Mechanisms of Regulation of Mitochondrial Dynamics by the Actin Cytoskeleton / Stephen Coscia.

Format:

Book

Thesis/Dissertation

Author/Creator:

Coscia, Stephen, author.

Contributor:

University of Pennsylvania. Cell and Molecular Biology, degree granting institution.

Language:

English

Subjects (All):

Cellular biology.

Molecular biology.

Developmental biology.

Cell and Molecular Biology--Penn dissertations.

Penn dissertations--Cell and Molecular Biology.

Local Subjects:

Cellular biology.

Molecular biology.

Developmental biology.

Cell and Molecular Biology--Penn dissertations.

Penn dissertations--Cell and Molecular Biology.

Physical Description:

1 online resource (199 pages)

Distribution:

Ann Arbor : ProQuest Dissertations & Theses, 2023

Contained In:

Dissertations Abstracts International 85-08B.

Place of Publication:

[Philadelphia, Pennsylvania] : University of Pennsylvania, 2022.

Language Note:

English

Summary:

Mitochondria are dynamic organelles that move as well as divide and fuse, but how these processes occur is not fully understood. We investigated mechanisms of regulation of mitochondrial dynamics by the actin cytoskeleton. First, we examined actin's influence over equivalent mitochondrial partitioning between daughter cells in mitosis. Propagating in the space surrounding mitochondria is a wave of actin polymerization and depolymerization. In control and wave-depleted metaphase cells we labeled mitochondrial subpopulations with photo-activatable GFP and tracked their dispersion, finding significantly less dispersion in wave-depleted cells - a result that indicated that in mitosis the actin wave spatially shuffles mitochondria for truly symmetric division. We next investigated the cellular function of the wave during interphase. In interphase the actin wave promotes mitochondrial fragmentation, so we hypothesized that during this cell cycle stage the wave promotes mitochondrial hetero-fusion and thus content mixing. To test this hypothesis we imaged with high temporal resolution to track mitochondria recently/not recently sampled by the actin wave and found that indeed the presence of the wave enhances mitochondrial content mixing and hetero-fusion. We suggest that in certain cell types this process maintains mitochondrial homeostasis via complementation, as we found actin wave-depleted cells featured lower mitochondrial polarization and ATP generation. Having investigated regulation of mitochondrial dynamics specifically by the actin wave, we lastly considered one other way the actin cytoskeleton exerts control over these dynamics. Mitochondrial fission can occur at mito-ER contacts, formed by polymerization of actin on the ER. Unclear is what protein links this ER-actin to mitochondria, and we investigated this point. We focused on mitochondrially-associated myosin-19, and found that knock-down caused reticular mitochondrial networks whereas Myo19 overexpression fragmented mitochondria, but not when actin-binding was interrupted. This overexpression-induced mitochondrial fragmentation depended on proteins that polymerize actin at mito-ER contacts as well as the key fission mediator Drp1. Also, Myo19 depletion reduced mito-ER contacts. These data are consistent with the hypothesis that in certain cell types Myo19 tethers mitochondria to ER-actin to promote mitochondrial fission, and synergize with our investigations on the actin wave to shed light on the topic of mechanisms of regulation of mitochondrial dynamics by the actin cytoskeleton.

Notes:

Source: Dissertations Abstracts International, Volume: 85-08, Section: B.

Advisors: Holzbaur, Erika L. F.; Committee members: Ostap, E. Michael; Svitkina, Tatyana; Lakadamyali, Melike; Bi, Erfei.

Department: Cell and Molecular Biology.

Ph.D. University of Pennsylvania 2023.

Local Notes:

School code: 0175

ISBN:

9798381471601

Access Restriction:

Restricted for use by site license.