VB

Exam Logistics

  • Exam Date: Exam 2 is a week from Wednesday.

  • Up Next: Lecture content for Exam 3 will follow today’s lecture (Lecture 8).

  • Upcoming Schedule: Regular lecture this Wednesday, followed by an ICP session on Monday next week.

Cell Death Overview

Wrap-up of Autophagy Discussion

  • Debate on Autophagy: Importance in cell death processes.

    • Associated with apoptosis and necrosis.

    • The role of autophagy in preventing vs. causing cell death is debated.

Findings on Autophagy

  • Damaged Mitochondria: Release pro-apoptotic factors.

    • Removal via Autophagy: Prevents release of these factors, potentially allowing recovery.

  • Experimental Evidence:

    • Blocking autophagy leads to cell death via necrosis.

    • Enhancing autophagy leads to apoptosis.

Key Concept: ATP Levels

  • Importance of ATP: Main deciding factor for cell fate during necrosis vs apoptosis.

  • Promoting autophagy aids in:

    • Removal of dysfunctional mitochondria (not producing ATP).

    • Providing substrates for ATP production.

Transition to Unique Cell Death: Necroptosis

  • Definition: Regulated necrosis.

    • Combines features of both necrosis (unregulated) and apoptosis (regulated).

Mechanism of Necroptosis

  • Releasing Contents: Leads to an inflammatory response.

  • Independent of Caspase Activity: Differs from apoptosis.

  • Requires RIPs (Receptor Interacting Proteins).

  • Pathological Relevance: Relevant in infections, neurodegenerative disorders, ischemia-reperfusion injuries.

    • Necrostatins: Inhibit necroptosis, small molecule inhibitors targeting IMPs.

Role of RIPs in Necroptosis

  • RIP as a Protein Interaction: Essential for the necroptotic process.

    • Inhibiting RIP with necrostatins reduces infarct size and speeds recovery in ischemic conditions.

Complex Mechanisms of Cell Death

Death Receptor Family Activation

  • Triad of Outcomes: Survival via growth factors, apoptosis, necroptosis.

  • Complex Formation: Different outcomes based on receptor interactions.

Cell Survival (Complex I)

  • Survival Factors Present:

    • Inhibitor of Apoptosis Proteins (cIAP) promotes survival by binding to RIP and promoting polyubiquitination.

    • Transcription Factors activated for cell survival (NF-kB pathway).

Apoptosis Induction (Complex II A)

  • Caspase Activation: Caspase 8 activates apoptosis pathway.

    • Caspase activation leads to a series of proteolytic events ensuring cell death via apoptosis.

Necroptotic Pathway (Complex II B)

  • Lack of Caspase Activation: Inhibition via compounds like ZVAD leads to necroptosis.

  • Necrosome Formation: Includes RIP3 and MLKL.

    • Cell Membrane Rupture: Adding ions causing cell swelling and content leakage into extracellular space, triggering inflammation.

Comparison to Other Cell Death Forms

  • Differences from Apoptosis:

    • Apoptosis involves a clean cell death while necroptosis causes inflammatory responses.

    • Understanding the balance of ATP helps distinguish pathways.

Pyroptosis: Inflammatory Cell Death

  • Caspase Dependency: Mediated primarily by caspase 1 (also known as ICE).

  • Associated with Inflammation: Causes fever and pro-inflammatory responses.

  • Mechanism: Explosive cell death liberating inflammatory signals.

Pyroptosis Mechanism

  • Inflammasomes: Multi-protein complexes facilitate interleukin production leading to fever and malaise.

  • Cell Bursting: Associated with infections from pathogens like Shigella and Salmonella.

PARP-mediated Cell Death (Parthanatos)

  • Trigger: Extensive DNA damage leading to PARP overactivation.

  • Mediators: Involves proteins AIF (apoptosis inducing factor) and MIF (macrophage migration inhibitory factor).

    • Mechanism: AIF moves to form a nuclease that degrades DNA.

NETosis and Immune Response

  • Definition: Neutrophil extracellular traps formed during an immune response.

  • Purpose: Traps pathogens and promotes immune response.

Types of NETosis

  • Suicidal NETosis: Neutrophils sacrifice themselves to trap pathogens.

  • Vital NETosis: Neutrophils survive and create traps rapidly.

Cancer Implications

  • Cancer Survival: NETs can inadvertently support cancer cells during surgery.

  • Inflammation Link: NETs contribute to diabetes and autoimmune disorders due to inflammation.

Ferroptosis: Iron-induced Cell Death

  • Mechanism: Driven by excess iron leading to lipid peroxidation.

  • Consequences: Lipid damage in mitochondria and cell swelling leading to rupture.

Comparison with Copper-driven Proptosis

  • Both lead to mitochondrial dysfunction but occur via different mechanisms.

Application to Health Conditions

  • Dietary Caution: Excessive iron intake can have deleterious health effects.

Interconnectedness of Cell Death Mechanisms

  • Complications in Understanding: Cell death pathways exhibit complex interconnections.

  • Shared Proteins and Responses: RIP and gasdermin play roles in multiple pathways, complicating cell death fate.

Conclusion

  • Exploration of Mechanisms: Emphasizes the necessity of understanding varying cell death pathways in health and disease.

  • Clinical Relevance: Knowledge of these mechanisms is vital for therapeutic interventions in various diseases, including cancer, infections, and inflammatory disorders.

  • Future discussions are needed to expand on the understanding of inflammation and cell death interconnections.