RT Journal Article
SR Electronic
T1 MITOL deletion in the brain impairs mitochondrial structure and ER tethering leading to oxidative stress
JF Life Science Alliance
JO Life Sci. Alliance
FD Life Science Alliance LLC
SP e201900308
DO 10.26508/lsa.201900308
VO 2
IS 4
A1 Shun Nagashima
A1 Keisuke Takeda
A1 Nobuhiko Ohno
A1 Satoshi Ishido
A1 Motohide Aoki
A1 Yurika Saitoh
A1 Takumi Takada
A1 Takeshi Tokuyama
A1 Ayumu Sugiura
A1 Toshifumi Fukuda
A1 Nobuko Matsushita
A1 Ryoko Inatome
A1 Shigeru Yanagi
YR 2019
UL https://www.life-science-alliance.org/content/2/4/e201900308.abstract
AB Mitochondrial abnormalities are associated with developmental disorders, although a causal relationship remains largely unknown. Here, we report that increased oxidative stress in neurons by deletion of mitochondrial ubiquitin ligase MITOL causes a potential neuroinflammation including aberrant astrogliosis and microglial activation, indicating that mitochondrial abnormalities might confer a risk for inflammatory diseases in brain such as psychiatric disorders. A role of MITOL in both mitochondrial dynamics and ER-mitochondria tethering prompted us to characterize three-dimensional structures of mitochondria in vivo. In MITOL-deficient neurons, we observed a significant reduction in the ER-mitochondria contact sites, which might lead to perturbation of phospholipids transfer, consequently reduce cardiolipin biogenesis. We also found that branched large mitochondria disappeared by deletion of MITOL. These morphological abnormalities of mitochondria resulted in enhanced oxidative stress in brain, which led to astrogliosis and microglial activation partly causing abnormal behavior. In conclusion, the reduced ER-mitochondria tethering and excessive mitochondrial fission may trigger neuroinflammation through oxidative stress.