Mitochondrial fusion and fission are critical to heart health; genetically interrupting either is rapidly lethal. To understand whether it is loss of, or the imbalance between, fusion and fission that underlies observed cardiac phenotypes, we engineered mice in which Mfn-mediated fusion and Drp1-mediated fission could be concomitantly abolished. Compared to fusion-defective Mfn1/Mfn2 cardiac knockout or fission-defective Drp1 cardiac knockout mice, Mfn1/Mfn2/Drp1 cardiac triple-knockout mice survived longer and manifested a unique pathological form of cardiac hypertrophy. Over time, however, combined abrogation of fission and fusion provoked massive progressive mitochondrial accumulation that severely distorted cardiomyocyte sarcomeric architecture. Mitochondrial biogenesis was not responsible for mitochondrial superabundance, whereas mitophagy was suppressed despite impaired mitochondrial proteostasis. Similar but milder defects were observed in aged hearts. Thus, cardiomyopathies linked to dynamic imbalance between fission and fusion are temporarily mitigated by forced mitochondrial adynamism at the cost of compromising mitochondrial quantity control and accelerating mitochondrial senescence.

中文翻译：

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小鼠心脏中线粒体动力学的减退加速线粒体衰老。

线粒体融合和裂变对心脏健康至关重要；基因上的任何一种中断都是致命的。为了了解所观察到的心脏表型是否是融合和裂变的丧失或失衡，我们设计了可以同时消除Mfn介导的融合和Drp1介导的裂变的小鼠。与融合缺陷型Mfn1 / Mfn2心脏基因敲除小鼠或裂变缺陷型Drp1心脏基因敲除小鼠相比，Mfn1 / Mfn2 / Drp1心脏三基因敲除小鼠存活时间更长，并且表现出心脏肥大的独特病理形式。然而，随着时间的流逝，裂变和融合的结合废除激起了大规模的线粒体累积，从而严重扭曲了心肌细胞的肌节结构。线粒体的生物发生与线粒体的丰度无关，尽管线粒体蛋白稳态受损，但线粒体被抑制。在老年心脏中观察到类似但较轻的缺损。因此，与强迫裂变和融合之间的动态失衡有关的心肌病可以通过强迫线粒体动态性来暂时缓解，其代价是损害线粒体的数量控制和加速线粒体衰老。