The Mitochondrial Rhomboid Protease PARL Is Regulated by PDK2 to Integrate Mitochondrial Quality Control and Metabolism
Mitochondrial quality control (MQC) systems are essential for mitochondrial health and normal cellular function. Dysfunction of MQC is emerging as a central mechanism for the pathogenesis of various diseases, including Parkinson’s disease. The mammalian mitochondrial rhomboid protease, PARL, has bee...
| Main Authors: | , |
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| Format: | Article |
| Language: | English |
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Elsevier
2017-02-01
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| Series: | Cell Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124717300669 |
| _version_ | 1818534084169695232 |
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| author | Guang Shi G. Angus McQuibban |
| author_facet | Guang Shi G. Angus McQuibban |
| author_sort | Guang Shi |
| collection | DOAJ |
| description | Mitochondrial quality control (MQC) systems are essential for mitochondrial health and normal cellular function. Dysfunction of MQC is emerging as a central mechanism for the pathogenesis of various diseases, including Parkinson’s disease. The mammalian mitochondrial rhomboid protease, PARL, has been proposed as a regulator of PINK1/PARKIN-mediated mitophagy, which is an essential component of MQC. PARL undergoes an N-terminal autocatalytic cleavage (β cleavage), which is required for efficient mitophagy. We demonstrate that β cleavage responds to mitochondrial stress, triggered by the depletion of mitochondrial ATP. Furthermore, we show that PDK2, a key regulator in metabolic plasticity, phosphorylates PARL and regulates β cleavage. Through regulating β cleavage and the production of a less active enzyme, PACT, PDK2 negatively regulates PINK1/PARKIN-mediated mitophagy. Taken together, we propose that PDK2/PARL senses defects in mitochondrial bioenergetics, integrating mitochondrial metabolism to mitophagy and MQC in human health and disease. |
| first_indexed | 2024-12-11T18:07:08Z |
| format | Article |
| id | doaj.art-25946113e3a54068b2c9d084a12bb84b |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-11T18:07:08Z |
| publishDate | 2017-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-25946113e3a54068b2c9d084a12bb84b2022-12-22T00:55:41ZengElsevierCell Reports2211-12472017-02-011861458147210.1016/j.celrep.2017.01.029The Mitochondrial Rhomboid Protease PARL Is Regulated by PDK2 to Integrate Mitochondrial Quality Control and MetabolismGuang Shi0G. Angus McQuibban1Department of Biochemistry, University of Toronto, 1 King’s College Circle, Toronto, ON M5S 1A8, CanadaDepartment of Biochemistry, University of Toronto, 1 King’s College Circle, Toronto, ON M5S 1A8, CanadaMitochondrial quality control (MQC) systems are essential for mitochondrial health and normal cellular function. Dysfunction of MQC is emerging as a central mechanism for the pathogenesis of various diseases, including Parkinson’s disease. The mammalian mitochondrial rhomboid protease, PARL, has been proposed as a regulator of PINK1/PARKIN-mediated mitophagy, which is an essential component of MQC. PARL undergoes an N-terminal autocatalytic cleavage (β cleavage), which is required for efficient mitophagy. We demonstrate that β cleavage responds to mitochondrial stress, triggered by the depletion of mitochondrial ATP. Furthermore, we show that PDK2, a key regulator in metabolic plasticity, phosphorylates PARL and regulates β cleavage. Through regulating β cleavage and the production of a less active enzyme, PACT, PDK2 negatively regulates PINK1/PARKIN-mediated mitophagy. Taken together, we propose that PDK2/PARL senses defects in mitochondrial bioenergetics, integrating mitochondrial metabolism to mitophagy and MQC in human health and disease.http://www.sciencedirect.com/science/article/pii/S2211124717300669mitophagyintramembrane proteolysisrhomboid proteasemetabolismmitochondrial biogenesis |
| spellingShingle | Guang Shi G. Angus McQuibban The Mitochondrial Rhomboid Protease PARL Is Regulated by PDK2 to Integrate Mitochondrial Quality Control and Metabolism Cell Reports mitophagy intramembrane proteolysis rhomboid protease metabolism mitochondrial biogenesis |
| title | The Mitochondrial Rhomboid Protease PARL Is Regulated by PDK2 to Integrate Mitochondrial Quality Control and Metabolism |
| title_full | The Mitochondrial Rhomboid Protease PARL Is Regulated by PDK2 to Integrate Mitochondrial Quality Control and Metabolism |
| title_fullStr | The Mitochondrial Rhomboid Protease PARL Is Regulated by PDK2 to Integrate Mitochondrial Quality Control and Metabolism |
| title_full_unstemmed | The Mitochondrial Rhomboid Protease PARL Is Regulated by PDK2 to Integrate Mitochondrial Quality Control and Metabolism |
| title_short | The Mitochondrial Rhomboid Protease PARL Is Regulated by PDK2 to Integrate Mitochondrial Quality Control and Metabolism |
| title_sort | mitochondrial rhomboid protease parl is regulated by pdk2 to integrate mitochondrial quality control and metabolism |
| topic | mitophagy intramembrane proteolysis rhomboid protease metabolism mitochondrial biogenesis |
| url | http://www.sciencedirect.com/science/article/pii/S2211124717300669 |
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