Preprint: mutant ATAD3A disrupts mTORC1-TFEB signalling and lysosomal homeostasis in a neurological syndrome

ATAD3A encodes a mitochondrial membrane-anchored ATPase, and de novo variants in this gene have been reported to cause a severe human neurological syndrome characterised by developmental delay and neurological deterioration. Prior work showed that pathogenic ATAD3A mutations induce aberrant lysosomal expansion with accumulation of undigested material, but the underlying mechanism linking mitochondrial dysfunction to lysosomal pathology had not been established.

A preprint posted to bioRxiv now reports that the pathogenic ATAD3A p.R528W variant disrupts the mTORC1-TFEB signalling axis. mTORC1 (mechanistic target of rapamycin complex 1) phosphorylates TFEB to retain it in the cytoplasm; when mTORC1 activity is reduced, TFEB translocates to the nucleus and activates lysosomal biogenesis genes (the CLEAR network). The authors found dysregulated mTORC1 substrate phosphorylation, altered TFEB nuclear localisation, and changes in CLEAR gene activation associated with expression of mutant ATAD3A. Upstream, dysregulation of the RagC/D GTPase complex — which recruits mTORC1 to lysosomal membranes — was implicated.

The findings mechanistically connect mitochondrial membrane protein dysfunction to lysosomal homeostasis disruption and suggest that aberrant TFEB activity may contribute to neurodevelopmental defects in this syndrome. The preprint has not yet been peer reviewed.

This study will be of primary interest to researchers in mitochondrial biology, lysosomal biology, mTOR signalling, and the molecular basis of rare neurodevelopmental disorders.