FUNDC 1 regulates mitochondrial dynamics at the ER –mitochondrial contact site under hypoxic conditions
- 4 May 2016
- journal article
- Published by Springer Science and Business Media LLC in The EMBO Journal
- Vol. 35 (13), 1368-1384
- https://doi.org/10.15252/embj.201593102
Abstract
In hypoxic cells, dysfunctional mitochondria are selectively removed by a specialized autophagic process called mitophagy. The ER–mitochondrial contact site (MAM) is essential for fission of mitochondria prior to engulfment, and the outer mitochondrial membrane protein FUNDC1 interacts with LC3 to recruit autophagosomes, but the mechanisms integrating these processes are poorly understood. Here, we describe a new pathway mediating mitochondrial fission and subsequent mitophagy under hypoxic conditions. FUNDC1 accumulates at the MAM by associating with the ER membrane protein calnexin. As mitophagy proceeds, FUNDC1/calnexin association attenuates and the exposed cytosolic loop of FUNDC1 interacts with DRP1 instead. DRP1 is thereby recruited to the MAM, and mitochondrial fission then occurs. Knockdown of FUNDC1, DRP1, or calnexin prevents fission and mitophagy under hypoxic conditions. Thus, FUNDC1 integrates mitochondrial fission and mitophagy at the interface of the MAM by working in concert with DRP1 and calnexin under hypoxic conditions in mammalian cells. See also: AM van der Bliek (July 2016)Keywords
Funding Information
- National Natural Science Foundation of China (31401182, 81270196, 81171244, 81571203, 31370824, 81470405)
This publication has 63 references indexed in Scilit:
- ER-associated mitochondrial division links the distribution of mitochondria and mitochondrial DNA in yeasteLife, 2013
- Autophagosomes form at ER–mitochondria contact sitesNature, 2013
- Optic Atrophy 1-Dependent Mitochondrial Remodeling Controls Steroidogenesis in TrophoblastsCurrent Biology, 2012
- Fine-Tuning of Drp1/Fis1 Availability by AKAP121/Siah2 Regulates Mitochondrial Adaptation to HypoxiaMolecular Cell, 2011
- Human MIEF1 recruits Drp1 to mitochondrial outer membranes and promotes mitochondrial fusion rather than fissionThe EMBO Journal, 2011
- During autophagy mitochondria elongate, are spared from degradation and sustain cell viabilityNature, 2011
- Conformational changes in Dnm1 support a contractile mechanism for mitochondrial fissionNature Structural & Molecular Biology, 2010
- Isolation of mitochondria-associated membranes and mitochondria from animal tissues and cellsNature Protocols, 2009
- Mitofusin 2 tethers endoplasmic reticulum to mitochondriaNature, 2008
- Mitochondrial fragmentation in neurodegenerationNature Reviews Neuroscience, 2008