Lamin Mutations Accelerate Aging via Defective Export of Mitochondrial mRNAs through Nuclear Envelope Budding.
Lamin Mutations Accelerate Aging via Defective Export of Mitochondrial mRNAs through Nuclear Envelope Budding.
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DOI：
10.1016/j.cub.2016.06.007
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发表时间：
2016-08-08
期刊：
影响因子：
--
通讯作者：
Budnik V
中科院分区：
文献类型：
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作者：
Li Y;Hassinger L;Thomson T;Ding B;Ashley J;Hassinger W;Budnik V
RNA代谢和转运缺陷与衰老和退化有关，但其潜在机制仍知之甚少。衰老的一个普遍特征是线粒体退化。在这里，我们链接到一个新的机制，通过核膜（NE）出芽，需要A型核纤层蛋白，一种内核膜相关蛋白，以加速衰老观察果蝇LaminC（LamC）突变的RNA出口。这些LamC突变是在A-核纤层蛋白（LMNA）突变导致人类早老综合征（PS）后建模的。我们确定了线粒体组装调节因子（marf），线粒体融合因子（mitofusin），以及线粒体完整性和功能所需的其他转录本，在筛选通过NE-出芽退出细胞核的RNA。PS模型的LamC突变诱导成年飞行肌肉过早衰老，包括特定线粒体蛋白转录物（RNA）水平降低和线粒体降解进行性。PS模型的LamC突变也诱导了与衰老相关的其他表型的加速出现，包括多聚泛素聚集体的进行性积累和肌原纤维解体。与这些观察结果一致，突变体具有渐进的跳跃和飞行缺陷。单独下调marf可诱导上述衰老缺陷。然而，恢复marf不足以挽救PS模型LamC突变中的衰老表型，因为其他线粒体RNA受到NE出芽抑制的影响。NE-出芽的显性和隐性PS模型LamC突变的分析表明，异常的叶片组织通过NE-出芽阻止这些RNA的出口的机制。这些研究将通过NE出芽的RNA输出缺陷与线粒体完整性的进行性丧失和过早衰老联系起来。Li等人将核膜（NE）出芽输出途径与A型核纤层蛋白突变诱导的早衰综合征的果蝇模型中的过早衰老联系起来。他们在NE出芽位点发现了线粒体RNA，如Mitofusin，并表明成年前NE出芽的破坏导致成年人加速衰老和线粒体变性。
Defective RNA metabolism and transport are implicated in aging and degeneration, but the underlying mechanisms remain poorly understood. A prevalent feature of aging is mitochondrial deterioration. Here we link a novel mechanism for RNA export through nuclear envelope (NE) budding that requires A-type Lamin, an inner nuclear membrane-associated protein, to accelerated aging observed in Drosophila LaminC (LamC) mutations. These LamC mutations were modeled after A-Lamin (LMNA) mutations causing progeroid syndromes (PS) in humans. We identified mitochondrial assembly regulatory factor (marf), a mitochondrial fusion factor (mitofusin), as well as other transcripts required for mitochondrial integrity and function, in a screen for RNAs that exit the nucleus through NE-budding. PS-modeled LamC mutations induced premature aging in adult flight muscles, including decreased levels of specific mitochondrial protein transcripts (RNA) and progressive mitochondrial degradation. PS-modeled LamC mutations also induced the accelerated appearance of other phenotypes associated with aging, including a progressive accumulation of poly-ubiquitin aggregates and myofibril disorganization. Consistent with these observations, the mutants had progressive jumping and flight defects. Downregulating marf alone induced the above aging defects. Nevertheless, restoring marf was insufficient for rescuing the aging phenotypes in PS-modeled LamC mutations, as other mitochondrial RNAs are affected by inhibition of NE-budding. Analysis of NE-budding in dominant and recessive PS-modeled LamC mutations suggests a mechanism by which abnormal lamina organization prevents the egress of these RNAs via NE-budding. These studies connect defects in RNA export through NE-budding to progressive loss of mitochondrial integrity and premature aging. Li et al. link the nuclear envelope (NE) budding export pathway to premature aging in fly models of progeroid syndromes induced by A-type lamin mutations. They find mitochondrial RNAs, such as Mitofusin, at NE budding sites and show that disruption of NE budding prior to adulthood results in accelerated aging and mitochondrial degeneration in adults.