Investigation of the anti-apoptotic role of mammalian CLPB protein in neutrophil precursors

Date

2025

Journal Title

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Volume Title

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Abstract

Mitochondrial function is a crucial regulator of cell life cycles, and aberration in mitochondrial function can have great cellular and physiological consequences. Further, protein aggregation within the mitochondria can be a causative event of apoptosis. Disaggregases within the cell are a vital class of proteins which work to maintain the solubility of various other proteins. CLPB is an important disaggregase residing in the intermembrane space of the mitochondria. When the Clpb gene is mutated, devastating clinical consequences can be observed, including diseases such as 3-methylglutaconic aciduria type 7 (MGCA7), and severe congenital neutropenia-9 (SCN9). Seen in these cases are abnormally low numbers of mature neutrophils, which work to destroy foreign materials such as bacteria, upon the onset of infection. CLPB deficiency can result in increased sensitivity to infection, cataracts, dystonia, cardiac disease, and even premature death. Previous work has shown that CLPB is a pro-survival factor in mouse myeloblastic cells (32Dcl3). When stimulated to differentiate, cells without CLPB more readily go through apoptosis. We have further elucidated the role of human CLPB in protein disaggregation within the mitochondrial intermembrane space. In the absence of CLPB, anti-apoptotic proteins such as HAX1 aggregate, possibly sensitizing myeloblastic cells to apoptosis. Additionally, we have identified other proteins involved in mitochondrial health and apoptosis which bind to CLPB, including MICU2, OPA1, YME1L1, and HTRA2. Based on this work, we can postulate possible mechanisms through which CLPB exerts its anti-apoptotic functions.

Description

Keywords

Protein-protein interactions, Neutropenia, Apoptosis, Mitochondria

Graduation Month

May

Degree

Master of Science

Department

Biochemistry and Molecular Biophysics Interdepartmental Program

Major Professor

Anna Zolkiewska

Date

Type

Thesis

Citation