ER-Mitochondria Crosstalk in Mitophagy Failure: Implication for Neurodegenerative Disorders

Abstract

The critical association between mitochondria-associated membranes (MAMs), which are endoplasmic reticulum (ER)-mitochondria contact sites, and mitophagy failure in neurodegenerative diseases is the subject of this review. Because of the high energy demands and restricted regeneration of neurons, they rely on specific mechanisms of mitochondrial quality control (MQC) including biogenesis, dynamics, and mitophagy to counteract ROS damage, bioenergetic deficits or collapse of proteostasis. By activating PINK1-Parkin-dependent ubiquitination of outer mitochondrial membrane proteins or receptor-mediated pathways, mitochondria degrades dysfunctional mitochondria through mitophagy, while its impairment damages toxic organelles, exacerbating diseases like PD, AD and amyotrophic lateral sclerosis (ALS). Additionally, MAMs function as active centers for Ca2+ mechanistic interactions. How does this explain the development of Parkinson's disease? Despite the maintenance of optimal 10-65 nm spacing by tethering proteins like MFN2, VAPB-PTPIP51, and PDZD8, disruptions such as MNF2 mutations in Charcot-MarieTooth disease or TDP-43 aggregates on ALS cause wide gaps, blunt signaling, (via PINK1/Parkin recruitment) or stall binding to LC3 adaptors. In this state, disease-specific insults converge as: - synuclein overloads MAM in PD, A/tau disrupts Ca2+ flux in AD, mutant SOD1/VAPB impairs contacts in the ALS, and mHTT blocks HD mitophagy blockade, ROS surges, inflammation (NLRP3 at MAFs), and neuronal death. By discussing mitophagy pathways, MAM architecture and crosstalk functions as well as failure mechanisms and disorder links, this synthesis concludes: "MAM stabilizers (e.g, the anti-tumor P-like pridopidine), with or without food coke, inducer[M] and ER stress modulators (4-PBA] are therapeutically effective in returning homeostasis to normal cells.". In the future, super-resolution imaging, CRISPR screens and biomarkers will be used for precision interventions balancing clearance with biogenesis.