A variety of key events in apoptosis focus on mitochondria, including the release of caspase activators (such as cytochrome c), changes in electron transport, loss of mitochondrial transmembrane potential, altered cellular oxidation-reduction, and participation of pro- and antiapoptotic Bcl-2 family proteins. The different signals that converge on mitochondria to trigger or inhibit these events and their downstream effects delineate several major pathways in physiological cell death.

https://science.sciencemag.org/content/sci/281/5381/1309.full.pdf

Mitochondria and apoptosis

https://www.cell.com/cell/pdf/S0092-8674(00)80434-1.pdf

Cytochrome c and dATP-Dependent Formation of Apaf-1/Caspase-9 Complex Initiates an Apoptotic Protease Cascade

Apoptosis, an evolutionarily conserved form of cell suicide, requires specialized machinery. The central component of this machinery is a proteolytic system involving a family of proteases called caspases. These enzymes participate in a cascade that is triggered in response to proapoptotic signals and culminates in cleavage of a set of proteins, resulting in disassembly of the cell. Understanding caspase regulation is intimately linked to the ability to rationally manipulate apoptosis for therapeutic gain.

https://science.sciencemag.org/content/sci/281/5381/1312.full.pdf

Caspases: Enemies Within

The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta.

Bcl-2 is an integral membrane protein located mainly on the outer membrane of mitochondria. Overexpression of Bcl-2 prevents cells from undergoing apoptosis in response to a variety of stimuli. Cytosolic cytochrome c is necessary for the initiation of the apoptotic program, suggesting a possible connection between Bcl-2 and cytochrome c, which is normally located in the mitochondrial intermembrane space. Cells undergoing apoptosis were found to have an elevation of cytochrome c in the cytosol and a corresponding decrease in the mitochondria. Overexpression of Bcl-2 prevented the efflux of cytochrome c from the mitochondria and the initiation of apoptosis. Thus, one possible role of Bcl-2 in prevention of apoptosis is to block cytochrome c release from mitochondria.

https://science.sciencemag.org/content/sci/275/5303/1129.full.pdf

Prevention of Apoptosis by Bcl-2: Release of Cytochrome c from Mitochondria Blocked

Induction of apoptotic program in cell-free extracts : requirement for datp and cytochrome c

Mitochondrial control of apoptosis: the role of cytochrome c.

The present study sought to examine how sea buckthorn (SBT) oil impacts mitochondrial and overall functionality in Aspergillus flavus. In order to assess the effect of SBT oil, it was used to treat mycelia across a range of concentrations, after which mitochondrial structures were imaged via transmission electron microscopy (TEM). In order to explore the functional impact of this treatment, we additionally examined reactive oxygen species (ROS) production, malondialdehyde (MDA) levels, enzyme activity, and shifts in mitochondrial membrane potential (ΔΨm) following treatment. We found that SBT oil induced mitochondrial damage in A. flavus in a dose-dependent manner, resulting in altered succinate dehydrogenase (SDH) and adenosine triphosphatase (ATPase) activity, reduced ΔΨm levels, and markedly elevated MDA and ROS levels. Together, these findings suggest that SBT oil can mediate antifungal activity against A. flavus through a mechanism associated with its ability to disrupt the tricarboxylic acid (TCA) cycle and mitochondrial potential, leading to MDA and ROS accumulation.

Sea buckthorn (Hippophae rhamnoides L.) oil exhibits antifungal activity against Aspergillus flavus via disrupting mitochondrial function

Functional disorders of mitochondria are closely related to muscle diseases. Many studies have also shown that oxidative stress can stimulate the production of a large number of reactive oxygen species (ROS), which have various adverse effects on mitochondria and can damage muscle cells.In this study, based on our previous research, we focused on the PINK1/Parkin pathway to explore the mechanism by which AS-IV alleviates muscle injury by inhibiting excessive mitophagy.L6 myoblasts were treated with AS-IV after stimulation with hydrogen peroxide (H2O2) and carbonyl cyanide m-chlorophenylhydrazone (CCCP). Then, we detected the related indices of oxidative stress and mitophagy by different methods. A PINK1 knockdown cell line was established by lentiviral infection to obtain further evidence that AS-IV reduces mitochondrial damage through PINK1/Parkin.After mitochondrial damage, the expression of malondialdehyde (MDA) and intracellular ROS in L6 myoblasts significantly increased, while the expression of superoxide dismutase (SOD) and ATP decreased. The mRNA and protein expression levels of Tom20 and Tim23 were decreased, while those of VDAC1 were increased. PINK1, Parkin, and LC3 II mRNA and protein expression increased, and P62 mRNA and protein expression decreased·H2O2 combined with CCCP strongly activated the mitophagy pathway and impaired mitochondrial function. However, abnormal expression of these factors could be reversed after treatment with AS-IV, and excessive mitochondrial autophagy could also be reversed, thus restoring the regulatory function of mitochondria. However, AS-IV-adjusted function was resisted after PINK1 knockdown.AS-IV is a potential drug for myasthenia gravis (MG), and its treatment mechanism is related to mediating mitophagy and restoring mitochondrial function through the PINK1/Parkin pathway. 

Jie Yang

Papers

Induction of apoptotic program in cell-free extracts : requirement for datp and cytochrome c

Prevention of Apoptosis by Bcl-2: Release of Cytochrome c from Mitochondria Blocked

Mitochondrial control of apoptosis: the role of cytochrome c.

Sea buckthorn (Hippophae rhamnoides L.) oil exhibits antifungal activity against Aspergillus flavus via disrupting mitochondrial function

PINK1/Parkin pathway-mediated mitophagy by AS-IV to explore the molecular mechanism of muscle cell damage.