What is the role of mitochondria in apoptosis?

From the Guidelines

Mitochondria play a crucial role in apoptosis by regulating cell survival and death through mitochondrial dynamics, including fission and fusion, which are intimately involved in the release of pro-apoptotic factors and the initiation of cell death. The process of mitochondrial fission, mediated by proteins such as Drp1, is an early upstream event in neuronal death after cerebral ischemia, and preventing mitochondrial fission can block cytochrome c release and delay cell death 1. Mitochondrial oxidative stress can upregulate Drp1 expression, leading to an imbalance of mitochondrial fission and fusion, resulting in mitochondrial fragmentation and dysfunction, and cell death 1.

Key Mechanisms

• Mitochondrial fission and fusion are critical for maintaining a healthy mitochondrial network and regulating cell survival and death
• Drp1 is a key regulator of fission, and its downregulation can reduce the infarct volume in focal cerebral ischemia 1
• Mitochondrial fusion proteins, including Mfn1, Mfn2, and Opa1, may exert anti-apoptotic effects via restoration of mitochondrial function 1
• Signaling lipids, such as cardiolipin and diacylglycerol, are involved in the control of mitochondrial fission and fusion 1

Clinical Implications

• Understanding the role of mitochondria in apoptosis is crucial for developing treatments for diseases characterized by excessive or insufficient apoptosis, such as cancer and neurodegenerative disorders
• Targeting mitochondrial dynamics, including fission and fusion, may provide a therapeutic strategy for preventing or treating diseases related to mitochondrial dysfunction and apoptosis 1

From the Research

Role of Mitochondria in Apoptosis

• Mitochondria play a crucial role in both the life and death of cells, with a significant function in apoptotic signaling pathways 2, 3, 4, 5, 6
• The mitochondria are considered "gatekeepers" that ultimately determine the fate of the cell, with malfunctioning at any level leading to the release of apoptogenic factors from the mitochondrial intermembrane space 2
• Apoptosis can be initiated by various stimuli, including multiple signaling pathways that converge at the mitochondria, leading to the release of mitochondrial intermembrane space proteins that activate caspases 3, 4, 5

Mechanisms of Mitochondrial Regulation of Apoptosis

• Mitochondrial outer membrane permeabilization (MOMP) is a key event in the regulation of apoptosis, leading to the release of various mitochondrial intermembrane space proteins that activate caspases 3
• The release of cytochrome c from the mitochondrial intermembrane space is a critical step in the apoptotic process, binding to the apoptosis protease activation factor (APAF-1) and forming a complex that activates pro-caspase 9 4, 5, 6
• Bcl-2 family members and other upstream proteins contribute to and regulate the apoptosis process, with antiapoptotic members antagonistic to proapoptotic proteins 2, 5, 6

Signaling Pathways and Cell Death

• The intrinsic pathway of apoptosis is assumed to initiate in mitochondria, involving the release of cytochrome c and other pro-apoptotic factors from the mitochondrial intermembrane space 4
• The extrinsic pathway of apoptosis also involves mitochondrial regulation, with the release of mitochondrial proteins contributing to both caspase-dependent and caspase-independent processes in apoptotic cell death 3, 5