To explore the role of PINK1, Drp1 and mitochondrial autophagy in transient global ischemia-induced hippocampal CA1 neuronal injury

A brief yet complete disruption of blood flow to the brain, or “transient global ischemia (TGI)”, may cause delayed neuronal death in hippocampus. This neuronal death occurs 2-4 d after TGI within a specific neuronal population of hippocampus, namely the CA1 pyramidal neurons and less involvement of CA2, 3 and dentate gurus. Clinically, TGI occurs in such serious cardiovascular disorders as a cardigan shock after myocardial infarction or reversible severe hypotension. The underlying mechanisms of delayed CA1 neuronal loss following TGI are not well understood. Cerebral ischemia can cause excessive reactive oxygen species (ROS) generation and result in neuronal damage which may relate to mitochondrial dysfunction. Recent studies showed mitochondrial fission is an early event in cell death and prior to, or simultaneous with cytochrome c release and caspase activation and dynamin-related protein 1 (Drp1) plays an important role in mitochondrial fission. PTEN-induced putative kinase 1 (PINK1) is a mitochondrial serine/threonine-protein kinase thought to protect cells from stress-induced mitochondrial dysfunction and regulates mitochondrial fission via autophagy machinery. It is thus reasonable to assume that PINK1 or PINK1/mitochondrial autophagy may act as an endogenous protective response, regulate Drp1 expression as well as ROS formation, accommodate cell metabolism to survive and would be vital to lessen TGI-induced neuronal injury. However, the role of PINK1 in cerebral ischemia is not well studied. In this project, we attempt to define a novel protective pathway involving PINK1 and autophagy in TGI-induced neuronal damage in hippocampus. Two specific aims will be tested. We’ll first test if TGI-induced neuronal damage in the hippocampus may relate to excessive ROS formation and concomitantly induce the change of PINK1, Drp1 and mitochondrial autophagy. Secondly, we’ll use pharmacological and molecular approach including anti-sense oligodeoxynucleotide or siRNA for PINK1 and Drp1 to validate this signaling pathway. Several commonly used medications such as pioglitazine, rosuvastatin and minocycline with neuroprotective effects may have a direct or an indirect mechanism involving induction of PINK1/autophagy and worth to explore. The ultimate goal of this project is to develop protective strategies to prevent TGI-induced neuronal injury in the hippocampus via modulation of the signaling pathways involving PINK1, Drp1 or PINK1/ autophagy, and hence lessens mitochondrial dysfunction and ROS formation and modulate cell metabolism to survive. The ability to reduce TGI-induced neuronal injury in the hippocampus may have therapeutic implication not only in TGI but also in other stroke syndromes.

Project ID:PC10202-0744
External Project ID:NSC101-2314-B182-081-MY2