Mitochondrial ubiquitin ligase MITOL blocks S-nitrosylated MAP1B-light chain 1-mediated mitochondrial dysfunction and neuronal cell death.
Nitric oxide (NO) is implicated in neuronal cell survival. However, excessive NO production mediates neuronal cell death, in part via mitochondrial dysfunction. Here, we report that the mitochondrial ubiquitin ligase, MITOL, protects neuronal cells from mitochondrial damage caused by accumulation of S-nitrosylated microtubule-associated protein 1B-light chain 1 (LC1). S-nitrosylation of LC1 induces a conformational change that serves both to activate LC1 and to promote its ubiquination by MITOL, indicating that microtubule stabilization by LC1 is regulated through its interaction with MITOL. Excessive NO production can inhibit MITOL, and MITOL inhibition resulted in accumulation of S-nitrosylated LC1 following stimulation of NO production by calcimycin and N-methyl-D-aspartate. LC1 accumulation under these conditions resulted in mitochondrial dysfunction and neuronal cell death. Thus, the balance between LC1 activation by S-nitrosylation and down-regulation by MITOL is critical for neuronal cell survival. Our findings may contribute significantly to an understanding of the mechanisms of neurological diseases caused by nitrosative stress-mediated mitochondrial dysfunction.
Laboratory of Molecular Biochemistry, School of Life Sciences,  Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo 192-0392,  Japan.
Ryo
R
Yonashiro
Yuya
Y
Kimijima
Takuya
T
Shimura
Kohei
K
Kawaguchi
Toshifumi
T
Fukuda
Ryoko
R
Inatome
Shigeru
S
Yanagi
D016923:Cell Death; D006801:Humans; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D008928:Mitochondria / Q000201:enzymology* / Q000502:physiology; D024101:Mitochondrial Proteins / Q000378:metabolism*; D009474:Neurons / Q000166:cytology*; D009603:Nitroso Compounds / Q000378:metabolism; D059748:Proteolysis; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D054875:Ubiquitination
D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D024101:Mitochondrial Proteins; D009603:Nitroso Compounds; C085284:microtubule-associated protein 1B; C515578:MARCHF5 protein, human; D044767:Ubiquitin-Protein Ligases