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  • br STAR Methods br Acknowledgments


    Acknowledgments We would like to thank V. Gladyshev (Harvard), H. Kornblum (UCLA), L. Greene (Columbia), and J. Baraban (Johns Hopkins) for constructive comments to the project and manuscript. We thank L. Gross and A. Kumar for assistance with editing. We thank L.M. Gerber and Z. Chen (Weill-Cornell) for assistance with statistical analysis. We thank R. Weigel and M. Kulak (U. Iowa) for the generous gift of their TFAP2c virus. We thank D. Spitz (U. Iowa) for generously sharing his GPX4-L virus. We thank the Microscopy and Image Analysis Core of Weill Cornell Medicine for use of their equipment. We thank S. Agger for graphical abstract design. This work was funded with support from the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, the Burke Foundation, the Sperling Center for Hemorrhagic Stroke Recovery at the Burke Medical Research Institute, the Laster Program in Peptide Therapeutics, and the NIH (grant P01 NIA AG014930, project 1, to R.R.R.). B.T.S. thanks the NIH (R01-EY026576). D.H.G. thanks the NIH (5R01 MH110927, 5R01 MH109912, 5U01 MH105991, and 5R01 MH100027), and V.S. thanks the Larry L. Hillblom Foundation (Postdoctoral Fellowship).
    Introduction Cellular dysfunction and death owing to the increased accumulation of reactive oxygen species is a well-established feature in the neuropathology of neurodegenerative diseases such as Alzheimer's (AD) and Parkinson's disease (PD), and after acute csf1r injury caused by cerebral ischemia, hemorrhagic insults or brain trauma [1]. The underlying mechanisms driving the formation of ROS, such as lipid peroxides, hydrogen peroxide or superoxide anion, hydroxyl radical or nitric oxide radicals, and their biochemical function in oxidative programmed neural cell death, however, remain poorly defined. Increasing evidence has linked impaired calcium homeostasis to the accumulation of ROS and concomitant excessive mitochondrial damage. In particular, loss of mitochondrial integrity and function is regarded as a hallmark in oxidative neuronal death, since neuronal activity and maintenance largely depend on high metabolic turnover and functional energy metabolism. Further, beyond their role in energy metabolism through ATP production, mitochondria are key organelles involved in regulating the cellular redox balance, intracellular calcium homeostasis and apoptosis signaling, thereby determining cellular viability and function in all tissues, and particularly in the nervous system. More recently, ferroptosis emerged as an iron-dependent form of oxidative programmed cell death in a variety of pathological conditions with particular emphasis on neurodegeneration in the brain. Death by ferroptosis has been defined as the fatal combination of iron toxicity, antioxidant depletion attributed to disruption of GPX4, and membrane damage through autoxidation of polyunsaturated phospholipids [2], [3], [4]. Of note, these features of oxidative death specific for ferroptosis are often identified in neuronal cell death associated with neurodegenerative diseases and after acute brain damage. For example, GPX4 impairment and lipid peroxidation have been described as key features of ferroptosis in cerebral ischemia [5], Alzheimer's disease [6], [7], [8], [9], Parkinson's disease [10], [11], [12], Friedreich's ataxia [13] and Huntington's disease [14], [15]. Further, regulated genetic deletion of GPX4 in the brain induced oxidative cell death in cultured neuronal cells in vitro and in hippocampal neurons in vivo [16]. Mechanistically, ferroptosis can be induced by either the indirect disruption of redox homeostasis through the inhibition of the cystine/glutamate antiporter (Xc-), subsequent cystine and glutathione depletion and reduced GPX4 activity by erastin or glutamate respectively [17], [18], or in a direct manner through RSL3-induced GPX4 inactivation [19]. Inactivation of GPX4 leads to enhanced 12/15-lipoxygenase (LOX) activity, thereby, promoting excessive lipid peroxide formation [16], [20], [21].