Gone fission: an asymptomatic STAT2 mutation elongates mitochondria and causes human disease following viral infection.

Abstract

This scientific commentary refers to ‘Signal transducer and activator of transcription 2 deficiency is a novel disorder of mitochondrial fission’, by Shahni et al. (doi:10.1093/brain/awv182). Mitochondria exist in dynamic networks, which undergo rapid cycles of fission (division) and fusion (union). The adaptive roles of fission and fusion depend on the state of the cell and include: mitotic fission (mitochondrial division coordinated with mitosis supporting equitable distribution of mitochondria to daughter cells); mitophagic fission (mitochondrial division isolating dysfunctional portions of the organelle for elimination by mitophagy, thereby maintaining mitochondrial quality control); apoptotic fission (a prelude to apoptosis); and oxygen-sensitive fission [mitochondrial division occurring in response to a change in PO2 which modulates the production of reactive oxygen species (ROS)], as reviewed in Archer (2013). Mitochondrial fusion regulates mitochondrial calcium, mitochondrial metabolism and cell cycle progression (Archer, 2013). In this issue of Brain, Shahni et al. (2015) identify signal transducer and activator of transcription 2 (STAT2) as a novel activator of dynamin-related protein 1 (DRP1)-induced fission and report that a clinically asymptomatic STAT2 mutation in three patients predisposed them to develop severe, multiorgan dysfunction associated with impaired mitochondrial fission, subsequent to receiving the measles-mumps-rubella (MMR) vaccination. The patients included siblings aged 12 and 13 months and a previously reported, unrelated subject diagnosed at 18 months of age (Hambleton et al. , 2013). All patients developed fever, and amongst the three of them showed other abnormalities including: conjunctivitis, lymphadenopathy, a sepsis-like syndrome, seizures, hepatitis and pneumonitis. The major mediators of mitochondrial fusion are GTPases in the outer mitochondrial membrane [mitofusin 1 (MFN1) and mitofusin 2 (MFN2)], and the inner mitochondrial membrane protein optic atrophy 1 (OPA1). Fission is regulated by a single GTPase, DRP1. On activation, DRP1 is recruited from the cytosol to the mitochondrial outer membrane where it …