The mitochondrial chaperone HSPD1 folds MTHFD2 independently of its co-chaperone HSPE1

ABSTRACT: Acquiring new cellular states entails metabolic reprogramming driven by adjustments to the expression of metabolic enzymes in the cytosol and mitochondria. Most mitochondrial proteins are synthesized in the cytosol and imported into the mitochondria in a linear form, after which they are folded by a network of mitochondrial chaperones and co-chaperones. Which mitochondrial protein is dependent upon which chaperone for its folding is largely unknown. HSPD1/HSPE1 (HSP60/HSP10) are evolutionarily conserved mammalian homologues of bacterial proteins GroEL/GroES, forming a chamber and lid chaperonin to facilitate folding of their client proteins. We used gene knockdown and SILAC-based proteomics to identify HSPD1 client proteins. We found that HSPD1 supports the expression of MTHFD2, a key mitochondrial one-carbon (1C) enzyme, in vivo and folds MTHFD2 in vitro, independently of its co-chaperone HSPE1. HSPD1 interacts with MTHFD2 in mitochondria, and MTHFD2 is degraded by LONP in HSPD1 knockdown cells. Consequently, we found reduced nucleotide and SAM levels in HSPD1 knockdown and found little overlap in the transcriptional or metabolic response to HSPD1 vs. HSPE1 depletion. Our data support that specific chaperones cater to the folding of specific proteins in the mitochondria and that HSPD1 and HSPE1 have distinct biological functions.

ORGANISM(S): Homo sapiens

PROVIDER: GSE303582 | GEO | 2026/10/07

REPOSITORIES: GEO