PERM1基因治疗通过肌节—线粒体能量微域预防压力超负荷诱导的心力衰竭
PERM1 Gene Therapy Prevents Pressure Overload-induced Heart Failure Through a Sarcomere-Mitochondria Energetic Microdomain
Res Sq · 2026 年 9 月 14 日 · Junco Warren, Karthi Sreedevi, Abigail Doku 等 20 人
射血分数降低的心力衰竭（心脏泵血能力下降）目前缺少同时恢复心肌能量代谢和收缩功能的疗法。研究者用腺相关病毒（AAV，常用作基因递送载体）在小鼠心脏过表达PERM1（一种横纹肌特有的线粒体调控蛋白），观察到它能减轻压力超负荷引起的心功能下降、维持线粒体呼吸和形态、减少病理性心肌肥厚和纤维化，并增强肌原纤维产力。意外的是，这些保护作用并非通过恢复氧化磷酸化和脂肪酸氧化相关基因的转录实现，而是PERM1定位于线粒体—肌节微域，与核糖体蛋白及肌酸激酶—肌钙蛋白C复合物结合，抑制病理性O-GlcNAc修饰，在转录后水平维持电子传递链蛋白丰度。作者认为这确立了转录后代谢控制的新范式，并将PERM1定位为心衰治疗靶点。该研究为预印本，尚未经同行评审。
为什么推荐给您：发现PERM1转录后调控线粒体—肌节耦合的新机制，并验证基因治疗概念，但仅动物实验且为预印本。
不需要生物学背景，多打比方
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摘要Abstract
Heart failure with reduced ejection fraction (HFrEF) remains a major cause of morbidity and mortality worldwide, characterized by impaired contractile function and mitochondrial dysfunction, yet therapies that simultaneously restore cardiac energetics and mechanical performance remain limited. Here, we show that adeno-associated virus-mediated overexpression of PERM1 (AAV-PERM1), a striated muscle-specific mitochondrial regulator, prevents pressure overload-induced HFrEF through a non-transcriptional mechanism that preserves both mitochondrial function and contractility. AAV-PERM1 mitigated declines in mitochondrial respiration and mitochondrial DNA content, maintained mitochondrial morphology under pressure overload, and attenuated pathological hypertrophy and fibrosis. Unexpectedly, these cardioprotective effects occurred despite persistent suppression of oxidative phosphorylation and fatty acid oxidation transcripts. Instead, PERM1 localized to a mitochondria-sarcomere microdomain, where it associated with ribosomal proteins and a creatine kinase-troponin C complex, suppressed pathological O-GlcNAcylation, and post-transcriptionally preserved electron transport chain protein abundance. Functionally, PERM1 enhanced myofibrillar force generation. These findings identify a previously unrecognized mechanism by which PERM1 preserves mitochondrial protein homeostasis and couples energy production to force generation, establishing a new paradigm for post-transcriptional metabolic control and positioning PERM1 as a therapeutic target for heart failure.