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Heart failure occurs when the heart is unable to pump enough blood to the other organs to satisfy their need for oxygen and nutrients. It usually manifests as tiredness and weakness, breathlessness and swelling of the legs and abdomen. Less than 50 percent of patients are living five years after their initial diagnosis and less than 25 percent are alive at 10 years. Poor prognosis can be attributed to a limited understanding of how the heart weakens. Many studies indicate that inflammation play an important role when people have got heart failure. However, a drug which inhibits one inflammation mediator (cytokine) worsened heart failure, suggesting that targeting a single component of the inflammation is not sufficient to cure the disease. If we understand how the inflammation is regulated, we can know useful information to mechanisms of heart failure and to identify therapeutic targets against heart failure.
Incomplete degradation of damaged mitochondria by autophagy results in cardiomyocyte death and heart failure. Mitochondria are damaged by various stresses. Mitochondria segregate or exchange materials to repair damaged components through fission and fusion mechanism. Damaged daughter mitochondria are degraded by autophagy. ROS, harmful proteins and mtDNA leaked from undigested dysfunctional mitochondria directly damage cellular components. When mtDNA is not completely degraded by autophagy, the remaining mtDNA binds to TLR9 to generate proinflammatory cytokines. As a result, insufficient induction of autophagy results cardiomyocyte death and heart failure
Mitochondria are small compartments in cell that generate energy needed to power the cell's biochemical reactions. Mitochondria have striking similarities to bacteria cells and have their own DNA containing unmethylated motif as bacteria. Damaged mitochondria are degraded by a system called as autophagy, by which mitochondria are engulfed in membrane and fused with lysosomes for degradation. Mitochondrial autophagy is called mitophagy. Lysosomes contain many enzymes such as DNase II, which digest DNA. We have previously reported that incomplete digestion of damaged mitochondria by DNase II in mitophagy-lysosome system results in inflammation and heart failure. In addition, we have reported a protein Bcl2-L-13 is involved in mitophagy, which is a mammalian counterpart of Atg32, an essential mitophagy receptor in yeast. In this project funded by ERC, we are attempting how Bcl2-L-13 induces mitophagy, how mitochondrial DNA is methylated, and how DNase activity is regulated in heart failure.
Project Leader: Kinya Otsu, MD, PhD, FMedSci, King's College London
Project Leader: Kinya Otsu, MD, PhD, FMedSci, King's College London
https://www.kcl.ac.uk/people/kinya-otsu
https://www.bhf.org.uk/what-we-do/our-research/our-top-professors/professor-kinya-otsu
A Mammalian Mitophagy Receptor, Bcl2-L-13, Recruits the ULK1 Complex to Induce Mitophagy
A Mammalian Mitophagy Receptor, Bcl2-L-13, Recruits the ULK1 Complex to Induce Mitophagy
CELL Report| Volume 26, ISSUE 2, P338-345.e6, January 08, 2019
Degradation of mitochondria by selective autophagy, termed mitophagy, contributes to the control of mitochondrial quality. Bcl2-L-13 is a mammalian homolog of Atg32, which is an essential mitophagy receptor in yeast. However, the molecular machinery involved in Bcl2-L-13-mediated mitophagy remains to be elucidated. Here, we show that the ULK1 (unc-51-like kinase) complex is required for Bcl2-L-13 to process mitophagy. Screening of a series of yeast Atg mutants revealed that a different set of ATG genes is used for Bcl2-L-13- and Atg32-mediated mitophagy in yeast. The components of the Atg1 complex essential for starvation-induced autophagy were indispensable in Bcl2-L-13-, but not Atg32-mediated, mitophagy. The ULK1 complex, a counterpart of the Atg1 complex, is necessary for Bcl2-L-13-mediated mitophagy in mammalian cells. We propose a model where, upon mitophagy induction, Bcl2-L-13 recruits the ULK1 complex to process mitophagy and the interaction of LC3B with ULK1, as well as Bcl2-L-13, is important for the mitophagy.
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