Protein disaggregases are important enzymes that reverse toxic protein aggregation in cells. Protein disaggregases are conserved across many species and are present in the cytoplasm, nucleus, chloroplast, and mitochondrion. In yeast the AAA+ protein, Hsp78, powers protein disaggregation within mitochondria. Curiously, Hsp78 is not found in metazoa. Thus, a major open question for the field is whether metazoan mitochondria can reactivate aggregated proteins. Here I describe Skd3 (CLPB) as the missing human mitochondrial protein disaggregase. Specifically, I identify Skd3 as a protein disaggregase. I show that PARL, a rhomboid protease embedded in the inner mitochondrial membrane, removes an autoinhibitory peptide to unleash Skd3 disaggregase activity by ~10-fold. I also show that Skd3 has chaperone activity in human cells and identify the endogenous substrates of Skd3. I demonstrate that Skd3 disaggregase activity (and not ATPase activity) predicts the clinical severity of 3-methylglutaconic aciduria (MGCA7) linked CLPB mutations. I show that newly discovered severe congenital neutropenia (SCN) mutations in Skd3 are dominant negative for both ATPase activity and disaggregase activity. I describe key structural and mechanistic details of Skd3 function and identify fundamental mechanistic differences in how MGCA7-linked and SCN-linked mutations affect Skd3 activity. These mechanistic differences underlie why MGCA7 mutations are generally bi-allelic and SCN mutations are dominant negative. These results suggest that protein replacement-based therapies may be a successful treatment strategy of CLPB MGCA7 mutations, but that eliminating the mutant protein is the only potential treatment option for treating CLPB SCN mutations. Overall, my work has identified a new hub of mitochondrial protein quality control that impinges upon mitochondrial morphology, mitochondrial cell death pathways, and most importantly, mitochondrial respiration. Discovering the cellular function of Skd3 opens possibilities for treatment of both neurodegenerative diseases where mitochondrial function goes awry and cancers where hyperactive mitochondria fuel aberrant cell growth.