DDHD2 is necessary for activity-driven fatty acid fueling of nerve terminal function

Abstract

HSP54, a hereditary spastic paraplegia associated with cognitive impairment, is caused by mutations in the neuron-specific triglyceride (TG) lipase DDHD2. Loss of DDHD2 function results in lipid accumulation in human brains1 and lipid droplets (LDs) in mouse neurons2. In metabolically demanding tissues, TG lipases generate a fatty acid (FA) flux from LDs to fuel mitochondrial ATP production, but neurons are considered unable to use fat as an energy source. Thus, the basis for cognitive impairment driven by DDHD2 loss remains enigmatic. To resolve this paradox, we took advantage of presynaptic sensitivity to metabolic perturbations to determine if FAs derived from LDs could power local {beta}-oxidation to support synaptic functions and whether DDHD2 activity would be required in the process. We demonstrate that nerve terminals are enriched with DDHD2 and blocking its activity leads to presynaptic accumulation of LDs. Moreover, we show that FAs derived from axonal LDs enter mitochondria in an activity-dependent fashion and drive local mitochondrial ATP production allowing nerve terminals to sustain function in the complete absence of glucose. Our data demonstrate that neurons and their nerve terminals can make use of LDs during electrical activity to provide metabolic support when glucose is in short supply.