High expression of nuclear factor 90 (NF90) leads to mitochondrial degradation in skeletal and cardiac muscles.
While NF90 has been known to participate in transcription, translation and microRNA biogenesis, physiological functions of this protein still remain unclear. To uncover this, we generated transgenic (Tg) mice using NF90 cDNA under the control of β-actin promoter. The NF90 Tg mice exhibited a reduction in body weight compared with wild-type mice, and a robust expression of NF90 was detected in skeletal muscle, heart and eye of the Tg mice. To evaluate the NF90 overexpression-induced physiological changes in the tissues, we performed a number of analyses including CT-analysis and hemodynamic test, revealing that the NF90 Tg mice developed skeletal muscular atrophy and heart failure. To explore causes of the abnormalities in the NF90 Tg mice, we performed histological and biochemical analyses for the skeletal and cardiac muscles of the Tg mice. Surprisingly, these analyses demonstrated that mitochondria in those muscular tissues of the Tg mice were degenerated by autophagy. To gain further insight into the cause for the mitochondrial degeneration, we identified NF90-associated factors by peptide mass fingerprinting. Of note, approximately half of the NF90-associated complexes were ribosome-related proteins. Interestingly, protein synthesis rate was significantly suppressed by high-expression of NF90. These observations suggest that NF90 would negatively regulate the function of ribosome via its interaction with the factors involved in the ribosome function. Furthermore, we found that the translations or protein stabilities of PGC-1 and NRF-1, which are critical transcription factors for expression of mitochondrial genes, were significantly depressed in the skeletal muscles of the NF90 Tg mice. Taken together, these findings suggest that the mitochondrial degeneration engaged in the skeletal muscle atrophy and the heart failure in the NF90 Tg mice may be caused by NF90-induced posttranscriptional repression of transcription factors such as PGC-1 and NRF-1 for regulating nuclear-encoded genes relevant to mitochondrial function.
Laboratory of Molecular Biology, Science Research Center, Kochi Medical School, Kochi, Japan.
Takuma
T
Higuchi
Shuji
S
Sakamoto
Yoshihiko
Y
Kakinuma
Shoko
S
Kai
Ken-Ichi
K
Yagyu
Hiroshi
H
Todaka
Eunsup
E
Chi
Shoshiro
S
Okada
Takako
T
Ujihara
Keiko
K
Morisawa
Masafumi
M
Ono
Yasunori
Y
Sugiyama
Waka
W
Ishida
Atsuki
A
Fukushima
Masayuki
M
Tsuda
Yasutoshi
Y
Agata
Taketoshi
T
Taniguchi
D000199:Actins / Q000235:genetics; D000818:Animals; D001343:Autophagy / Q000502:physiology*; D001794:Blood Pressure; D015153:Blotting, Western; D001835:Body Weight / Q000235:genetics; D018076:DNA, Complementary / Q000235:genetics; D005838:Genotype; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D063306:Mitophagy / Q000502:physiology*; D018482:Muscle, Skeletal / Q000378:metabolism*; D009133:Muscular Atrophy / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D050779:Nuclear Factor 90 Proteins / Q000235:genetics / Q000378:metabolism*; D051266:Nuclear Respiratory Factor 1 / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012269:Ribosomal Proteins / Q000378:metabolism; D014057:Tomography, X-Ray Computed; D014157:Transcription Factors / Q000378:metabolism
D000199:Actins; D018076:DNA, Complementary; C495634:Nrf1 protein, mouse; D050779:Nuclear Factor 90 Proteins; D051266:Nuclear Respiratory Factor 1; D012269:Ribosomal Proteins; D014157:Transcription Factors; C111264:peroxisome-proliferator-activated receptor-gamma coactivator-1