**6. Role of mitochondria in cell death**

72 Apoptosis and Medicine

the executioner caspases.

**Apoptotic trigger**

and engagement of the caspase cascade [29].

**Bcl-2 proapoptotic**

**MITOCHONDRION**

**members activation Bid cleavage**

**Figure 3.** The extrinsic and intrinsic apoptotic pathways.

**endoG**

**5. Death receptors** 

7 [26].

which leads to autocatalyisis and consequently activation of executioner caspases -3, -6 and -

The intrinsic mitochondrial pathway is characterized by the action of B-cell lymphoma (Bcl-2) proteins. This family consists of proapoptotic and antiapoptotic proteins. The proapoptotic members promote mitochondrial outer membrane permeabilization (MOMP) and the antiapoptotic members counteract this action, so that the balance between these two groups of proteins determines the final outcome [27,28]. If the balance is in favour of the proapoptotic members, the outer mitochondrial membrane is permeabilized through pore formation and cytchrome c and other proteins such as Smac/DIABLO and Omi/HtrA2 are released to the cytosol. Then, cytochrome c binds to the adaptor protein Apaf-1 and dATP, forming the apoptosome, a catalytic complex that activates caspase-9 which in turn activates

The extrinsic and intrinsic pathways are interconnected through Bid. In some cases, when DISC formation is low, caspase-8 activation can induce MOMP through Bid cleavage, which translocates to the mitochondria and induces cytchrome c release, apoptosome formation

> **Caspase-8 activation**

> > **Caspase-9**

**Executioner caspases activation**

> **DNA fragmentation NUCLEUS**

Death receptors belong to the TNF-R superfamily of receptors. They participate in proliferation, differentiation, immune response, gene expression, survival and cell death. In

**cytochrome c release apoptosome formation**

**Apaf-1**

**activation dATP**

**AIF**

**Death receptor**

> MMP, a crucial event of the intrinsic mitochondrial apoptotic pathway, is considered a "point of no return" in the sequence of events leading to apoptosis. This phenomenon is associated with mitochondrial membrane potential loss (∆Ψm) that occurs as a result of assymetrical distribution of protons on both sides of the inner mitochondrial membrane. This irreversible process can take place before, during or after MOMP. The pore formation caused by Bcl-2 proteins induces MOMP, which leads to ∆Ψm dissipation, inhibition of ATP synthesis and ∆Ψm-dependent transport activities. Consequently, the respiratory change ceases, causing reactive oxygen species (ROS) generation and release of proteins confined within the inner mitochondrial space [35]. The contribution of the inner mitochondrial permeabilization, however, is controversial. MOMP can also result from the phenomenon called mitochondrial permeability transition that implies the opening of a non-selective pore in the inner mitochondrial membrane known as the mitochondrial permeability transition pore complex [12].
