Journal
CELL DEATH AND DIFFERENTIATION
Volume 22, Issue 11, Pages 1812-1823Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/cdd.2015.34
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Funding
- National Basic Research Program of China 973 Program [2015CB553800]
- Fundamental Research Funds for the Central Universities [2012121043]
- National Natural Science Foundation of China [31170718, 31300627]
- National Science Foundation for Fostering Talents in Basic Research of the National Natural Science Foundation of China [J1310027/J0106]
- 111 Project of Ministry of Education of China [B06016, B12001]
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Mitophagy mediates clearance of dysfunctional mitochondria, and represents one type of mitochondrial quality control, which is essential for optimal mitochondrial bioenergetics. p32, a chaperone-like protein, is crucial for maintaining mitochondrial membrane potential and oxidative phosphorylation. However, the relationship between p32 and mitochondrial homeostasis has not been addressed. Here, we identified p32 as a key regulator of ULK1 stability by forming complex with ULK1. p32 depletion potentiated K48-linked but impaired K63-linked polyubiquitination of ULK1, leading to proteasome-mediated degradation of ULK1. As a result, silencing p32 profoundly impaired starvation-induced autophagic flux and the clearance of damaged mitochondria caused by mitochondrial uncoupler. Importantly, restoring ULK1 expression in p32-depleted cells rescued autophagy and mitophagy defects. Our findings highlight a cytoprotective role of p32 under starvation conditions by regulating ULK1 stability, and uncover a crucial role of the p32-ULK1-autophagy axis in coordinating stress response, cell survival and mitochondrial homeostasis.
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