Role of apoptotic processes and energy metabolism in Paracetamol-induced liver necrosis

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Paracetamol (Acetaminophen, APAP) is one of the most commonly used pain killers world-wide, but its overdosing provokes severe liver damage, eventually leading to acute liver failure and mortality. Within this thesis, we used the model of APAP-induced liver injury (AILI) to study crosstalk and potential switches between different forms of cell death. Cell death can be broadly subdivided into apoptosis, as regulated, intended form, necrosis, as accidental and often deleterious process, and several regulated, but necrotic forms of cell death. Intriguingly, APAP overdose triggers several apoptotic processes in hepatocytes, but the eventual outcome is fulminant necrotic cell death. Within the scope of this thesis, cell death processes within AILI were extensively characterized by investigating the induction of apoptotic proteins upon APAP and whether these proteins implement their canonical function or exert a yet unknown apoptosis-unrelated role. We also studied at which stage and how the apoptotic signaling after APAP is blocked and switches to necrotic cell death. We revealed that apoptotic signaling proceeds regularly until caspase activation comprising the interactome of apoptosis-regulating BCL-2 proteins and mitochondrial outer membrane permeabilization. APAP did not only fail to activate caspases, but more strikingly, even prevented their activation upon classical apoptosis induction. We provide strong evidence that APAP-provoked oxidative stress and glutathione depletion render caspases unfunctional via glutathionylation, explaining the caspase-independent, necrotic cell death. We furthermore revealed a novel, non-canonical role of the proapoptotic BCL-2 homolog BIM in regulating mitochondrial morphology and bioenergetics. BIM deficiency enhanced total ATP production and shifted the bioenergetic profile towards glycolysis, which resulted in persistent protection from APAP-induced necrosis. By modulating glucose levels of several hepatocellular systems and mice, we found that severe APAP toxicity only occurs in cells that are dependent on oxidative phosphorylation. Glycolytic hepatocytes survived APAP intoxication by maintaining elevated ATP levels and reduced oxidative stress, which enabled lysosomal recycling of damaged mitochondria. We further challenged the dogma that fasting prior to APAP injections is required for AILI in mice as we reveal that fasting rather primes for beneficial antioxidant and autophagic processes. Taken together, this thesis highlights how metabolism and bioenergetic conditions affect drug-induced liver toxicity, it proves that the cellular redox status decisively affects switches between cell death modes and identifies BIM as important novel regulator of glycolysis, mitochondrial respiration, and oxidative stress signaling.

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ISO 690LAMBRECHT, Rebekka, 2023. Role of apoptotic processes and energy metabolism in Paracetamol-induced liver necrosis [Dissertation]. Konstanz: University of Konstanz
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@phdthesis{Lambrecht2023apopt-67328,
  year={2023},
  title={Role of apoptotic processes and energy metabolism in Paracetamol-induced liver necrosis},
  author={Lambrecht, Rebekka},
  address={Konstanz},
  school={Universität Konstanz}
}
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June 23, 2023
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Konstanz, Univ., Diss., 2023
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