Over the past decade, the Nomenclature Committee on Cell Death (NCCD) has formulated guidelines for the definition and interpretation of cell death from morphological, biochemical, and functional perspectives. Since the field continues to expand and novel mechanisms that orchestrate multiple cell death pathways are unveiled, we propose an updated classification of cell death subroutines focusing on mechanistic and essential (as opposed to correlative and dispensable) aspects of the process. As we provide molecularly oriented definitions of terms including intrinsic apoptosis, extrinsic apoptosis, mitochondrial permeability transition (MPT)-driven necrosis, necroptosis, ferroptosis, pyroptosis, parthanatos, entotic cell death, NETotic cell death, lysosome-dependent cell death, autophagy-dependent cell death, immunogenic cell death, cellular senescence, and mitotic catastrophe, we discuss the utility of neologisms that refer to highly specialized instances of these processes. The mission of the NCCD is to provide a widely accepted nomenclature on cell death in support of the continued development of the field.

A single cell clonal line which responds reversibly to nerve growth factor (NGF) subjected to three cycles of washing (with phosphate-buffered saline) and pelleting (500 X g for 5 min) in order to free them from cell debris, and were resuspended in growth medium and plated on plastic tissue culture dishes (Falcon Plastics). The following day, the lightly-adhering pheochromocytoma cells were mechanically dislodged from the plates by forceful aspiration and expulsion of the medium with a pasteur pipette, and replated on culture dishes which were coated with rat tail collagen (10). The cells were subsequently passaged two more times on collagen-coated culture dishes and three more times on plastic culture dishes. This strategy was employed for two reasons. First, newly dissociated pheochromocytoma cells adhered very poorly to plastic culture dishes. After several passages on collagen-coated dishes (to which the cells more firmly attached), the cells had adapted to culture and could be passaged onto plastic dishes. Second, the dissociated tumors contained, in addition to the cells of interest, other cell types which grew much more rapidly than the pheochromocytoma cells and which overgrew the cultures. Such cells adhered very firmly to plastic and collagen-coated substrates and tended to be left behind on the culture dishes after mechanical dislodgement. By the means described, the slowly growing pheochromocytoma cells could be adapted to culture without being overgrown.

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6-hydroxydopamine, 1-methyl-4-phenyl-pyridinium (MPP+), and rotenone cause the death of dopaminergic neurons in vitro and in vivo and are widely used to model Parkinson's disease. To identify regulated genes in such models, we performed serial analysis of gene expression on neuronal PC12 cells exposed to 6-hydroxydopamine. This revealed a striking increase in transcripts associated with the unfolded protein response. Immunoblotting confirmed phosphorylation of the key endoplasmic reticulum stress kinases IRE1alpha and PERK (PKR-like ER kinase) and induction of their downstream targets. There was a similar response to MPP+ and rotenone, but not to other apoptotic initiators. As evidence that endoplasmic reticulum stress contributes to neuronal death, sympathetic neurons from PERK null mice in which the capacity to respond to endoplasmic reticulum stress is compromised were more sensitive to 6-hydroxydopamine. Our findings, coupled with evidence from familial forms of Parkinson's disease, raise the possibility of widespread involvement of endoplasmic reticulum stress and the unfolded protein response in the pathophysiology of this disease.