Necrotic cell death: From reversible mitochondrial uncoupling to irreversible lysosomal permeabilization
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Updated: Jun 28, 2026
Live-cell Imaging of Lysosomal Membrane Permeabilization During Necroptosis
Published on: November 14, 2025
Corinne Giusti1, Marie-Françoise Luciani, Gérard Klein
1Centre d'Immunologie de Marseille-Luminy (CIML), Faculté des Sciences de Luminy, Aix Marseille Université, Marseille F-13288, France.
Abstract:
Dictyostelium atg1- mutant cells provide an experimentally and genetically favorable model to study necrotic cell death (NCD) with no interference from apoptosis or autophagy. In such cells subjected to starvation and cAMP, induction by the differentiation-inducing factor DIF or by classical uncouplers led within minutes to mitochondrial uncoupling, which causally initiated NCD. We now report that (1) in this model, NCD included a mitochondrial-lysosomal cascade of events, (2) mitochondrial uncoupling and therefore initial stages of death showed reversibility for a surprisingly long time, (3) subsequent lysosomal permeabilization could be demonstrated using Lysosensor blue, acridin orange, Texas red-dextran and cathepsin B substrate, (4) this lysosomal permeabilization was irreversible, and (5) the presence of the uncoupler was required to maintain mitochondrial lesions but also to induce lysosomal lesions, suggesting that signaling from mitochondria to lysosomes must be sustained by the continuous presence of the uncoupler. These results further characterized the NCD pathway in this priviledged model, contributed to a definition of NCD at the lysosomal level, and suggested that in mammalian NCD even late reversibility attempts by removal of the inducer may be of therapeutic interest.
Insights
Necrotic cell death (NCD) in Dictyostelium involves a reversible mitochondrial-lysosomal cascade. Lysosomal permeabilization marks an irreversible stage, requiring sustained uncoupler presence for mitochondrial and lysosomal damage.
Area of Science:
- Cell Biology
- Molecular Biology
- Biochemistry
Background:
- Dictyostelium atg1- mutant cells offer a model for studying necrotic cell death (NCD) without apoptosis or autophagy.
- Mitochondrial uncoupling initiates NCD in these cells upon starvation and cAMP induction.
Purpose of the Study:
- To elucidate the mitochondrial-lysosomal cascade in NCD.
- To investigate the reversibility of NCD stages.
- To define NCD at the lysosomal level.
Main Methods:
- Utilized Dictyostelium atg1- mutant cells.
- Induced NCD using differentiation-inducing factor (DIF) or uncouplers.
- Assessed mitochondrial uncoupling and lysosomal permeabilization using specific dyes and substrates (Lysosensor blue, acridin orange, Texas red-dextran, cathepsin B substrate).
Main Results:
- NCD involves a mitochondrial-lysosomal cascade.
- Early stages of mitochondrial uncoupling were reversible.
- Lysosomal permeabilization was demonstrated and found to be irreversible.
- Continuous presence of the uncoupler was necessary for both mitochondrial and lysosomal lesions.
Conclusions:
- Characterized the NCD pathway in Dictyostelium, highlighting a mitochondrial-lysosomal cascade.
- Defined NCD at the lysosomal level, identifying irreversible permeabilization as a key event.
- Suggests potential therapeutic strategies targeting late-stage reversibility in mammalian NCD.
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