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FKBP8 LIRL-dependent mitochondrial fragmentation facilitates mitophagy under stress conditions
Seung-Min Yoo1, Shun-Ichi Yamashita2, Hyunjoo Kim1
1School of Biological Sciences, Seoul National University, Seoul, Korea.
Abstract:
Mitochondrial quality control maintains mitochondrial function by regulating mitochondrial dynamics and mitophagy. Despite the identification of mitochondrial quality control factors, little is known about the crucial regulators coordinating both mitochondrial fission and mitophagy. Through a cell-based functional screening assay, FK506 binding protein 8 (FKBP8) was identified to target microtubule-associated protein 1 light chain 3 (LC3) to the mitochondria and to change mitochondrial morphology. Microscopy analysis revealed that the formation of tubular and enlarged mitochondria was observed in FKBP8 knockdown HeLa cells and the cortex of Fkbp8 heterozygote-knockout mouse embryos. Under iron depletion-induced stress, FKBP8 was recruited to the site of mitochondrial division through budding and colocalized with LC3. FKBP8 was also found to be required for mitochondrial fragmentation and mitophagy under hypoxic stress. Conversely, FKBP8 overexpression induced mitochondrial fragmentation in HeLa cells, human fibroblasts and mouse embryo fibroblasts (MEFs), and this fragmentation occurred in Drp1 knockout MEF cells, FIP200 knockout HeLa cells and BNIP3/NIX double knockout HeLa cells, but not in Opa1 knockout MEFs. Interestingly, we found an LIR motif-like sequence (LIRL), as well as an LIR motif, at the N-terminus of FKBP8 and LIRL was essential for both inducing mitochondrial fragmentation and binding of FKBP8 to OPA1. Together, we suggest that FKBP8 plays an essential role in mitochondrial fragmentation through LIRL during mitophagy and this activity of FKBP8 together with LIR is required for mitophagy under stress conditions.
Insights
FK506 binding protein 8 (FKBP8) is crucial for mitochondrial fragmentation and mitophagy, a key process for cellular health. This protein coordinates mitochondrial division and removal, especially under stress conditions like hypoxia.
Area of Science:
- Cell Biology
- Mitochondrial Biology
- Molecular Mechanisms
Background:
- Mitochondrial quality control is vital for cellular function, involving mitochondrial dynamics and mitophagy.
- Key regulators coordinating mitochondrial fission and mitophagy remain largely unknown.
Purpose of the Study:
- To identify novel regulators of mitochondrial quality control, specifically those coordinating mitochondrial fission and mitophagy.
- To elucidate the role of FK506 binding protein 8 (FKBP8) in mitochondrial morphology and mitophagy.
Main Methods:
- Cell-based functional screening assay to identify FKBP8.
- Microscopy analysis of FKBP8 knockdown and knockout cells/embryos.
- Investigation of FKBP8 localization and interaction with LC3 and OPA1 under stress conditions (iron depletion, hypoxia).
- Functional assays using knockout cells for key mitochondrial proteins (Drp1, FIP200, BNIP3/NIX, Opa1).
Main Results:
- FKBP8 targets microtubule-associated protein 1 light chain 3 (LC3) to mitochondria, influencing mitochondrial morphology.
- FKBP8 knockdown/knockout leads to tubular and enlarged mitochondria; FKBP8 overexpression induces mitochondrial fragmentation.
- FKBP8 is recruited to mitochondrial division sites and colocalizes with LC3 under iron depletion stress.
- FKBP8 is essential for mitochondrial fragmentation and mitophagy under hypoxic stress.
- FKBP8's N-terminus contains a LIR motif-like sequence (LIRL) essential for inducing mitochondrial fragmentation and binding to OPA1.
Conclusions:
- FKBP8 plays a critical role in regulating mitochondrial fragmentation via its LIRL motif during mitophagy.
- FKBP8's interaction with OPA1 and its LIR motif are required for efficient mitophagy under cellular stress.
- FKBP8 emerges as a key coordinator of mitochondrial fragmentation and mitophagy, essential for maintaining mitochondrial quality control.
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