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Cell cycle-dependent association of plectin 1b regulates mitochondrial morphology and function

Aebig, Trudy J.
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1307440587

Abstract Details

2011, PhD, University of Cincinnati, Medicine: Cell and Molecular Biology.
Mitochondria are cellular organelles that have long been recognized for their crucial role in producing energy in the form of ATP for cellular activities. Very recently, mitochondrial ATP production during the cellular duplication cycle was shown to be highest at the G1/S transition, the stage just prior to DNA synthesis, or S-phase. Without sufficient energy to allow competent DNA replication, normal cells arrest before the proliferation cycle. Energy production at this critical juncture in the cell cycle depends on a striking change in mitochondrial morphology, one in which individual mitochondria become fused into an interconnected, tubular network. Prior to G1/S, during the lengthy G1 phase, individual mitochondria become increasingly elongated in shape, and then after formation of an interconnected mass at G1/S, the mass fragments into many mitochondria that become increasingly shorter during S-phase. Transient remodeling of mitochondrial shape is tightly controlled through a balance of fusion and fission and many proteins required for these processes have been identified, but the ways in which they are regulated during the cell cycle are unknown. This thesis explored the possible role in cell cycle-dependent mitochondrial remodeling of plectin 1b, a nuclear-encoded protein targeted to mitochondria via its amino-terminus and linked to the intermediate filament cytoskeleton via its carboxy-terminus. Strikingly, the association of plectin 1b with mitochondria in mouse fibroblasts was governed by position in the cell cycle. A tagged amino-terminal fragment of plectin 1b was associated with mitochondria maximally in late G1 and then exited mitochondria beginning in G1/S. By late S-phase, plectin 1b was completely diffuse in the cytoplasm. Mutations induced in the second through fourth amino-terminal amino acids altered mitochondrial targeting behavior, raising the possibility that some forms of mitochondrial protein delivery are subject to cell cycle-dependent control. Studies of plectin knockout cells throughout the cell cycle showed that mitochondria are aberrantly long specifically in S-phase in knockout cells, suggesting a role for plectin 1b in precise regulation of mitochondrial fragmentation in S-phase. This result clarifies a prior observation that plectin 1b knockout cells growing asynchronously display an abnormally high proportion of elongated mitochondria. These changes have important functional consequences, as mitochondrial respiration in plectin-null cells is elevated compared to wild-type cells. Overall, these data indicate a cell cycle-regulated role for plectin 1b in mitochondrial length determination and energy status.
Linda Parysek, PhD (Committee Chair)
Peter Hollenbeck, PhD (Committee Member)
Anil Menon, PhD (Committee Member)
David Plas, PhD (Committee Member)
Carolyn Price, PhD (Committee Member)
133 p.
Cellular Biology
Plectin 1b; Mitochondrial fission; Mitochondrial respiration; Mitochondrial shape; Cell cycle

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Citations

  • Aebig, T. J. (2011). Cell cycle-dependent association of plectin 1b regulates mitochondrial morphology and function [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1307440587

    APA Style (7th edition)

  • Aebig, Trudy. Cell cycle-dependent association of plectin 1b regulates mitochondrial morphology and function. 2011. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1307440587.

    MLA Style (8th edition)

  • Aebig, Trudy. "Cell cycle-dependent association of plectin 1b regulates mitochondrial morphology and function." Doctoral dissertation, University of Cincinnati, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1307440587

    Chicago Manual of Style (17th edition)

ucin1307440587
546
© 2011, all rights reserved.
This open access ETD is published by University of Cincinnati and OhioLINK.