvate dehydrogenase extracellular signal-regulated kinase |
| title | The Critical Role Played by Mitochondrial MITF Serine 73 Phosphorylation in Immunologically Activated Mast Cells |
| title_full | The Critical Role Played by Mitochondrial MITF Serine 73 Phosphorylation in Immunologically Activated Mast Cells |
| title_fullStr | The Critical Role Played by Mitochondrial MITF Serine 73 Phosphorylation in Immunologically Activated Mast Cells |
| title_full_unstemmed | The Critical Role Played by Mitochondrial MITF Serine 73 Phosphorylation in Immunologically Activated Mast Cells |
| title_short | The Critical Role Played by Mitochondrial MITF Serine 73 Phosphorylation in Immunologically Activated Mast Cells |
| title_sort | critical role played by mitochondrial mitf serine 73 phosphorylation in immunologically activated mast cells |
| topic | allergy mast cells mitochondria microphthalmia-associated transcription factor pyruvate dehydrogenase extracellular signal-regulated kinase |
| url | https://www.mdpi.com/2073-4409/11/3/589 |
| work_keys_str_mv | AT lakshmibhargaviparuchuru thecriticalroleplayedbymitochondrialmitfserine73phosphorylationinimmunologicallyactivatedmastcells AT sharmilagovindaraj thecriticalroleplayedbymitochondrialmitfserine73phosphorylationinimmunologicallyactivatedmastcells AT ehudrazin thecriticalroleplayedbymitochondrialmitfserine73phosphorylationinimmunologicallyactivatedmastcells AT lakshmibhargaviparuchuru criticalroleplayedbymitochondrialmitfserine73phosphorylationinimmunologicallyactivatedmastcells AT sharmilagovindaraj criticalroleplayedbymitochondrialmitfserine73phosphorylationinimmunologicallyactivatedmastcells AT ehudrazin criticalroleplayedbymitochondrialmitfserine73phosphorylationinimmunologicallyactivatedmastcells |