Mitochondrial outer-membrane protein FUNDC1 mediates hypoxia-induced mitophagy in mammalian cells

Quan Chen, et al. Nature cell biology 14, number 2,177-185 (Feb 2012)

Speaker: Kuan-Jung Lin (林冠蓉)                                        Time:14:00~15:00, May.09, 2012

Commentator: Pei-Jane Tsai, Ph.D. (蔡佩珍老師)               Place: Room 601

Abstract:

Mitochondria are involved in regulating cellular energy homeostasis and cellular damaged signal from pathogen- associated molecular pattern[1]. Autophagy selectively removes organelles to maintain their quality control. A selective elimination of damaged mitochondria by autophagy is called mitophagy[2]. How mitochondria are primed for selective autophagy in mammalian cells remains unclear. First, over-expression of a mitochondrial outer-membrane protein FUNDC1 led to  mitophagy. To explore how FUNDC1 associate with autophagy, using GST pull-down assay and co-IP, the authors found the interaction between FUNDC1 and ubiquitin-like microtubule-associated protein light chain 3 (LC3). Further analyses with truncated FUNDC1 mutants revealed that the LC3 interacting motif (LIR) of FUNDC1was  essential  for binding  LC3 and induction of mitophagy.Knockdown of FUNDC1 failed to induce mitophagy and degradation of mitochondrial proteins under hypoxia. In addition,  under hypoxia , dephosphorylation of FUNDC1on tyrosine 18 residue by inactivating Src kinas enhanced the binding of FUNDC1 to  LC3.Together, this study demonstrates that dephosphorylation of FUNDC1 is an important mechanism to regulate mitophagy under hypoxia.

Reference:

1. West AP, Shadel GS, Ghosh S (2011) Mitochondria in innate immune responses. Nat Rev Immunol 11: 389-402.

2. Novak I (2012) Mitophagy: A Complex Mechanism of Mitochondrial Removal. Antioxid Redox Signal.