Distinct types of intramitochondrial protein aggregates protect mitochondria against proteotoxic stress - Data Set3: VAR1 AP-MS

Mitochondria consist of hundreds of proteins, most of which are long-lived and inaccessible to the proteasomal quality control system of the cytosol. How cells stabilize the mitochondrial proteome during challenging conditions is poorly understood. Here we show that mitochondria form spatially defined protein aggregates as a stress-protecting mechanism. Thereby different types of intramitochondrial protein aggregates can be distinguished. The mitoribosomal protein Var1 (uS3m) undergoes a stress-induced transition from a soluble, chaperone-stabilized protein that is prevalent under benign conditions to an insoluble aggregated form upon acute stress. The formation of Var1 bodies stabilizes mitochondrial proteostasis presumably by sequestration of aggregation-prone proteins. The AAA chaperone Hsp78 associates with a different type of intramitochondrial aggregate. These Hsp78-bound aggregates sequester non-native matrix proteins to promote their subsequent folding or Pim1-mediated degradation. Our study shows that mitochondrial proteins actively control the formation of different types of intramitochondrial protein aggregates which actively cooperate to stabilize the mitochondrial proteome during proteotoxic stress conditions.

线粒体含有数百种蛋白质，其中大多数寿命较长，且难以被细胞质的蛋白酶体质量控制系统（proteasomal quality control system）识别并清除。细胞在应激条件下如何稳定线粒体蛋白质组（mitochondrial proteome），目前尚不完全明确。本研究发现，线粒体可形成具有空间特异性的蛋白质聚集体，以此作为应激保护机制。据此可区分两类不同的线粒体内蛋白质聚集体：线粒体核糖体蛋白Var1（uS3m）会发生应激诱导的构象转变——在正常生理条件下，它以可溶、分子伴侣稳定的形式存在；而在急性应激时，会转变为不溶性的聚集形式。Var1聚集体（Var1 bodies）的形成推测可通过捕获易聚集蛋白质，从而稳定线粒体蛋白质稳态（proteostasis）。AAA分子伴侣（AAA chaperone）Hsp78则与另一类线粒体内聚集体结合，这类聚集体会捕获非天然状态的线粒体基质蛋白，以促进其后续折叠或通过Pim1介导的降解途径被清除。本研究表明，线粒体蛋白质可主动调控不同类型线粒体内蛋白质聚集体的形成，这些聚集体协同发挥作用，在蛋白毒性应激（proteotoxic stress）条件下稳定线粒体蛋白质组。