Valerian E. Kagan, PhD, DSc

Professor and Vice Chairman
Department of Environmental and Occupational Health
University of Pittsburgh, Pittsburgh, PA

 image of Dr. Valerian Kagan
Abstract: The reliability of biological processes is achieved, to a large extent, through the initial generation of excessive amounts of biological material, including organelles and cells, which upon successful completion of their specific functions become unnecessary. Removal of the unnecessary in a timely manner is essential to prevent the unnecessary from becoming undesired or even harmful. This principle applies to the elimination of damaged unnecessary organells and cells. While mitophagy is a pro-survival rescue pathway, the continued accumulation of mitochondrial impairments and the insufficiency and/or failure of repair mechanisms may necessitate the elimination of the entire cell through the activation of the apoptotic program. This requires a process of externalization of a mitochondria-specific phospholipid, cardiolipin (CL) followed by oxidation of its polyunsaturated acyl chain(s). The oxidation reaction is catalyzed by intramembrane space hemoprotein, cytochrome c that forms a high affinity complex with carrdiolipin. There is thus, a transformative structural shift for cytochrome c from being an electron carrier shuttling electrons between respiratory complexes III and IV while located on the outer surface of the IMM, to a CL-specific peroxidase function in apoptosis. Another type of programmed cell death is a newly discovered ferroptosis, a form of regulated necrotic cell death controlled by glutathione peroxidase 4 (GPX4). Enigmatic lipid peroxidation products are the proximate executioners of ferroptosis. We discovered that ferroptosis involves a highly organized oxygenation center, wherein oxidation in endoplasmic-reticulum-associated compartments occurs in only one class of phospholipids (phosphatidylethanolamines (PEs)) and is specific toward two fatty acyls—arachidonoyl (AA) and adrenoyl (AdA). Suppression of AA or AdA esterification into PE by genetic or pharmacological inhibition of acyl-CoA synthase 4 (ACSL4) acts as a specific antiferroptotic rescue pathway. 15-Lipoxygenase (15-LOX) generates doubly and triply-oxygenated (15-hydroperoxy)-diacylated PE species, which act as death signals.