PARL and HtrA2: Another Intricate Ischemic Neuronal Apoptotic Process Starting within Mitochondria

Abstract

Mitochondria integrity is essential for maintaining neuronal viability. Under ischemic stress, neurons undergo apoptosis with death signaling processes originating within mitochondria. The intricate actions of dysfunctional mitochondria in causing ischemic neuronal death were delineated in a recent review in this Journal1 as targets for developing neuroprotective strategies. The featured article by Yoshioka et al2 in this issue reports a novel death signaling process in striatal neurons under ischemic stress, involving presenilin-associated rhomboid-like (PARL) protein and high temperature requirement factor A2 (HtrA2). In elegantly designed experimental paradigms, the authors have established that PARL, an inner mitochondrial membrane protein, has a pivotal role in limiting striatal neuronal apoptosis by binding to HtrA2. Under global ischemia, PARL is degraded to release the processed form of HtrA2 from mitochondria into cytosol to bind to an inhibitor of apoptosis, the X-chromosome-linked inhibitor-of-apoptosis protein (XIAP). This results in striatal neuronal apoptosis. Presenilin-associated rhomboid-like protein is an intramembrane serine protease in the rhomboid subfamily in mitochondria. The complex name containing Presenilin is based on the original findings in yeast two-hybrid studies using a C-terminal region of Presenilin-2 as the bait to identify PARL.3 Presenilin-associated rhomboid-like protein has been shown to interact with a number of other mitochondrial proteins to constrain proapoptotic activities, starting within mitochondria. Presenilin-associated rhomboid-like protein acts in concert with OPA1, another antiapoptotic protein in mitochondria, to serve as ‘a lid on apoptosis',4 or with HtrA2 to act as ‘gate keepers of mitochondrial dynamics and apoptosis'.3 This is the first report linking PARL–HtraA2 interaction inside mitochondria to neuronal apoptosis in a setting of global cerebral ischemia. It adds another death signaling cascade that starts within mitochondria to those described in a comprehensive review of neuroprotective strategies targeting mitochondria.1 The novel findings reported in this featured article raise a number of questions for future exploration. First, is Hax 1, a mitochondrial protein resembling antiapoptotic proteins in the Bcl-2 family carrying BH-1and BH-2 domains, involved in PARL–HtrA2 interaction in ischemic striatal neuronal apoptosis? Hax 1 has been shown to present HtrA2 to PARL to retain the former in the mitochondrial intermembrane space for maintaining cell viability.5 It would be interesting to know if Hax 1 is engaged in this death signaling process in striatal neurons. Second, is this novel apoptotic cascade restricted to striatal neurons only? Does PARL–HtrA2 interaction contribute to cortical neuronal apoptosis under global ischemic stress as well? Presenilin-associated rhomboid-like protein has been linked to Parkinson's disease involving Parkin and PINK1.6 It is not impossible that the antiapoptotic action of PARL is restricted only to striatal neurons. Finally, to what extent can ischemic striatal neuronal apoptosis be ascribed to PARL–HtrA2 interaction, beyond well-established death signaling processes originating within mitochondria? In summary, this featured article reports a novel death signaling cascade in ischemic striatal neurons apoptosis. It broadens our insight into the complex mechanisms of ischemic neuronal death involving mitochondria.