Non-enzymatic Roles Of GLS1 In The Sensing Of Glutamine Availability And The Regulation Of Mitochondrial Fusion

Glutamine is considered as a conditional essential amino acid.Although mammalian cells could synthesize glutamine by transamination,additional exogenous glutamine is required for cells undergo vigorous metabolism to meet the needs of carbon and nitrogen sources.In light of the observation that many types of cancer exhibit a marked dependence of glutamine,the glutamine-related metabolic pathways have drawn a significant amount of attention as a potent target for cancer intervention.However,the cellular metabolic regulations and the underlying mechanisms under the conditions of glutamine deprivation remain unclear.Here,we show that glutaminase(GLS1),the first and rate-limiting enzyme in glutaminolysis,senses glutamine levels in a non-enzymatic manner and triggers mitochondrial fusion,which in turn restricts the cellular level of reactive oxygen species(ROS)and maintains cellular metabolic homeostasis.Glutamine per se,but not the other downstream products in glutamine metabolism,is directly sensed by GLS1.Our findings of the signal-transduction role of metabolic enzyme GLS1 will provide insights into the regulatory mechanisms of mitochondrial morphology and open new avenues for therapeutic intervention of cancer and the other diseases related with mitochondrial disorders.