Mitochondrial associated molecule DPYSL4 regulates adipose function and tumor suppressor

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K08464
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54040:Metabolism and endocrinology-related
• Research Institution: Chiba University
• Principal Investigator: Nagano Hidekazu 千葉大学, 大学院医学研究院, 特任講師 (60788876)
• Co-Investigator(Kenkyū-buntansha): 田中 知明 千葉大学, 大学院医学研究院, 教授 (50447299)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: ミトコンドリア / 脂肪細胞 / 細胞内代謝 / 酸化的リン酸化

Outline of Final Research Achievements

Dihydropyrimidinase-like 4 (DPYSL4) has been identified a p53-inducible regulator of energy metabolism using RNA sequencing in both cancer cells and adipocytes. DPYSL4 was localized in the mitochondria in response to DNA damage or hypoxia. Mitochondria was subjected to 2-D BN/SDS-PAGE followed by immunoblotting. DPYSL4 was detected in the same vertical position as complexes I, III and IV. The knockdown of p53 or DPYSL4 by the CRISPR/Cas9 showed reduction in oxygen consumption rate (OCR) using flux analyzer in preadipocytes. A reduction of matrigel invasion correlates with OCR change in cancer cells. Additionally, immunohistology of adipose tissues demonstrated that p53 was upregulated in obese patients. This is concomitant with high expression of DPYSL4 mRNA in adipose of obese patients. Taken together, these data indicate that DPYSL4 has a tumor suppressor function associated with OXPHOS regulation and may be concerned with pathogenesis of cancer and obesity regulated under p53.

Free Research Field

代謝及び内分泌学

Academic Significance and Societal Importance of the Research Achievements

遺伝子の網羅的発現解析から同定したDPYSL4は、がん細胞と脂肪細胞に共通して認められる。この分子は、エネルギーの産生工場であるミトコンドリアの「呼吸鎖超複合体」と呼ばれる構造に働きかけることで、細胞のエネルギー・代謝調節作用を発揮したり、脂肪細胞の機能を制御する。また、細胞増殖に対して抑制的に働くことから、生活習慣病とがんに関わる重要な分子であることを明らかにした。