Methylation-controlled J protein (MCJ) (MCJ)

Methylation-controlled J protein (MCJ), also known as DNAJC15, is a small mitochondrial resident protein that acts as a negative regulator of the mitochondrial respiratory chain, specifically inhibiting Complex I (UniProt: Q9Y677). By limiting mitochondrial respiration and ATP production, MCJ plays a critical role in metabolic homeostasis and energy expenditure (PubMed: 24631837). In metabolic diseases such as metabolic dysfunction-associated steatohepatitis (MASH), MCJ is often upregulated, leading to decreased fatty acid oxidation and increased lipid accumulation in the liver (PubMed: 31167900). Conversely, in various cancers, the MCJ gene is frequently silenced by promoter methylation, and its absence is linked to increased mitochondrial activity and resistance to chemotherapeutic agents like cisplatin (PubMed: 11507054). Therapeutic strategies, such as the RNA interference (RNAi) candidate ARO-MCJ, aim to silence MCJ expression to enhance mitochondrial activity and promote the clearance of hepatic fat (Arrowhead Pharmaceuticals). This approach represents a novel mechanism for treating metabolic disorders by effectively "unleashing" mitochondrial capacity.

Other names

DnaJ homolog subfamily C member 15DNAJC15DnaJ protein MCJ

RNA interference (RNAi) mediated silencing of the DNAJC15 gene to reduce MCJ protein levels, thereby increasing mitochondrial Complex I activity and fatty acid oxidation.