Beyond autophagy: a novel role for autism-linked Wdfy3 in brain mitophagy

Eleonora Napoli, Gyu Song, Alexios Panoutsopoulos, M. Asrafuzzaman Riyadh, Gaurav Kaushik, Julian Halmai, Richard Levenson, Konstantinos S. Zarbalis, Cecilia Giulivi

Research output: Contribution to journalArticlepeer-review

34 Scopus citations


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.

Original languageEnglish (US)
Article number11348
JournalScientific Reports
Issue number1
StatePublished - Dec 1 2018

ASJC Scopus subject areas

  • General


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