The compartmentalised nature of neuronal mitophagy: molecular insights and implications

Abstract

The maintenance of a healthy mitochondrial network and the ability to adjust organelle population in response to internal or external stimuli are essential for the function and the survival of eukaryotic cells. Over the last two decades several studies have demonstrated the paramount importance of mitophagy, a selective form of autophagy that removes damaged and/or superfluous organelles, in organismal physiology. Post-mitotic neuronal cells are particularly vulnerable to mitochondrial damage, and mitophagy impairment has emerged as a causative factor in multiple neurodegenerative pathologies, including Alzheimer's disease and Parkinson's disease among others. Although mitochondrial turnover is a multifaceted process, neurons have to tackle additional complications, arising from their pronounced bioenergetic demands and their unique architecture and cellular polarisation that render the degradation of distal organelles challenging. Mounting evidence indicates that despite the functional conservation of mitophagy pathways, the unique features of neuronal physiology have led to the adaptation of compartmentalised solutions, which serve to ensure seamless mitochondrial removal in every part of the cell. In this review, we summarise the current knowledge concerning the molecular mechanisms that mediate mitophagy compartmentalisation and discuss their implications in various human pathologies.

Meeting Summary of The NYO3 5th NO-Age/AD Meeting and the 1st Norway–UK Joint Meeting on Aging and Dementia: Recent Progress on the Mechanisms and Interventional Strategies

“…Neuronal mitophagy is a challenging event because the majority of mitochondria reside in distal neuronal processes, far away from the cell body, where mature lysosomes are primarily located. Despite spatial limitations, rapid mitochondrial elimination is essential for protecting neurons against cell death, highlighting the presence of localized quality control mechanisms to cope with mitochondrial stress and uphold neuronal function ( 34 , 35 ). While providing neuroprotection, precise regulation of mitophagy is crucial for cellular viability, as uncontrolled mitophagy can decrease mitochondrial numbers, cause energy depletion, and eventually result in cell demise ( 36 , 37 ).…”

Role of Mitochondria–ER Contact Sites in Mitophagy

“…Although mitochondria and lysosomes might be in contact at times, and lysosomes can promote fission, they are not reported to mediate mitochondrial degradation by this direct contact [ 48 ]. Lysosomes have a distinct distribution pattern in neurons, where many lysosomes are localized in the cell body, while fewer lysosomes are abundant in the long neuronal processes [ 49 , 50 ]. Therefore, specific mechanisms may be required to circumvent the spread of reactive oxygen species (ROS) that are produced by damaged mitochondria inside autophagosomes during their transport towards the cell body.…”

“…The second stimulus upon which ULK1 becomes activated by AMPK and forms a macromolecular complex, is hypoxia ( Figure 1 B) [ 81 , 82 ]. The ULK1–AMPK complex translocates to the mitochondria, where it interacts with Fun14 domain containing protein 1 (FUNDC1) [ 49 , 83 ]. FUNDC1 is an integral protein on the OMM and highly conserved in most mammals [ 5 ].…”