Mitochondria and Programmed Cell Death

Introduction to Mitochondria and Apoptosis
- Mitochondria play a significant role in programmed cell death known as apoptosis.

Definition of Apoptosis:
- Apoptosis is a normal, healthy process where cells are intentionally removed in a controlled manner.
- It is not the result of accidental damage but a planned part of life crucial for maintaining tissue health.
- Cells must constantly remove old, damaged, or unnecessary cells to support growth and development.
Significance in Development:
- Apoptosis is essential for normal anatomy and function, as illustrated during embryonic development; for example, in human hands and feet, web-like tissue between digits is removed through apoptosis.
Visual Example:
- Early developmental images show connected digits in a fetus where apoptosis allows for the formation of separate fingers, preventing a paddle-like structure.

Key Regulators:
- Mitochondria help signal when a cell should initiate the apoptosis sequence.

Bone Morphogenic Protein (BMP):
- BMP is a secreted signaling protein that binds to BMP receptors on cells and triggers apoptosis during limb development, particularly between developing digits.
- Example in Chickens:
- Research shows that expressing a non-active BMP receptor in chicken embryos drastically reduces apoptosis between digits, leading to webbed feet instead of separated toes.
- Natural Variation:
- Chickens typically display high interdigital apoptosis for non-webbed feet while ducks have reduced apoptosis and retain webbed structures as an adaptation to aquatic environments.

Example - Madagascar Lace Plant:
- This plant grows underwater and exhibits intentional programmed cell death that creates lace-like holes in leaves without damaging structural veins, aiding in reducing drag in moving water and allowing better light penetration.

Distinct Features of Apoptosis:
- Cell Shrinkage: The cytoplasm condenses, and the cell shrinks.
- Blebbing: Formation of bulges or protrusions on the plasma membrane which will pinch off.
- DNA Fragmentation: Chromatin condenses and breaks apart; nuclear fragmentation happens.
- Loss of Attachment: Apoptotic cells detach cleanly from neighboring cells.
- Engulfment: The cell forms small sealed packages called apoptotic bodies that are recognized and removed by immune cells (phagocytes).
Contrast with Necrosis:
- Apoptosis is a controlled process compared to necrosis, which is messy, leaky, and inflammatory.

Early Apoptosis:
- Chromatin condensation and cell shrinkage occur, while the cell remains intact.
Membrane Changes:
- Blebbing occurs, and the nuclear envelope collapses while maintaining cell integrity.
Packing into Apoptotic Bodies:
- The cell breaks into self-contained apoptotic bodies, which are then neatly cleared away by phagocytes.

Intrinsic Pathway Activation:
- Activated by internal stress signals like DNA damage, oxidative stress, hypoxia, or viral infections, leading to the activation of BAX proteins (killer protein).
- Mechanism:
- BAX translocates to the mitochondria, increasing membrane permeability, which allows cytochrome c to leak out, committing the cell to apoptosis.
Formation of the Apoptosome:
- Cytochrome c binds to cytoplasmic factors (APAF-1, procaspase 9), forming the apoptosome, inducing further caspase activation necessary for apoptosis execution.

Role of Caspases:
- Caspases act as molecular scissors dismantling the cell systematically by targeting key structures like cell adhesion proteins, lamins, and cytoskeletal components.
- They also activate DNases, fragmenting nuclear DNA without causing inflammation or damage to neighboring cells.

Consequences of Apoptosis Dysregulation:
- Insufficient apoptosis allows damaged cells to survive (e.g., cancer).
- Excessive apoptosis leads to loss of important cells and can be detrimental, especially in non-regenerative tissues (e.g., neurons).
Examples of Diseases:
- Cancer: Cells avoid apoptotic pathways to proliferate.
- Alzheimer's Disease: Excess neuronal death correlates with brain shrinkage.
- Parkinson's Disease: Neurons in substantia nigra diminish, impairing motor control.

Components:
- Includes endoplasmic reticulum (ER), transport vesicles, Golgi apparatus, lysosomes, and vacuoles.
- The system is integral for protein and lipid processing, transport, and cellular organization.
ER Functionality:
- Rough ER synthesizes proteins and modulates them for secretion and membrane incorporation.
Vesicular Transport:
- Vesicles bud off from one compartment, transporting materials through targeted pathways within the cell.

Budding and Transport:
- Specific cargo binds receptors in the membrane, causing vesicles to bud off, traveling via motor proteins along cytoskeletal tracks.
Docking and Fusion:
- RAB proteins facilitate tethering, while SNARE proteins ensure the correct vesicle fusion with target membranes and cargo delivery.

Proteins in the ER:
- Transmembrane proteins inserted into the ER maintain orientation throughout transport, ensuring functionality when integrated into the plasma membrane.

Exocytosis:
- Example in neuronal synapses: neurotransmitter release involves vesicles fusing with the plasma membrane and spilling content into the synaptic cleft.
Endocytosis:
- Occurs in neurons internally to regulate neurotransmitter receptor levels (e.g., AMPA receptors) by internalizing them during changes in synaptic activity.

Reflect on the regulatory mechanisms of apoptosis and its implications in development and disease.
Consider how vesicular transport processes illustrate cellular organization and functionality in the endomembrane system, and how these systems are integral to maintaining cellular homeostasis.