Mitochondrial dysfunction is a key mechanism of cell death in hypoxic-ischemic brain injury. Neuronal pentraxin 1 (NP1) has been shown to play crucial roles in mitochondria-mediated neuronal death. However, the underlying mechanism(s) of NP1-induced mitochondrial dysfunction in hypoxia-ischemia (HI) remains obscure. Here, we report that NP1 induction following HI and its subsequent localization to mitochondria, leads to disruption of key regulatory proteins for mitochondrial biogenesis. Brain mitochondrial DNA (mtDNA) content and mtDNA-encoded subunit I of complex IV (mtCOX-1) expression was increased post-HI, but not the nuclear DNA-encoded subunit of complex II (nSDH-A). Up-regulation of mitochondrial proteins COXIV and HSP60 further supported enhanced mtDNA function. NP1 interaction with active Bax (Bax6A7) was increased in the brain after HI and in oxygen-glucose deprivation (OGD)-induced neuronal cultures. Importantly, NP1 colocalized with mitochondrial hexokinase II (mtHKII) following OGD leading to HKII dissociation from mitochondria. Knockdown of NP1 or SB216763, a GSK-3 inhibitor, prevented OGD-induced mtHKII dissociation and cellular ATP decrease. NP1 also modulated the expression of mitochondrial transcription factor A (Tfam) and peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), regulators of mitochondrial biogenesis, following HI. Together, we reveal crucial roles of NP1 in mitochondrial biogenesis involving interactions with Bax[6A7] and mtHKII in HI brain injury.
Keywords: hexokinase II; hypoxia-ischemia; mitochondrial transcription factor A; neonatal brain injury; neuronal pentraxin 1; peroxisome proliferator-activated receptor γ coactivator-1α.