CLPX (caseinolytic mitochondrial matrix peptidase chaperone subunit X) is an ATP-dependent AAA+ unfoldase that functions as the catalytic subunit of the ClpXP protease complex 1. As part of ClpXP, CLPX recognizes protein substrates, unfolds them using ATP hydrolysis energy, and translocates them to the CLPP peptidase subunit for degradation 2. CLPX exhibits substrate specificity through variable contacts with substrate degrons and can process diverse protein topologies including multi-chain substrates 2. Beyond proteolysis, CLPX functions as a chaperone in heme biosynthesis by activating δ-aminolevulinate synthase (ALAS), the rate-limiting enzyme in heme synthesis, through pyridoxal phosphate cofactor incorporation 3. CLPX also regulates mitochondrial nucleoid organization by modulating mitochondrial transcription factor A (TFAM) activity 1. Clinically, CLPX mutations cause erythropoietic protoporphyria type 2 (EPP2), characterized by protoporphyrin IX accumulation 3. Dominant mutations in CLPX's ATPase domain (p.Gly298Asp) inactivate ATP hydrolysis, reducing enzyme activity and increasing ALAS protein stability, leading to excessive heme intermediate accumulation and photosensitivity 3. CLPX dysfunction also impairs heavy metal homeostasis 1, underscoring its role in maintaining mitochondrial proteostasis and metabolic regulation.