FAF1 mediates necrosis through JNK1-mediated mitochondrial dysfunction leading to retinal degeneration in the ganglion cell layer upon ischemic insult

Abstract

Background Aberrant cell death induced by ischemic stress is implicated in the pathogenesis of ischemic diseases. Fas-associated factor 1 (FAF1) has been identified as a death-promoting protein. This study demonstrates that FAF1 functions in death signaling triggered by ischemic insult.

Methods The expression changes of FAF1 and phophorylated JNK1 were detected by Western blotting. Immunoprecipitation was employed to investigate protein-protein interaction. We determined the cell death using flow cytometry and lactate dehydrogenase release measurement. To validate the death-promoting role of FAF1 in the retina, we generated conditional retinal FAF1 knockout mice. We used hematoxylin and eosin staining to detect retinal cell death in retinal ganglion cell layer.

Results FAF1 was found to function upstream of c-Jun N-terminal kinase 1 (JNK1), followed by mitochondrial dysregulation and necrotic cell death processes upon ischemic insult. We investigated whether FAF1 is involved in the pathogenesis of ischemic diseases using a retinal ischemia model. Indeed, FAF1 potentiated necrosis through JNK1 activation upon ischemic stress in retinal cells demonstrating retinal ganglion–like character. Conditional FAF1 depletion attenuated JNK1 activation in the retinas of Dkk3-Cre;Faf1flox/flox mice and ameliorated death of retinal cells due to elevated intraocular pressure (IOP).

Conclusions Our results show that FAF1 plays a key role in ischemic retinal damage and may be implicated in the pathogenesis of retinal ischemic disease.