Date of Award

Fall 1-1-2025

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Genetics

First Advisor

Hammarlund, Marc

Abstract

Axons extend far from the neuronal soma and depend on local energy metabolism to sustain signaling and structural integrity. Mitochondria are normally abundant in axons, where they provide numerous utilities. In many neurodegenerative diseases, however, mitochondrial function or trafficking is impaired, but the mechanisms linking mitochondrial loss to axon degeneration remain unclear.In this dissertation, I use C. elegans mitochondrial trafficking mutants, in which axons completely lack mitochondria, to define the metabolic basis of degeneration. I find that glycolysis, typically viewed as a protective energy source, unexpectedly promotes axon breakdown. Elevated glycolytic flux in axons without mitochondria leads to accumulation of lactate and pyruvate, sustained cytoplasmic acidification, and structural degeneration. Using genetically encoded biosensors, I show that acidification precedes and predicts degeneration. Interventions that buffer protons or enhance proton consumption suppress degeneration. Additional exploratory experiments broaden these insights. Neuronal vulnerability varies by cell type, with long ventral nerve cord axons particularly susceptible. Alternative lactate-modifying enzymes, citrate synthase mutations, and mitochondrial calcium uniporter perturbations further modulate degeneration, while the psychedelic compound DOI provides partial protection and reveals potential links between metabolism and plasticity. Together, these findings reframe the role of axonal mitochondria beyond ATP supply, identifying proton handling as a central determinant of axon integrity. By establishing metabolic acidification as a driver of axon degeneration, this work highlights new therapeutic strategies targeting glycolysis, lactate metabolism, and proton buffering for neurodegenerative diseases associated with mitochondrial dysfunction.

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