Age-related disruptions in ubiquitination and mitochondrial proteostasis are associated with neuronal...

Declining aerodigestive neuromotor function is a major aspect of human aging, with impaired airway defense and swallow manoeuvres implicated in pneumonia and dysphagia. Hypoglossal motor neurons (MNs) innervate tongue muscles, essential for these behaviours. Their degeneration contributes to age-related aerodigestive dysfunctions. In neurodegenerative diseases, the ubiquitin-proteasome system (UPS) is altered, disturbing mitochondrial proteostasis. We have previously shown reduced mitochondrial abundance, dysfunction and mitochondrial fragmentation in aging hypoglossal MN somas and dendrites. However, the relationship between the UPS (pUB^S65 and ubiquitinated proteins), mitochondrial fragmentation (pDRP1^S616) and fusion promoting proteins (MFN2) in MN aging is unexplored. In other neurons, aging changes mitochondria within axons in an opposite way to somas and dendrites. We used Western blotting to show impairment in mitophagy-related pUB^S65, increased fragmentation-promoting pDRP1^S616 and unchanged MFN2. Serial Block-Face Scanning Electron Microscopy showed increased mitochondrial volume density and larger, more simplistic mitochondria in old, myelinated hypoglossal axons, while somas and dendrites showed reduced mitochondrial volume density and increased fragmentation. Our results suggest that a more nuanced compartment-specific evaluation of mitochondrial structure and function is required to fully elucidate the pathophysiology underlying age-related neuromotor dysfunction.