Mitochondrial lactate dehydrogenase regulator (MLDHR)

Mitochondrial lactate dehydrogenase regulator (MLDHR), also known as MP31 or PTEN upstream open reading frame, is a mitochondria-localized micropeptide encoded by a conserved upstream open reading frame in the 5′ untranslated region of the PTEN mRNA[2][3][4][5]. MP31/MLDHR acts as a regulatory “circuit breaker” for mitochondrial lactate metabolism: it limits the conversion of lactate to pyruvate by competing with mitochondrial lactate dehydrogenase B (LDHB) for NAD^+^, and thereby modulates mitochondrial oxidative phosphorylation and lactate utilization[2]. Loss of MLDHR increases oxidative phosphorylation and promotes lactate metabolism, which in astrocytes initiates gliomagenesis and accelerates tumor progression[2][6]. Reintroduction of the peptide in glioblastoma models inhibits tumor growth, disrupts mitochondrial quality control by impairing mitophagy and lysosomal function, induces reactive oxygen species, and sensitizes cells to chemotherapy (temozolomide), all without observable toxicity in normal cells[2][6]. This micropeptide is a recently discovered therapeutic candidate with tumor-suppressing roles, especially in glioblastoma, and represents a new class of non-canonical regulatory molecules derived from translated upstream open reading frames[2][6][8].

Other names

PTEN upstream open reading frame MP31MP31PTENURFMicropeptide 31

Inhibits mitochondrial lactate dehydrogenase B (LDHB) by competing for NAD^+^, acting as a metabolic "circuit breaker" to limit lactate-pyruvate conversion[2] Disrupts lysosomal function by interfering with V-ATPase A1 and LDHB interaction, leading to lysosomal alkalinization and impaired mitophagy[6]