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Published on: July 13, 2018
Ripk3 induces mitochondrial apoptosis via inhibition of FUNDC1 mitophagy in cardiac IR injury
Hao Zhou1, Pingjun Zhu1, Jun Guo1
1Department of Cardiology, Chinese PLA General Hospital, Beijing, China.
Abstract:
Ripk3-required necroptosis and mitochondria-mediated apoptosis are the predominant types of cell death that largely account for the development of cardiac ischemia reperfusion injury (IRI). Here, we explored the effect of Ripk3 on mitochondrial apoptosis. Compared with wild-type mice, the infarcted area in Ripk3-deficient (Ripk3-/-) mice had a relatively low abundance of apoptotic cells. Moreover, the loss of Ripk3 protected the mitochondria against IRI and inhibited caspase9 apoptotic pathways. These protective effects of Ripk3 deficiency were relied on mitophagy activation. However, inhibition of mitophagy under Ripk3 deficiency enhanced cardiomyocyte and endothelia apoptosis, augmented infarcted area and induced microvascular dysfunction. Furthermore, ischemia activated mitophagy by modifying FUNDC1 dephosphorylation, which substantively engulfed mitochondria debris and cytochrome-c, thus blocking apoptosis signal. However, reperfusion injury elevated the expression of Ripk3 which disrupted FUNDC1 activation and abated mitophagy, increasing the likelihood of apoptosis. In summary, this study confirms the promotive effect of Ripk3 on mitochondria-mediated apoptosis via inhibition of FUNDC1-dependent mitophagy in cardiac IRI. These findings provide new insight into the roles of Ripk3-related necroptosis, mitochondria-mediated apoptosis and FUNDC1-required mitophagy in cardiac IRI.
Insights
Ripk3 promotes cardiac cell death in ischemia reperfusion injury (IRI) by inhibiting mitophagy. Blocking Ripk3 protects the heart by activating mitophagy, reducing apoptosis and infarct size.
Area of Science:
- Cardiovascular Biology
- Cell Death Mechanisms
- Mitochondrial Dynamics
Background:
- Cardiac ischemia reperfusion injury (IRI) involves necroptosis and mitochondria-mediated apoptosis.
- Ripk3 (Receptor-interacting protein kinase 3) plays a key role in these cell death pathways.
Purpose of the Study:
- To investigate the specific role of Ripk3 in mitochondria-mediated apoptosis during cardiac IRI.
- To elucidate the interplay between Ripk3, mitophagy, and apoptosis in the context of cardiac IRI.
Main Methods:
- Utilized Ripk3-deficient (Ripk3-/-) and wild-type mice models.
- Assessed infarct size, apoptotic cell counts, and mitochondrial function post-IRI.
- Investigated the role of mitophagy and the FUNDC1 protein in regulating apoptosis.
Main Results:
- Ripk3 deficiency significantly reduced infarct size and apoptotic cells in cardiac IRI.
- Loss of Ripk3 protected mitochondria and inhibited caspase-9 pathways, dependent on mitophagy activation.
- Inhibition of mitophagy in Ripk3-deficient mice exacerbated apoptosis and cardiac damage.
- Ischemia activated mitophagy via FUNDC1 dephosphorylation, clearing mitochondrial debris and blocking apoptosis.
- Reperfusion increased Ripk3, disrupting FUNDC1, reducing mitophagy, and promoting apoptosis.
Conclusions:
- Ripk3 promotes mitochondria-mediated apoptosis in cardiac IRI by inhibiting FUNDC1-dependent mitophagy.
- Targeting Ripk3 and modulating mitophagy presents a potential therapeutic strategy for cardiac IRI.
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