Dr Shen Qing

Temasek Life Sciences Laboratory Limited

• Abstract:Ferroptosis, an iron-dependent demise driven by lethal levels of intracellular lipid peroxides, precisely regulates cell death in spores or conidia of the fungal pathogen Magnaporthe oryzae, and subsequently determines its ability to cause the destructive blast disease in rice. Despite its importance, little is known about the molecular mechanisms underlying such developmental cell death in fungi. Here, through gene deletion(s) or pharmacological inhibition, we establish a specific functional correlation between ferroptosis and mitochondrial degradation via mitophagy. The requirement of mitophagy for accumulation of lipid peroxides and thus ferroptosis was further attributed to its ability to maintain a pool of metabolically active mitochondria. Disrupting the electron transport chain or decreasing the mitochondrial membrane potential caused mitochondrial fusion and inhibited ferroptosis, thus simulating the loss of mitophagy phenotypes. Graded inhibition of Coenzyme Q (CoQ) biosynthesis in the presence or absence of the lipophilic antioxidant Liproxstation-1 further distinguished the antioxidant function of CoQ from its roles in electron carrier and membrane potential. Such membrane potential-dependent regulation of cellular iron homeostasis and ATP synthesis further linked mitochondrial metabolism to ferroptosis. Rather surprisingly, loss of mitochondrial -oxidation of fatty acids for acetyl-CoA generation, had no effect on mitochondrial membrane potential and ferroptosis in conidial cells. Therefore, metabolically active mitochondria capable of undergoing precise mitophagy are necessary for fungal ferroptosis. Together, results here reveal a novel mitochondrial regulon for ferroptosis, occurrence of which enables M. oryzae in timely establishment and spread of the devastating blast disease in rice.