JNK2 is required for stress-induced mitophagy and protects against tissue damage and mortality.
Major finding: JNK2 is required for stress-induced mitophagy and protects against tissue damage and mortality.
Mechanism: JNK2 promotes proteasomal degradation of small mitochondrial ARF and increases steady-state p62 levels.
Impact: JNK2 inhibits inflammasome activation, limits ROS, and maintains organ integrity under hypoxia.
Dysregulation of mitophagy, a type of autophagy that degrades damaged or excessive mitochondria, leads to increased reactive oxygen species (ROS) accumulation and inflammasome hyperactivation, and has been associated with many pathophysiologic conditions, including immunologic disorders and cancer. The small mitochondrial isoform of the tumor suppressor ARF (smARF) and p62 (also known as sequestosome 1) have been shown to have roles in mitophagy, but the mechanisms underlying the regulation of mitophagy remain largely unknown. Zhang and colleagues found that the kinase JNK2 (also known as MAPK9) is required for stress-induced mitophagy. In contrast to wild-type mouse embryonic fibroblasts (MEF), which exhibited decreased mitochondrial proteins due to active mitophagy in hypoxic conditions, Jnk2−/− MEFs were characterized by impaired mitochondrial clearance and increased ROS production under hypoxic stress. Mechanistically, this defect in mitophagy was mediated by decreased levels of p62 at steady state in Jnk2−/− MEFs as a result of increased steady-state autophagy, which promotes p62 degradation. In addition, Jnk2−/− MEFs had significantly higher steady-state levels of smARF, which induces upregulation of autophagy. Specific depletion of smARF resulted in decreased autophagy, increased p62 expression, and restoration of mitophagy in Jnk2−/− MEFs. Ectopic expression of kinase-deficient JNK2 in Jnk2−/− MEFs decreased smARF levels, suggesting that JNK2 regulates smARF independent of its kinase activity. Indeed, JNK2 interacted with smARF and promoted its polyubiquitination and subsequent proteasomal degradation. Importantly, in vivo analysis of hypoxia-induced tissue damage in wild-type and Jnk2−/− mice revealed that JNK2-dependent regulation of stress-induced mitophagy protected against tissue damage. Furthermore, loss of JNK2 resulted in the hyperactivation of inflammasomes and excessive mitochondrial ROS production in bone marrow–derived macrophages and increased susceptibility to lipopolysaccharide-induced mortality in mice. These data support a critical role for JNK2 in stress-induced mitophagy and the maintenance of organ integrity during environmental stress.