Published online: May 29, 2017

Research Article

MSTO1 is a cytoplasmic pro-mitochondrial fusion , whose mutation induces myopathy and ataxia in humans

Aniko Gal1,2, Peter Balicza2, David Weaver1, Shamim Naghdi1, Suresh K Joseph1, Péter Várnai3, Tibor Gyuris4, Attila Horváth4, Laszlo Nagy4, Erin L Seifert1, Maria Judit Molnar2 & György Hajnóczky1,*

Abstract Introduction

The protein MSTO1 has been localized to mitochondria and linked Mitochondria are highly dynamic organelles whose morphology, to mitochondrial morphology, but its specific role has remained distribution, and activity are dependent on fusion and fission (Chan, unclear. We identified a c.22G > A (p.Val8Met) mutation of MSTO1 2006). Several neurodegenerative diseases such as optic atrophy, in patients with minor physical abnormalities, myopathy, ataxia, Charcot–Marie–Tooth, Alzheimer’s, Parkinson, and Huntington and neurodevelopmental impairments. Lactate stress test and disease are associated with alterations of mitochondrial dynamics myopathological results suggest mitochondrial dysfunction. In (Chan, 2006; Itoh et al, 2013). patient fibroblasts, MSTO1 mRNA and protein abundance are MSTO1 (Misato) is an evolutionarily conserved nuclear DNA- decreased, mitochondria display fragmentation, aggregation, and encoded protein showing some structural similarity to eukaryotic decreased network continuity and fusion activity. These character- tubulins and prokaryotic FtsZ. Null mutations of the misato in istics can be reversed by genetic rescue. Short-term silencing of Drosophila are associated with irregular chromosomal segregation MSTO1 in HeLa cells reproduced the impairment of mitochondrial (Miklos et al, 1997; Gurvitz et al, 2002; Mottier-Pavie et al, 2011). morphology and dynamics observed in the fibroblasts without However, depletion of MSTO1 by siRNA was also linked to mito- damaging bioenergetics. At variance with a previous report, we chondrial fragmentation and cell death, and overexpressed EGFP- find MSTO1 to be localized in the cytoplasmic area with limited Misato was localized in the mitochondria and was shown to induce colocalization with mitochondria. MSTO1 interacts with the fusion aggregation of mitochondria at the perinuclear region and cell death machinery as a soluble factor at the cytoplasm-mitochondrial in HeLa cells (Kimura & Okano, 2007). In this study, MSTO1 was outer membrane interface. After plasma membrane permeabiliza- proposed to contribute to the cell’s health as an outer mitochondrial tion, MSTO1 is released from the cells. Thus, an MSTO1 loss-of- membrane (OMM) resident affecting mitochondrial morphology. function mutation is associated with a human disorder showing However, the mechanism by which MSTO1 supports mitochondrial mitochondrial involvement. MSTO1 likely has a physiologically morphogenesis and its potential human disease relevance remains relevant role in mitochondrial morphogenesis by supporting mito- elusive. chondrial fusion. Disorders with primary mitochondrial dysfunction are clinically heterogeneous disorders that can manifest at any age, and can affect Keywords misato; mitochondria; mitochondrial disease; mitochondrial fusion; multiple tissues and organs, commonly the most energy demanding MSTO1 tissues, such as the central nervous system, skeletal and cardiac Subject Categories Genetics, Therapy & Genetic Disease; Metabolism muscle, liver, endocrine glands, kidney, and the eyes. Mitochondrial DOI 10.15252/emmm.201607058 | Received 13 September 2016 | Revised 13 diseases can result from mutations of located in either the April 2017 | Accepted 21 April 2017 | Published online 29 May 2017 nuclear DNA or the maternally inherited mitochondrial DNA. Until EMBO Mol Med (2017) 9: 967–984 now, based on the relevant databases (Mitomap, MitoMiner, NCBI, Nexprot), approximately 300 different mtDNA pathogenic mutations have been found. The collection of