De novoserine biosynthesis is protective in mitochondrial disease

Abstract

AbstractImportance of serine as a metabolic regulator is well known in tumors and raising attention also in degenerative diseases. Recent data indicate thatde novoserine biosynthesis is an integral component of metabolic response to mitochondrial disease, but the roles of the response have remained unknown. Here, we report that glucose-drivende novoserine biosynthesis maintains metabolic homeostasis in energetic stress. Pharmacological inhibition of the rate-limiting enzyme, phosphoglycerate dehydrogenase (PHGDH), aggravated mitochondrial muscle disease, suppressed oxidative phosphorylation and mitochondrial translation, altered whole-cell lipid profiles and enhanced mitochondrial integrated stress response (ISRmt),in vivo,in skeletal muscle and in cultured cells. Our evidence indicates thatde novoserine biosynthesis is essential to maintain mitochondrial respiration, redox balance, and cellular lipid homeostasis in skeletal muscle with mitochondrial dysfunction. Our evidence implies that interventions activatingde novoserine synthesis may protect against mitochondrial failure in the skeletal muscle.Bullet pointsSerine becomes an essential amino acid in mitochondrial translation defectsBlockingde novoserine biosynthesis promotes progression of mitochondrial diseaseDe novoserine biosynthesis maintains phospholipid homeostasis upon mitochondrial insultSerine biosynthesis sustains redox-balance and mitochondrial translation in disease