The critical roles of mitophagy in cerebral ischemia

Abstract

Mitochondria play a key role in various cell processes including ATP production, Ca²⁺ homeostasis, reactive oxygen species (ROS) generation, and apoptosis. The selective removal of impaired mitochondria by autophagosome is known as mitophagy. Cerebral ischemia is a common form of stroke caused by insufficient blood supply to the brain. Emerging evidence suggests that mitophagy plays important roles in the pathophysiological process of cerebral ischemia. This review focuses on the relationship between ischemic brain injury and mitophagy. Based on the latest research, it describes how the signaling pathways of mitophagy appear to be involved in cerebral ischemia.

Keywords: autophagy; cerebral ischemia; mitochondria; mitophagy.

Figure 1

Trends in research on mitophagy in human disease. Summary of the study trends of mitophagy and its related human disease from 2011 to 2015

Figure 2

Mechanisms of mitophagy. (a) In yeast, the outer mitochondrial membrane protein Autophagy-related 32 (Atg32) binds the isolation membrane protein Atg8 through its WXXL-like motif. This process requires adaptor protein Atg11, which can form a complex with Atg32 and Atg8 and physically link mitochondria with isolated membranes. Finally, the mitochondria are sealed by the isolation membranes and fuse with lysosome to be degraded. Uth1p and Aup1p are both mitochondria membrane proteins and can facilitate mitophagy under certain special conditions, such as starvation. (b) In mammalian cells, (1) Parkin-dependent pathway. After treatment with CCCP or other mitochondria inhibitors, the mitochondria are damaged and lose membrane potential, which can lead to impaired PINK1 cleavage and stabilization. At that point, PINK1 phosphorylates Parkin and ubiquitin at Ser65 to recruit Parkin to damaged mitochondria from the cytosol. Parkin ubiquitylates the mitochondrial substrates and generates more ubiquitin substrate for PINK1 to phosphorylate; then, the ubiquitin-binding adaptor p62/NDP52/OPTN aggregates ubiquitylated proteins and recruits ubiquitylated cargo into autophagosome by binding to LC3. Finally, the mitochondria are sealed by the isolation membranes and fuse with lysosomes to be degraded. (2) Parkin-independent pathway. The most important Parkin-independent pathway is the NIX/Bnip3 and FUNDC1 pathway. Under hypoxic conditions or starvation, the protein level of NIX or Bnip3 increase. NIX and Bnip3 localize on the outer membrane of mitochondria and contain a WXXL-like motif facing the cytosol which can directly bind to the mammalian Atg8 orthologue and LC3, thereby facilitate mitophagy. FUNDC1 is a mitochondria outer membrane protein containing a classical LC3-interacting region. Activated FUNDC1 directly binds with LC3 or ATG8 to induce subsequent mitophagy

Figure 3

Possible mitophagy signalling pathways involved in cerebral ischemia. During the process of cerebral ischemia, many different signalling pathways are involved in the activation or suppression of mitophagy. (1) The process of cerebral ischemia can cause hypoxic conditions in tissue, which can increase the Bnip3 and NIX levels, and cause release of Beclin1 from the Bcl-2-Beclin1 complex, and finally induce mitophagy. (2) Reperfusion is the most effective therapy for cerebral ischemia. Reperfusion increases the level of ROS, which can decrease the mitochondria membrane potential, and lead to the translocation of Parkin from cytosol to damaged mitochondria. Then, mitophagy can be facilitated in Parkin-dependent or Parkin-independent ways. (3) Mitochondrial fragmentation and fission are essential for mitophagy. Cerebral ischemia can decrease the level of mitochondrial fusion proteins, such as Opa1 and Mfn2, and increase the level of mitochondrial fission proteins, such as DRP1 and Fis. (4) Rapamycin can significantly increase the expression of LC3-II and Beclin1, and promote the translocation of P62 to damaged mitochondria, and finally facilitate mitophagy to exhibit neuroprotective functions. The process of mitophagy must be restricted to dysfunctional mitochondria and kept at a balanced level. Insufficient removal damaged mitochondria or excessive degradation of essential mitochondria will both cause cell death