Analysis of mitochondrial DNA as a cause of cancer-derived myocardial damage

• Project/Area Number: 20K11260
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 59010:Rehabilitation science-related
• Research Institution: Nara Medical University
• Principal Investigator: Ohmori Hitoshi 奈良県立医科大学, 医学部, 研究員 (80213875)
• Co-Investigator(Kenkyū-buntansha): 國安 弘基 奈良県立医科大学, 医学部, 教授 (00253055)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2022: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2021: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: がん性心筋障害 / DAMP / ミトコンドリアDNA / Covid-19 / HMGB1 / がん性悪液質 / 中鎖脂肪酸 / ケトン体 / サイトカイン / ミトコンドリア / エネルギー代謝障害 / がん性心筋悪液質 / 心筋分化 / 酸化ストレス / がん / 悪液質 / 心筋障害

Outline of Research at the Start

近年、がん患者の死因として心機能障害が重視されているが、申請者はその原因として癌に由来する変性産物であるDAMPが心筋障害をもたらすことを見出した。さらに、そのDAMPの中でもミトコンドリアDNAが心筋の炎症性サイトカイン産生を促進し無菌性炎症を惹起したが、ミトコンドリアDNAに炎症を惹起する特異的な配列が存在する可能性が示唆された。本研究では、このDAMPコンセンサスとも考えられる配列を解明し、がん性心筋障害の診断マーカーに、さらに、治療標的として応用可能にする基礎的知見を得ることを目的とする。本研究の結果は、がん性心筋障害の機序を解明し、予防・治療を可能にすると期待される。

Outline of Final Research Achievements

Among the mitochondrial DNA, a fragment of Complex V showed growth inhibition in rat cardiomyoblasts. Furthermore, we found a fragment with homology to Covid-19 in the Complex V gene sequence. This fragment, in the form of double-stranded DNA, impaired cellular function by inducing HMGB1 expression, oxidative stress and decreased ATP production. Furthermore, this fragment was detected in the blood of a rat model of cancer cachexia. These findings suggest that this Covid-19 homologous mitochondrial DNA fragment plays an important role in myocardial damage in cancer cachexia.

Academic Significance and Societal Importance of the Research Achievements

がん患者における心筋障害は、患者予後を増悪する重要な因子であったが、その発生機序は不明な点が多かった。本研究では、ミトコンドリアDNAの中でもコンプレックスVに存在するCovid-19と相同性を有する配列が、心筋障害に有用な役割を果たすことを見出した。この結果は、がん性悪液質のみならず、コロナ感染症やその他のDAMPに関連する心筋障害において、診断や治療の標的となる物質の同定の可能性を示唆するもので、その意義は大きい。

Research Products

• [Int'l Joint Research] Nantong university(中国)
• [Int'l Joint Research] Saveetha Dental College(インド)
• [Int'l Joint Research] 南通大学(中国)
• [Int'l Joint Research] 南通大学(中国)
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• [Journal Article] BRAF Mutation Is Associated with Hyperplastic Polyp-Associated Gastric Cancer (2021)
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• [Presentation] Effect of nutritional intervention with medium-chain fatty acids and glucose on cancer-derived myocardial atrophy. (2021)
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• [Presentation] がん悪液質における心筋ミトコンドリア機能障害に対する中鎖脂肪酸の影響 (2020)
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  • Organizer: 第109回日本病理学会総会
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  • Organizer: 第109回日本病理学会総会
• [Presentation] Effects of medium-chain fatty acids on cancer-derived myocardial atrophy (2020)
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• [Remarks] 奈良県立医科大学分子病理学講座
  • URL: http://www.naramed-u.ac.jp/~molepath/
• [Remarks] 奈良県立医科大学分子病理学
  • URL: http://www.naramed-u.ac.jp/~molepath/