JNK2 Regulates Stress-induced Mitophagy And Tissue Damage By Targeting SmARF For Degradation

Autophagy is a process of self-cannibalization, by which the cytoplasmic constituents of protein and organelles are sequestered in a double membrane autophagosome and consume them in lysosomes, in order to achieve their own metabolic needs and certain cell organelles update. Mitophagy is a process referred to mitochondria degradation via autophagy. Here our study focus on mitophagy. Mitophagy is essential for cellular homeostasis but the regulatory mechanism is largely unknown. Deregulation of mitophagy has been implicated in many pathophysiological activities and diseases. Now more and more researches show JNK signal pathway play a delicate and complicate role on many human diseases. JNK is c-Jun N-terminal protein kinase, JNK protein kinase encoded by three genes,JNK1,JNK2 and JNK3.JNK l and JNK2 are ubiquitously expressed,whereas JNK3 shows a tissue specific expression profile. Here we report that JNK2 is required for stress-induced mitophagy. Small mitochondrial ARF(smARF) is a short isoform of the tumor suppressor ARF,it has been reported that over-expression of smARF is capable of inducing mitochondria depolarization and subsequent mitophagy. In our study, we find JNK2 promotes ubiquitination and proteasomal degradation of endogenous smARF. Loss of JNK2 leads to accumulation of smARF, which in turn to suppress stress-induced mitophagy activity and defects in clearance of damaged mitochondria by mitophagy result in the production of excessive reactive oxygen species(ROS).Defective mitophagy has been reported to induce excessive mitochondrial ROS,leading to inflammasome hyperactivation. In JNK2-deficient mice display defective mitophagy, resulting in tissue damage under hypoxic stress. Thus, our study reveals a novel mechanism of maintaining immune homeostasis that protects the host from tissue damage, it may throw some light on future therapeutic strategies design for some disease.