Data AHA_CDA.xlsx

Mitochondria are the foremost player in ischemia-reperfusion (I/R) injury, which is one of the major contributors to myocardial infarction. Although current therapeutic options provide symptomatic relief, they fail to restore cardiomyocyte function, which represents a key roadblock in the treatment of reperfusion injury. Therefore, the ability to target mitochondrial pathways will likely provide a means to restore cardiomyocyte function, resulting in an effective and enhanced efficacy treatment. Efficient mitochondrial matrix protein quality control (mPQC) by LONP1 is crucial for cardiac bioenergetics. We compared young adult mice with cardiomyocyte-specific (Lonp1CKO-HET) or whole-body (Lonp1GKO-HET) haploinsufficiency and evaluated mitochondrial dynamics, including mitophagy markers, biogenesis markers, and mitochondrial stress markers. Despite similar cardiac Lonp1 reductions, only Lonp1CKO-HET mice showed mild dysfunction with mitochondrial stress response activation, altered dynamics, reduced biogenesis, and Tfam upregulation. Lonp1GKO-HET hearts lacked these changes, suggesting systemic mPQC deficiency can protect the heart via inter-organ signaling, a potential therapeutic strategy.

线粒体是缺血再灌注（ischemia-reperfusion, I/R）损伤的核心介导因子，而该损伤是心肌梗死（myocardial infarction）的主要致病因素之一。当前的治疗手段仅能实现症状缓解，却无法恢复心肌细胞功能，这成为了再灌注损伤治疗的关键瓶颈。因此，靶向线粒体通路的策略有望成为恢复心肌细胞功能的有效途径，从而提供疗效更优的治疗方案。

LONP1介导的高效线粒体基质蛋白质量控制（mitochondrial matrix protein quality control, mPQC）对心脏能量代谢至关重要。本研究将成年年轻小鼠分为心肌细胞特异性（Lonp1CKO-HET）单倍体不足组与全身型（Lonp1GKO-HET）单倍体不足组，并评估了线粒体动力学（mitochondrial dynamics）相关指标，包括线粒体自噬（mitophagy）标记物、生物发生（biogenesis）标记物及线粒体应激标记物（mitochondrial stress markers）。

尽管两组小鼠的心脏LONP1表达降幅相近，但仅Lonp1CKO-HET小鼠出现了轻度心功能异常，伴随线粒体应激反应激活、线粒体动力学改变、生物发生能力下降及Tfam表达上调。而Lonp1GKO-HET小鼠的心脏未出现上述变化，这提示全身性mPQC缺陷可通过器官间信号传导发挥心脏保护作用，为再灌注损伤的治疗提供了潜在策略。