Molecular mechanisms of mitochondrial autophagy in the ischemic heart

2023 Fiscal Year Final Research Report

• Project/Area Number: 19K17601
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53020:Cardiology-related
• Research Institution: Wakayama Medical University (2022-2023); Yamaguchi University (2019-2021)
• Principal Investigator: Toshiro Saito 和歌山県立医科大学, 医学部, 博士研究員 (60648484)
• Project Period (FY): 2019-04-01 – 2024-03-31
• Keywords: 心筋虚血 / ミトコンドリア / マイトファジー / オートファジー

Outline of Final Research Achievements

Despite the great advance in recent medical science, numerous patients are still suffering from highly morbid and disabling conditions. Heart failure, a final common state for cardiovascular disease, manifests multiple disorders that exacerbate others (e.g. mitochondrial abnormality, alteration in metabolism, etc.). Accordingly, it appears difficult to identify the ideal target therein to therapeutically intervene. Mitochondrial quality control may be a good candidate for the target.
This study shows that autophagy characterized by Ulk1-dependent and Rab9-positive autophagosomes, distinct from that characterized by LC3-positive autophagosomes, predominantly mediates mitophagy and is responsible for the mitochondrial quality in the heart. Energy stress induces a multi-protein complex consisting of Ulk1, Rab9, Rip1, and Drp1, which recruits late endosome associated with Rab9 to damaged mitochondria through the coordinated actions of Rab9 and Drp1.

Free Research Field

循環器内科学

Academic Significance and Societal Importance of the Research Achievements

超高齢社会の本邦で慢性心不全は主要な死因である。原疾患として虚血性心疾患の割合が増加している。迅速な血行再建により救命される急性冠症候群の症例は増加したが、心筋障害が大きく、慢性心不全への移行も増加した。従って、血行再建に加えて心筋を保護する新たな治療標的が望まれる。
本研究は心臓のマイトファジーがその治療標的に成り得る可能性を示した。今後は如何にしてマイトファジーを制御するかを検討していく。