Structure and function of mitochondrial AAA+ proteases and their roles in neurological disorders*

Among them, a group of mitochondrial AAA+ proteases, relying on ATP-binding and ATP-hydrolysis, not only degrade misfolded proteins but also perform critical functions in the maturation of mitochondrial fusion proteins, the assembly of respiratory-chain complexes, and the replication and transcription of mtDNA. Mutations in or aberrant expression of these mitochondrial AAA+ proteases alter their enzymatic activity, severely compromise mitochondrial structure and function, and give rise to a spectrum of severe neurological disorders.

Focusing on three mitochondrial AAA+ proteases (ATPases associated with diverse cellular activities), LONP1, YME1L1, and AFG3L2, this review summarizes their sequence similarities and structural features, distinct sub-mitochondrial localizations and functions. We found that the reported genetic mutations among these three proteases, which are associated with both common and rare neurological disorders, are mostly located within their ATPase domain and the hydrolase/peptidase domains.

Elucidating the structures of these key domains, the functional consequences of their mutations, and their impact on mitochondrial and cellular homeostasis will therefore provide valuable insights for understanding disease mechanisms and for developing targeted interventions.