Mitophagy receptor FUNDC1 regulates mitochondrial homeostasis and protects the heart from I/R injury.
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.
a The State Key Laboratory of Membrane Biology , Institute of Zoology, Chinese Academy of Sciences , Beijing , China.
Weilin
W
Zhang
a The State Key Laboratory of Membrane Biology , Institute of Zoology, Chinese Academy of Sciences , Beijing , China.
Sami
S
Siraj
a The State Key Laboratory of Membrane Biology , Institute of Zoology, Chinese Academy of Sciences , Beijing , China.|b Sino-Danish Center for Education and Research , Beijing , China.
Rong
R
Zhang
a The State Key Laboratory of Membrane Biology , Institute of Zoology, Chinese Academy of Sciences , Beijing , China.|c Tianjin Key Laboratory of Protein Science , College of Life Sciences, Nankai University , Tianjin , China.
Quan
Q
Chen
D000818:Animals; D006706:Homeostasis; D008565:Membrane Proteins / Q000378:metabolism*; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000378:metabolism*; D063306:Mitophagy; D008954:Models, Biological; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology*; D015427:Reperfusion Injury / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*
C000588786:FUNDC1 protein, mouse; D008565:Membrane Proteins; D024101:Mitochondrial Proteins
heart injury; hypoxic mitophagy; ischemia/reperfusion; mitochondrial quality; mitophagy receptor; platelets