Diminished OPA1 expression and impaired mitochondrial morphology and homeostasis are prominent features of aprataxin-deficient cells

Ataxia with oculomotor apraxia type 1 (AOA1) is an early onset progressive spinocerebellar ataxia caused by mutation in aprataxin (APTX). APTX removes 5´-AMP groups from DNA, a product of abortive ligation during DNA repair and replication. APTX deficiency has been suggested to compromise mitochondrial function; however, a detailed characterization of mitochondrial homeostasis in APTX-deficient cells is not available. Here we show that cells lacking APTX undergo mitochondrial stress and display significant changes in the expression of the mitochondrial inner membrane fusion protein OPA1, and components of the oxidative phosphorylation complexes. At the cellular level, APTX deficiency impairs mitochondrial morphology and network formation, and autophagic removal of damaged mitochondria by mitophagy. Thus, our results show that aberrant mitochondrial function is a key component of AOA1 pathology. This work corroborates the emerging evidence that impaired mitochondrial dynamics and mitophagy are at the hub of an increasing number of genetically diverse neurodegenerative disorders. Three biological replicates of normal control (U2OS_N1-3) and CRISPR-mediated aprataxin (APTX) knock-out (APTX_KO1-3) U2OS cells were employed for this comparison.