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A Model Membrane Platform for Reconstituting Mitochondrial Membrane Dynamics
Published on: September 2, 2020
Mitophagy receptor FUNDC1 regulates mitochondrial homeostasis and protects the heart from I/R injury
Weilin Zhang1, Sami Siraj1, Rong Zhang1,2
1a The State Key Laboratory of Membrane Biology , Institute of Zoology, Chinese Academy of Sciences , Beijing , China.
Abstract:
Mitophagy plays pivotal roles in the selective disposal of unwanted mitochondria, and accumulation of damaged mitochondria has been linked to aging-related diseases. However, definitive proof that mitophagy regulates mitochondrial quality in vivo is lacking. It is also largely unclear whether damaged mitochondria are the cause or just the consequence of these diseases. We previously showed that FUNDC1 is a mitophagy receptor that interacts with LC3 to mediate mitophagy in response to hypoxia in cultured cells. We established Fundc1 knockout mouse models and used genetic and biochemical approaches, including a synthetic peptide that blocks the FUNDC1-LC3 interaction, to demonstrate that mitophagy regulates both mitochondrial quantity and quality in vivo in response to hypoxia or hypoxic conditions caused by ischemia-reperfusion (I/R) heart injury. We found that hypoxic mitophagy regulates platelet activities. Furthermore, we found that hypoxic preconditioning induces FUNDC1-dependent mitophagy in platelets and reduces I/R-induced heart injury, suggesting a new strategy to protect cardiac function and fight cardiovascular diseases.
Insights
This study shows mitophagy regulates mitochondrial health in vivo. Hypoxic mitophagy protects against heart injury, offering a new strategy for cardiovascular disease treatment.
Area of Science:
- Cell Biology
- Mitochondrial Biology
- Cardiovascular Research
Background:
- Mitophagy, the selective removal of damaged mitochondria, is crucial for cellular health.
- Accumulation of damaged mitochondria is implicated in aging and related diseases.
- In vivo evidence for mitophagy's role in mitochondrial quality control and its causal link to disease has been limited.
Purpose of the Study:
- To definitively prove that mitophagy regulates mitochondrial quantity and quality in vivo.
- To investigate the role of FUNDC1-mediated mitophagy in response to hypoxia and ischemia-reperfusion (I/R) injury.
- To explore the therapeutic potential of modulating mitophagy for cardiovascular protection.
Main Methods:
- Generation of Fundc1 knockout mouse models.
- Utilizing genetic and biochemical approaches to study mitophagy.
- Employing a synthetic peptide to block the FUNDC1-LC3 interaction.
- Assessing mitochondrial quantity and quality under hypoxic and I/R conditions.
- Investigating the impact of mitophagy on platelet activity and I/R-induced heart injury.
Main Results:
- Demonstrated that mitophagy regulates mitochondrial quantity and quality in vivo under hypoxic or I/R conditions.
- Confirmed FUNDC1 as a key mediator of hypoxic mitophagy in vivo.
- Showed that hypoxic mitophagy influences platelet activities.
- Found that hypoxic preconditioning, via FUNDC1-dependent mitophagy, reduces I/R-induced heart injury.
Conclusions:
- Mitophagy is essential for maintaining mitochondrial quality and quantity in vivo.
- FUNDC1-mediated mitophagy plays a protective role against I/R-induced heart injury.
- Targeting hypoxic mitophagy, particularly in platelets, presents a novel therapeutic strategy for cardiovascular diseases.
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