ULK1-Rab9-dependent alternative mitophagy pathway (Alternative mitophagy)

The ULK1-Rab9-dependent alternative mitophagy pathway is a specialized cellular process responsible for the selective degradation of damaged or redundant mitochondria, operating independently of the canonical Atg5/Atg7 and PINK1/Parkin pathways [1]. This mechanism is characterized by the recruitment of the kinase ULK1 and the GTPase Rab9 to mitochondria, where they facilitate the formation of mitophagosomes using membranes derived from the trans-Golgi network and late endosomes [1][2]. It plays a vital role in physiological processes such as the clearance of mitochondria during erythroid maturation and provides a protective response in the heart during stress conditions like ischemia-reperfusion [2][3]. Impairment of this pathway is linked to the accumulation of dysfunctional mitochondria, contributing to the pathogenesis of heart failure, neurodegenerative disorders, and certain cancers [2][5]. Although the pathway involves multiple proteins, ULK1 is the primary druggable node, with various small molecules being developed to either inhibit its activity in cancer or activate it to enhance mitochondrial clearance in degenerative diseases [5]. Consequently, targeting this pathway offers a unique therapeutic window for managing diseases characterized by mitochondrial dysfunction.

Other names

Atg5-independent mitophagyNon-canonical mitophagyULK1-mediated alternative autophagyRab9-dependent mitophagy

Modulation of ULK1 kinase activity to regulate the initiation and flux of the alternative mitophagy pathway [1][5].