PYROXD2 is a mitochondrial oxidoreductase localized to the inner membrane/matrix that plays a critical regulatory role in mitochondrial function and cellular metabolism. The protein is imported via the Tom40 and Tim23 translocase complex and interacts with respiratory complex IV subunit COX5B 1. PYROXD2 regulates multiple aspects of mitochondrial homeostasis: knockout studies demonstrate it controls mitochondrial membrane potential, ATP production, mtDNA copy number, and complex IV activity while suppressing mitochondrial ROS and immature mitochondria accumulation 1. Biallelic PYROXD2 variants cause severe mitochondrial dysfunction characterized by heightened metabolic stress sensitivity, increased superoxide production, and reduced respiratory chain complex I and ribosomal subunit levels, manifesting as childhood mitochondrial disease with Leigh syndrome-like features 2. PYROXD2 expression is transcriptionally regulated by the myeloid zinc finger 1 (MZF1) transcription factor binding to its promoter 3. Clinically, PYROXD2 is downregulated in hepatocellular carcinoma and serves as a prognostic biomarker in esophageal squamous cell carcinoma when included in multi-gene signatures predicting patient survival 4. Genome-wide metabolomic studies confirm PYROXD2 as a genetic determinant of plasma methyl lysine and other metabolite levels 56. Together, these findings establish PYROXD2 as essential for mitochondrial bioenergetics and redox homeostasis with important implications for both cancer and mitochondrial disease.