Cytosolic cytochrome C plays an important function in -

NEET PG Pathology
#1

Cytosolic cytochrome C plays an important function in -

    1. Apoptosis
    1. Cell necrosis
    1. Electron transport chain
    1. Cell division

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Mechanism of Apoptosis

  • Apoptosis is induced by a cascade of molecular events that may be initiated in distinct ways but culminate in the activation of caspases.
  • Caspases are central to the pathogenesis of apoptosis
  • The process of apoptosis is divided into two phases
  1. Initiation phase → During this phase caspases become catalytically active
  2. Execution phase → During this phase caspases act to cause cell death.

(i) Initiation phase of apoptosis

  • Initiation of apoptosis occurs principally by signals from two distinct but convergent pathways
  1. Intrinsic or mitochondrial pathway
  2. Extrinsic or receptor initiated pathway

A.Intrinsic (mitochondrial pathway)

  • In a healthy cell, the outer membrane of its mitochondria displays the proteins C1-2 and Cl-X
  • These proteins are antiapoptotic, i.e., they inhibit apoptosis.
  • Internal damage to the cell (e.g., from reactive oxygen species, stress) causes migration of proapoptotic proteins (BaK, I ax and I im) to the outer membrane of mitochondria at the same time antiapoptotic proteins (BCl - 2, BCl - X) are lost from the mitochondrial membrane.
  • This leads to increase permeability of the mitochondrial membrane.
  • Cytochrome ‘c’ leaks out from the mitochondria.
  • The released cytochrome ‘C’ binds to Apaf - 1 (apoptosis activating factor - 1) in the cytoplasm.
  • These complexes aggregate to from apoptosomes.
  • The apoptosomes bind to an activate Caspase - 9 (initiate caspase).

B. Extrinsic or Death receptor pathway

  • This pathway is initiated by expression of cell surface death receptors on variety of cells.
  • Death receptors are members of tumor necrosis factor receptor family.
  • The receptors are TNF receptor Type 1(TNFR - 1) and Fas (CD-95).
  • Binding of the complementory death activator, e.g., Fas ligand (Fas L) to Fas and TNF to TNFR-1, transmits a signal to the cytoplasm.
  • This leads to activation of caspase - 8 (another initiate caspase like caspase - 9).
  • This pathway can be inhibited by an antipoptotic protein FLIP, which can bind to inactive caspases (procaspases) and prevent their activation.
  • So, the final result of both the pathways that is extrinsic receptor mediated pathway and intrinsic mitochondrial pathway is the same i.e. activation of the caspase.

(ii) Execution phase of apoptosis

In this phase, initiate caspases (Caspase - 8 & 9) activate other caspases known as execution Caspases (Caspases- 3 & 7).

  • After being activated the caspases act on many cellular components.
  • They cleave cytoskeletal and nuclear matrix proteins and thus disrupts the cytoskeleton.
  • They also lead to the breakdown of the nucleus.
  • In the nucleus the target of caspase activation includes proteins involved in transcription, DNA replication and DNA repair.
  • Caspases activates endonucleases (DNAases) that causes double-stranded breaks in DNA.
  1. Apoptosis inducing factors
  • Neurons have another way to self destruct, i.e., to undergo apoptosis, but it does not use caspases unlike the two pathways described above.
  • AIF is a protein that is located in the internzembrane space of mitochondria.
  • At the time of apoptosis, AIF is released from the mitochondria and it migrates into nucleus where it binds to DNA and triggers its destruction.