Mitophagy and mitochondrial fission machinery

The mitophagy and mitochondrial fission machinery is a sophisticated quality control system essential for maintaining cellular health by regulating mitochondrial number, morphology, and integrity [1, 3, 6]. Mitochondrial fission, primarily mediated by the GTPase Dynamin-related protein 1 (DRP1), facilitates the segregation of damaged or dysfunctional mitochondrial segments from the healthy network [1, 13, 20]. These segregated fragments are subsequently targeted for selective degradation via mitophagy, a specialized form of autophagy [3, 12, 17]. The canonical mitophagy pathway is governed by the PINK1 kinase and the E3 ubiquitin ligase Parkin, which sense mitochondrial depolarization and mark the organelle for engulfment by autophagosomes [2, 12, 16]. Dysregulation of this machinery is a hallmark of various pathologies, particularly neurodegenerative diseases like Parkinson's, where the accumulation of damaged mitochondria leads to oxidative stress and neuronal death [2, 7, 17]. In cancer, the machinery can play dual roles, either promoting tumor survival under stress or inducing mitophagic cell death [3, 5, 11]. Therapeutic strategies currently under development include small-molecule inhibitors of mitochondrial fission (e.g., DRP1 inhibitors) and enhancers of mitophagy (e.g., USP30 inhibitors or PINK1 activators) to restore mitochondrial homeostasis and prevent disease progression [1, 7, 19].

Other names

Mitochondrial quality control (MQC) systemMitophagy pathwayMitochondrial dynamics machineryMitochondrial fission-mitophagy axis

Modulation of mitochondrial dynamics and quality control through the inhibition of fission proteins (e.g., DRP1) or the activation of mitophagy-inducing proteins (e.g., PINK1, Parkin) and inhibition of deubiquitinating enzymes (e.g., USP30) [1, 2, 7, 19].