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Basonuclin 1 (BNC1) is a transcription factor mainly expressed in proliferative keratinocytes and germ cells. A frameshift mutation of BNC1 was identified in a large Chinese primary ovarian insufficiency pedigree. The expression of BNC1 was significantly decreased in the testis biopsies of infertile patients with nonobstructive azoospermia. Previous studies have revealed that mice with BNC1 deficiency are generally subfertile and undergo gradual spermatogenic failure. We observed that apoptosis of spermatogonia is tightly related to spermatogenic failure in mice with a Bnc1 truncation mutation. Such impairment is related to mitochondrial dysfunction causing lower mitochondrial membrane potential and higher reactive oxygen species. We showed that downregulation of CREB\/SIRT1\/FOXO3 signaling participates in the above impairment. Administration of nicotinamide riboside or metformin reversed mitochondrial dysfunction and inhibited apoptosis in Bnc1-knockdown spermatogonia by stimulating CREB\/SIRT1\/FOXO3 signaling. Dietary supplementation with nicotinamide riboside or metformin in mutated mice increased SIRT1 signaling, improved the architecture of spermatogenic tubules, inhibited apoptosis of the testis, and improved the fertility of mice with a Bnc1 truncation mutation. Our data establish that oral nicotinamide riboside or metformin can be useful for the treatment of spermatogenic failure induced by Bnc1 mutation.<\/jats:p>","DOI":"10.1093\/biolre\/ioad168","type":"journal-article","created":{"date-parts":[[2023,12,7]],"date-time":"2023-12-07T10:22:16Z","timestamp":1701944536000},"page":"615-631","source":"Crossref","is-referenced-by-count":10,"title":["BNC1 deficiency induces mitochondrial dysfunction-triggered spermatogonia apoptosis through the CREB\/SIRT1\/FOXO3 pathway: the therapeutic potential of nicotinamide riboside and metformin"],"prefix":"10.1093","volume":"110","author":[{"given":"Feida","family":"Ni","sequence":"first","affiliation":[{"name":"Key Laboratory of Reproductive Genetics (Ministry of Education) , Department of Reproductive Endocrinology, , Hangzhou, Zhejiang , China"},{"name":"Women\u2019s Hospital, Zhejiang University School of Medicine , Department of Reproductive Endocrinology, , Hangzhou, Zhejiang , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feixia","family":"Wang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Reproductive Genetics (Ministry of Education) , Department of Reproductive Endocrinology, , Hangzhou, Zhejiang , China"},{"name":"Women\u2019s Hospital, Zhejiang University School of Medicine , Department of Reproductive Endocrinology, , Hangzhou, Zhejiang , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingyi","family":"Li","sequence":"additional","affiliation":[{"name":"Key Laboratory of Reproductive Genetics (Ministry of Education) , Department of Reproductive Endocrinology, , Hangzhou, Zhejiang , China"},{"name":"Women\u2019s Hospital, Zhejiang University School of Medicine , Department of Reproductive Endocrinology, , Hangzhou, Zhejiang , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yifeng","family":"Liu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Reproductive Genetics (Ministry of Education) , Department of Reproductive Endocrinology, , Hangzhou, Zhejiang , China"},{"name":"Women\u2019s Hospital, Zhejiang University School of Medicine , Department of Reproductive Endocrinology, , Hangzhou, Zhejiang , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao","family":"Sun","sequence":"additional","affiliation":[{"name":"Key Laboratory of Reproductive Genetics (Ministry of Education) , Department of Reproductive Endocrinology, , Hangzhou, Zhejiang , China"},{"name":"Women\u2019s Hospital, Zhejiang University School of Medicine , Department of Reproductive Endocrinology, , Hangzhou, Zhejiang , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianpeng","family":"Chen","sequence":"additional","affiliation":[{"name":"Key Laboratory of Reproductive Genetics (Ministry of Education) , Department of Reproductive Endocrinology, , Hangzhou, Zhejiang , China"},{"name":"Women\u2019s Hospital, Zhejiang University School of Medicine , Department of Reproductive Endocrinology, , Hangzhou, Zhejiang , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaqun","family":"Li","sequence":"additional","affiliation":[{"name":"Key Laboratory of Reproductive Genetics (Ministry of Education) , Department of Reproductive Endocrinology, , Hangzhou, Zhejiang , China"},{"name":"Women\u2019s Hospital, Zhejiang University School of Medicine , Department of Reproductive Endocrinology, , Hangzhou, Zhejiang , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanye","family":"Zhang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Reproductive Genetics (Ministry of Education) , Department of Reproductive Endocrinology, , Hangzhou, Zhejiang , China"},{"name":"Women\u2019s Hospital, Zhejiang University School of Medicine , Department of Reproductive Endocrinology, , Hangzhou, Zhejiang , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiani","family":"Jin","sequence":"additional","affiliation":[{"name":"Key Laboratory of Reproductive Genetics (Ministry of Education) , Department of Reproductive Endocrinology, , Hangzhou, Zhejiang , China"},{"name":"Women\u2019s Hospital, Zhejiang University School of Medicine , Department of Reproductive Endocrinology, , Hangzhou, Zhejiang , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaohang","family":"Ye","sequence":"additional","affiliation":[{"name":"Key Laboratory of Reproductive Genetics (Ministry of Education) , Department of Reproductive Endocrinology, , Hangzhou, Zhejiang , China"},{"name":"Women\u2019s Hospital, Zhejiang University School of Medicine , Department of Reproductive Endocrinology, , Hangzhou, Zhejiang , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mixue","family":"Tu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Reproductive Genetics (Ministry of Education) , Department of Reproductive Endocrinology, , Hangzhou, Zhejiang , China"},{"name":"Women\u2019s Hospital, Zhejiang University School of Medicine , Department of Reproductive Endocrinology, , Hangzhou, Zhejiang , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianhua","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Pathology, Women\u2019s Hospital, Zhejiang University School of Medicine , Hangzhou, Zhejiang , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chuan","family":"Chen","sequence":"additional","affiliation":[{"name":"Key Laboratory of Reproductive Genetics (Ministry of Education) , Department of Reproductive Endocrinology, , Hangzhou, Zhejiang , China"},{"name":"Women\u2019s Hospital, Zhejiang University School of Medicine , Department of Reproductive Endocrinology, , Hangzhou, Zhejiang , 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