CLEARING THE CLUTTER: A NEW PARADIGM OF MITOCHONDRIAL QUALITY CONTROL IN AXONS

Neurons rely on a highly efficient mitochondrial network to sustain their energy-intensive functions across vast cellular landscapes. Chronic mitochondrial dysfunction is a hallmark of many neurodegenerative and neurological diseases, yet the mechanisms by which neurons maintain mitochondrial quality across their uniquely polarized morphology remain incompletely understood. As distal axonal compartments represent the nexus of neuronal function, we sought to dissect the mechanisms by axon-specific mitochondrial quality control may occur. We induced mitochondrial DNA (mtDNA) damage in Caenorhabditis elegans neurons by targeting the restriction endonuclease PstI to the mitochondrial matrix. Using fluorescent labelling of neuronal subtypes and their mitochondria, we uncovered a striking phenomenon: damaged mitochondria are selectively packaged into vesicle-like structures, termed “mitophers,” which bud from the distal axonal region. This process occurs naturally during ageing but is markedly accelerated and enhanced by mitochondrial stress. Through targeted genetic and pharmacological approaches, we identified a suite of molecular regulators orchestrating mitopher formation and trafficking. Furthermore, we determined that genetically ablating mitopher biogenesis alters neuronal function. Our findings suggest that mitopher biogenesis represents a critical adaptation to the spatial constraints of neuronal architecture and enables distal compartments to offload dysfunctional mitochondria. Thus, mitopher formation may represent a modifiable mechanism to promote the quality of the axonal mitochondrial population during mitochondrial duress. By elucidating the molecular underpinnings of mitopher formation, we provide new insights into neuronal resilience and mitochondrial homeostasis and offer a foundation for therapeutic strategies aimed at preserving neuronal integrity in the face of mitochondrial dysfunction.