TY - JOUR TI - Skd3 (human ClpB) is a potent mitochondrial protein disaggregase that is inactivated by 3-methylglutaconic aciduria-linked mutations AU - Cupo, Ryan R AU - Shorter, James A2 - Zoghbi, Huda Y A2 - Berger, James M A2 - Glynn, Steven VL - 9 PY - 2020 DA - 2020/06/23 SP - e55279 C1 - eLife 2020;9:e55279 DO - 10.7554/eLife.55279 UR - https://doi.org/10.7554/eLife.55279 AB - Cells have evolved specialized protein disaggregases to reverse toxic protein aggregation and restore protein functionality. In nonmetazoan eukaryotes, the AAA+ disaggregase Hsp78 resolubilizes and reactivates proteins in mitochondria. Curiously, metazoa lack Hsp78. Hence, whether metazoan mitochondria reactivate aggregated proteins is unknown. Here, we establish that a mitochondrial AAA+ protein, Skd3 (human ClpB), couples ATP hydrolysis to protein disaggregation and reactivation. The Skd3 ankyrin-repeat domain combines with conserved AAA+ elements to enable stand-alone disaggregase activity. A mitochondrial inner-membrane protease, PARL, removes an autoinhibitory peptide from Skd3 to greatly enhance disaggregase activity. Indeed, PARL-activated Skd3 solubilizes α-synuclein fibrils connected to Parkinson’s disease. Human cells lacking Skd3 exhibit reduced solubility of various mitochondrial proteins, including anti-apoptotic Hax1. Importantly, Skd3 variants linked to 3-methylglutaconic aciduria, a severe mitochondrial disorder, display diminished disaggregase activity (but not always reduced ATPase activity), which predicts disease severity. Thus, Skd3 is a potent protein disaggregase critical for human health. KW - disaggregase KW - AAA+ protein KW - protein misfolding KW - Skd3 KW - Hsp78 KW - Hsp104 JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -