Authors:

Lymphocytes Author

Date Created:

Not specified

Course Title:

Professor:

Not specified

About Paper:

The B-cell lymphoma-2 (BCL-2) family of proteins controls mitochondrial-based intrinsic apoptosis. BH3 mimetics are small-molecule inhibitors that were developed to specifically engage anti-apoptotic BCL-2 family members, including BCL-2, BCL-X,, and MCL-1, to induce apoptosis in a wide range of malignancies. However, little is known about how these drugs affect healthy immune cells, which rely on the BCL-2 family of proteins for survival, development, and function. BCL-2 proteins have also been shown to regulate mitochondrial dynamics and mitophagy, but this has not been extensively studied in immune cells. Given that changes in mitochondrial morphology have been shown to alter T cell energy production and effector functions, we investigated how BH3 mimetics alter mitochondrial dynamics in T cells isolated from human peripheral blood mononuclear cells and expanded ex vivo in the presence of these therapeutics. To do this, T cells were treated with sublethal doses of BH3 mimetics to enable assessment of mitochondrial dynamics in non-apoptotic cells. Confocal microscopy of CD4* T cells revealed that inhibition of BCL-2 promotes mitochondrial fission, whereas inhibition of MCL-1 induces mitochondrial fusion. However, treatment of CD4* T cells with either BCL-2 or MCL-1-specific BH3 mimetics caused a two-fold increase in mitochondrial mass and membrane potential measured by flow cytometry, suggesting improved mitochondrial health and energy capacity. Thus, it appears that different anti-apoptotic BCL-2 family proteins may exert distinct effects on mitochondrial morphology independently of their anti-apoptotic functions. Future work will test whether these changes are mediated through phosphorylation and subcellular translocation of the fission mediator Drp-1, and whether distinct BH3 mimetics alter protein-protein interactions between BCL-2 family members and fission and fusion-related proteins. This work will uncover how BH3 mimetics alter mitochondrial morphology in immune cells, shedding light on their non-apoptotic immunomodulatory potential for the treatment of immunologically-relevant diseases.

Source:

University of Chicago

Topics:

No topics listed

Co-authors:

Lymphocytes Author