期刊
JOURNAL OF BIOCHEMISTRY
卷 168, 期 3, 页码 305-312出版社
OXFORD UNIV PRESS
DOI: 10.1093/jb/mvaa050
关键词
dwarfism; growth hormone; mitochondrial ubiquitin ligase MITOL; Pit1; pituitary
资金
- MEXT/JSPS KAKENHI [16K08246, 17K08793, 18H04869, 17H04053]
- MEXT-Supported Program for the Strategic Research Foundation at Private Universities [S1411014]
- Tokyo Biochemical Research Foundation
- AMED [JP17gm5010002, 18gm5010002s1402, 19gm5010002h0003]
- Grants-in-Aid for Scientific Research [18H04869, 17H04053, 17K08793, 16K08246] Funding Source: KAKEN
In mitochondrial disorders, short stature and growth failure are common symptoms, but their underlying mechanism remains unknown. In this study, we examined the cause of growth failure of mice induced by nestin promoter-driven knockout of the mitochondrial ubiquitin ligase MITOL (MARCH5), a key regulator of mitochondrial function. MITOL-knockout mice have congenital hypoplasia of the anterior pituitary caused by decreased expression of pituitary transcript factor 1 (Pit1). Consistently, both mRNA levels of growth hormone (GH) and prolactin levels were markedly decreased in the anterior pituitary of mutant mice. Growth failure of mutant mice was partly rescued by hypodermic injection of recombinant GH. To clarify whether this abnormality was induced by the primary effect of MITOL knockdown in the anterior pituitary or a secondary effect of other lesions, we performed lentiviral-mediated knockdown of MITOL on cultured rat pituitary GH3 cells, which secrete GH. GH production was severely compromised in MITOL-knockdown GH3 cells. In conclusion, MITOL plays a critical role in the development of the anterior pituitary; therefore, mice with MITOL dysfunction exhibited pituitary dwarfism caused by anterior pituitary hypoplasia. Our findings suggest that mitochondrial dysfunction is commonly involved in the unknown pathogenesis of pituitary dwarfism.
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