HSP60 chaperone deficiency disrupts the mitochondrial matrix proteome and dysregulates cholesterol synthesis

Mitochondrial proteostasis is critical for cellular function and survival. HSP60 is a molecular chaperone that interacts with more than 260 mitochondrial matrix proteins to assist in their folding and few genetic variants of HSP60 are compatible with life. The few reported human patients with HSP60 variants show phenotypes of neurodevelopmental delay associated with brain hypomyelination. It is currently unknown how deficiency of the HSP60 links to hypomyelination. Here, we studied the onset and progression of HSP60 deficiency in: (1) a HSP60 mutation-inducible cell system, (2) skin fibroblasts from patients with disease-associated HSP60 variants, and (3) zebrafish HSP60 knockout larvae. Collectively, we show how HSP60 deficiency leads to pervasive dysfunctions: (1) downregulated mitochondrial matrix proteome, (2) transcriptional activation of cytosolic stress responses, (3) and lipid accumulation with dysregulated cholesterol biosynthesis. In zebrafish larvae HSP60 deficiency induced early developmental abnormalities. Our comprehensive data identifies HSP60 as a master regulator of mitochondrial proteostasis and suggests a pivotal effect of HSP60 dysfunction on myelination through dysregulation of cholesterol biosynthesis.