Mechanisms of selective autophagy and mitophagy: Implications for neurodegenerative diseases
Over the past 20 years, the concept of mammalian autophagy as a nonselective degradation system has been repudiated, due in part to important discoveries in neurodegenerative diseases, which opened the field of selective autophagy. Protein aggregates and damaged mitochondria represent key pathologic...
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| Format: | Article |
| Language: | English |
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Elsevier
2019-02-01
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| Series: | Neurobiology of Disease |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996118302754 |
| _version_ | 1818350371472408576 |
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| author | Charleen T. Chu |
| author_facet | Charleen T. Chu |
| author_sort | Charleen T. Chu |
| collection | DOAJ |
| description | Over the past 20 years, the concept of mammalian autophagy as a nonselective degradation system has been repudiated, due in part to important discoveries in neurodegenerative diseases, which opened the field of selective autophagy. Protein aggregates and damaged mitochondria represent key pathological hallmarks shared by most neurodegenerative diseases. The landmark discovery in 2007 of p62/SQSTM1 as the first mammalian selective autophagy receptor defined a new family of autophagy-related proteins that serve to target protein aggregates, mitochondria, intracellular pathogens and other cargoes to the core autophagy machinery via an LC3-interacting region (LIR)-motif. Notably, mutations in the LIR-motif proteins p62 (SQSTM1) and optineurin (OPTN) contribute to familial forms of frontotemporal dementia and amyotrophic lateral sclerosis. Moreover, a subset of LIR-motif proteins is involved in selective mitochondrial degradation initiated by two recessive familial Parkinson's disease genes. PTEN-induced kinase 1 (PINK1) activates the E3 ubiquitin ligase Parkin (PARK2) to mark depolarized mitochondria for degradation. An extensive body of literature delineates key mechanisms in this pathway, based mostly on work in transformed cell lines. However, the potential role of PINK1-triggered mitophagy in neurodegeneration remains a conundrum, particularly in light of recent in vivo mitophagy studies. There are at least three major mechanisms by which mitochondria are targeted for mitophagy: transmembrane receptor-mediated, ubiquitin-mediated and cardiolipin-mediated. This review summarizes key features of the major cargo recognition pathways for selective autophagy and mitophagy, highlighting their potential impact in the pathogenesis or amelioration of neurodegenerative diseases. |
| first_indexed | 2024-12-13T18:20:47Z |
| format | Article |
| id | doaj.art-573b8c222561482da5db12940e7a9f53 |
| institution | Directory Open Access Journal |
| issn | 1095-953X |
| language | English |
| last_indexed | 2024-12-13T18:20:47Z |
| publishDate | 2019-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj.art-573b8c222561482da5db12940e7a9f532022-12-21T23:35:44ZengElsevierNeurobiology of Disease1095-953X2019-02-011222334Mechanisms of selective autophagy and mitophagy: Implications for neurodegenerative diseasesCharleen T. Chu0Corresponding author at: 200 Lothrop Street, S701 Scaife Hall, University of Pittsburgh, Pittsburgh, PA 15213, USA.; Departments of Pathology and Ophthalmology, Pittsburgh Institute for Neurodegenerative Diseases, McGowan Institute for Regenerative Medicine, Center for Protein Conformational Diseases, Center for Neuroscience at the University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USAOver the past 20 years, the concept of mammalian autophagy as a nonselective degradation system has been repudiated, due in part to important discoveries in neurodegenerative diseases, which opened the field of selective autophagy. Protein aggregates and damaged mitochondria represent key pathological hallmarks shared by most neurodegenerative diseases. The landmark discovery in 2007 of p62/SQSTM1 as the first mammalian selective autophagy receptor defined a new family of autophagy-related proteins that serve to target protein aggregates, mitochondria, intracellular pathogens and other cargoes to the core autophagy machinery via an LC3-interacting region (LIR)-motif. Notably, mutations in the LIR-motif proteins p62 (SQSTM1) and optineurin (OPTN) contribute to familial forms of frontotemporal dementia and amyotrophic lateral sclerosis. Moreover, a subset of LIR-motif proteins is involved in selective mitochondrial degradation initiated by two recessive familial Parkinson's disease genes. PTEN-induced kinase 1 (PINK1) activates the E3 ubiquitin ligase Parkin (PARK2) to mark depolarized mitochondria for degradation. An extensive body of literature delineates key mechanisms in this pathway, based mostly on work in transformed cell lines. However, the potential role of PINK1-triggered mitophagy in neurodegeneration remains a conundrum, particularly in light of recent in vivo mitophagy studies. There are at least three major mechanisms by which mitochondria are targeted for mitophagy: transmembrane receptor-mediated, ubiquitin-mediated and cardiolipin-mediated. This review summarizes key features of the major cargo recognition pathways for selective autophagy and mitophagy, highlighting their potential impact in the pathogenesis or amelioration of neurodegenerative diseases.http://www.sciencedirect.com/science/article/pii/S0969996118302754 |
| spellingShingle | Charleen T. Chu Mechanisms of selective autophagy and mitophagy: Implications for neurodegenerative diseases Neurobiology of Disease |
| title | Mechanisms of selective autophagy and mitophagy: Implications for neurodegenerative diseases |
| title_full | Mechanisms of selective autophagy and mitophagy: Implications for neurodegenerative diseases |
| title_fullStr | Mechanisms of selective autophagy and mitophagy: Implications for neurodegenerative diseases |
| title_full_unstemmed | Mechanisms of selective autophagy and mitophagy: Implications for neurodegenerative diseases |
| title_short | Mechanisms of selective autophagy and mitophagy: Implications for neurodegenerative diseases |
| title_sort | mechanisms of selective autophagy and mitophagy implications for neurodegenerative diseases |
| url | http://www.sciencedirect.com/science/article/pii/S0969996118302754 |
| work_keys_str_mv | AT charleentchu mechanismsofselectiveautophagyandmitophagyimplicationsforneurodegenerativediseases |