Abstract
WD repeat and FYVE domain-containing 3 (WDFY3; also known as Autophagy-Linked FYVE or Alfy) is an identified intellectual disability, developmental delay and autism risk gene. This gene encodes for a scaffolding protein that is expressed in both the developing and adult central nervous system and required for autophagy and aggrephagy with yet unexplored roles in mitophagy. Given that mitochondrial trafficking, dynamics and remodeling have key roles in synaptic plasticity, we tested the role of Wdfy3 on brain bioenergetics by using Wdfy3+/lacZ mice, the only known Wdfy3 mutant animal model with overt neurodevelopmental anomalies that survive to adulthood. We found that Wdfy3 is required for sustaining brain bioenergetics and morphology via mitophagy. Decreased mitochondrial quality control by conventional mitophagy was partly compensated for by the increased formation of mitochondria-derived vesicles (MDV) targeted to lysosomal degradation (micromitophagy). These observations, extended through proteomic analysis of mitochondria-enriched cortical fractions, showed significant enrichment for pathways associated with mitophagy, mitochondrial transport and axon guidance via semaphorin, Robo, L1cam and Eph-ephrin signaling. Collectively, our findings support a critical role for Wdfy3 in mitochondrial homeostasis with implications for neuron differentiation, neurodevelopment and age-dependent neurodegeneration.
Highlights
The human central nervous system has relatively high energy demands, with approximately 20% of total metabolic expenditure being incurred by about 2% of body mass
While the exact function of the Wdfy[3] BEACH domain is still not completely understood, some insight arises from our previous studies on Wdfy3disc mice, an animal model that lacks both WD40 repeats and the zinc-finger-FYVE domain, but still preserves the BEACH domain resulting in a substantially milder phenotype compared to the Wdfy3lacZ mice [with disruption at amino acid 191, and missing BEACH domain, WD40 repeats and zinc-finger-FYVE domain; Fig. 1A)16]
We investigated the role of Wdfy[3] on selective autophagy by utilizing Wdfy3+/lacZ mice, the only known heterozygous Wdfy[3] mouse model that displays overt neurodevelopmental anomalies and that survive to adulthood[16]
Summary
The human central nervous system has relatively high energy demands, with approximately 20% of total metabolic expenditure being incurred by about 2% of body mass. The rationale for our search for potential deficits in mitochondrial function of Wdfy[3] haploinsufficiency is based on (i) the high expression of Wdfy[3] in both the developing central nervous system and adult brain[18]; (ii) the critical role of mitochondrial fatty acid β-oxidation at controlling the transition from neural stem cells (NSC) to intermediate progenitor cells (IPC) in the mammalian neocortex[20]; and (iii) the premise that clearance of damaged mitochondria via mitophagy is vital to proper mitochondrial trafficking, an essential aid to brain plasticity[21,22] To this end, we assessed the role of Wdfy[3] in brains from adult Wdfy3+/lacZ and wild type (WT) mice via detailed biochemical, microscopic, and proteomic methods. We observed significant over-representation of pathways regulating mitophagy and autophagy, and mitochondrial transport, axonal transport and remodeling of the axonal cytoskeleton, with the involvement of Semaphorin, Robo, L1cam, and Eph-ephrin signaling
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