The need to maintain the membrane integrity is underscored by the observation that all eight mutations (R45C, M48V, T50A, R73C, S78G, P99L, R109W, and R144Q) identified from patients with GRACILE syndrome38,54, a severe form of Bcs1L-linked mitochondrial disease, are clustered at the border between the TM region and Bcs1-specific region and at the subunit interface (Supplementary Fig. 11). This evidence concerns the gene BCS1L and inborn mitochondrial metabolism disorder.