The loss of protein homeostasis (proteostasis) is a primary driver of age-related tissue dysfunction. Recent studies have revealed that the failure of proteostasis with age is triggered by developmental and reproductive cues that repress the activity of proteostasis-related pathways in early adulthood. In Caenorhabditis elegans, reduced mitochondrial electron transport chain (ETC) function during development can override signals that promote proteostasis collapse in aged tissues. However, it is unclear precisely how these beneficial effects are mediated. Here, we reveal that in response to ETC impairment, the PP2A complex generates a dephosphorylated, mitochondrial stress-specific variant of the transcription factor HSF-1. This results in the selective induction of small heat shock proteins in adulthood, thereby protecting against age-related proteostasis collapse. We propose that mitochondrial signals early in life can protect the aging cytosolic proteome by tailoring HSF-1 activity to preferentially drive the expression of non-ATP-dependent chaperones.

蛋白质稳态（蛋白稳态）的丧失是与年龄有关的组织功能障碍的主要驱动力。最近的研究表明，随着年龄增长，蛋白稳态失灵是由发育和生殖线索触发的，这些线索抑制了成年早期与蛋白稳态相关的通路的活动。在秀丽隐杆线虫中，在发育过程中降低的线粒体电子传输链（ETC）功能可能会覆盖促进蛋白质在老年人组织中塌陷的信号。但是，目前尚不清楚这些有益作用是如何介导的。在这里，我们揭示了对ETC损伤的响应，PP2A复合物产生了转录因子HSF-1的去磷酸化，线粒体应激特异性变体。这导致成年期小的热激蛋白的选择性诱导，从而防止与年龄有关的蛋白稳态崩溃。我们建议线粒体信号在生命的早期可以通过调整HSF-1活性来优先驱动非ATP依赖性伴侣的表达，从而保护衰老的细胞质蛋白质组。