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Mitochondrial Dynamics and Mitophagy during Male Germline Development

Citation

Varuzhanyan, Grigor (2020) Mitochondrial Dynamics and Mitophagy during Male Germline Development. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/1mes-yw82. https://resolver.caltech.edu/CaltechTHESIS:09232020-201548312

Abstract

Mitochondrial fusion and fission (mitochondrial dynamics) and mitophagy are well-established mitochondrial quality control mechanisms that safeguard cellular homeostasis. However, their role during development remains poorly understood. In this thesis, we establish the role of mitochondrial dynamics and mitophagy during the development of the male germline (spermatogenesis).

Spermatogenesis is one of biology’s most complex and lengthy differentiation processes, transforming spermatogonial stem cells into highly specialized sperm cells capable of fertilization. This elaborate differentiation program requires multiple transitions in mitochondrial morphology and extensive degradation of mitochondria, making it an attractive model system for investigating mitochondrial dynamics and mitophagy in vivo. Indeed, the field of mitochondrial dynamics has a long history with spermatogenesis. The first mitochondrial dynamics gene, Fuzzy onions (Fzo), was discovered in 1997 to mediate mitochondrial fusion during Drosophila spermatogenesis. However, the role of mitochondrial dynamics during mammalian spermatogenesis remained unknown for nearly two decades after discovery of Fzo. To address this gap in knowledge, we investigate mitochondrial dynamics and mitophagy during mammalian spermatogenesis. We uncover essential roles for mitochondrial fusion (Chapter 2), mitochondrial fission (Chapter 3), and mitophagy (Chapter 4) during spermatogenesis and show that each of these mitochondrial quality control mechanisms regulates a distinct stage of germ cell development. Our analyses reveal requirements for mitochondrial fusion, fission, and mitophagy that correspond to the mitochondrial and metabolic needs of the developing germ cells.

We also investigate the role of mitochondrial fusion and fission in regulating subcellular mitochondrial domains upon fusion of a skeletal muscle stem cell with a myofiber (Chapter 5). Thus, the work presented in this thesis characterizes the in vivo role of mitochondrial dynamics in two systems: male germline development and skeletal muscle regeneration. However, we focus on the role of mitochondrial dynamics and mitophagy during male germline development.

Item Type:Thesis (Dissertation (Ph.D.))
Subject Keywords:Mitochondrial fusion, fission, mitophagy, autophagy, spermatogenesis
Degree Grantor:California Institute of Technology
Division:Biology and Biological Engineering
Major Option:Biology
Thesis Availability:Public (worldwide access)
Research Advisor(s):
  • Chan, David C.
Thesis Committee:
  • Sternberg, Paul W. (chair)
  • Bronner, Marianne E.
  • Aravin, Alexei A.
  • Chan, David C.
Defense Date:18 September 2020
Non-Caltech Author Email:gvaruzhanyan (AT) gmail.com
Funders:
Funding AgencyGrant Number
National Science Foundation Graduate Research FellowshipDGE-1144469
NIHGM07616T32
California Institute for Regenerative Medicine (Stem Cell Bridges Program)TB1-01176
NIHR35GM127147A
NIHGM119388
NIHGM127147
NIHGM062967
Projects:Mitochondrial dynamics during spermatogenesis, Mitochondrial fusion is required for spermatogonial differentiation and meiosis, Mitochondrial fission is required for organization of the mitochondrial sheath in spermatids, Fis1-mediated mitophagy is required for spermatid development, Mitochondrial dynamics is a distinguishing feature of skeletal muscle fiber types and regulates organellar compartmentalization
Record Number:CaltechTHESIS:09232020-201548312
Persistent URL:https://resolver.caltech.edu/CaltechTHESIS:09232020-201548312
DOI:10.7907/1mes-yw82
Related URLs:
URLURL TypeDescription
https://doi.org/10.1242/jcs.235937DOIArticle adapted for Chapters 1 and 6.
https://doi.org/10.7554/eLife.51601DOIArticle adapted for Chapter 2.
https://doi.org/10.1016/j.cmet.2015.09.027DOIArticle adapted for Chapter 5.
https://doi.org/10.22002/D1.1622DOISupplementary files for Chapter 2.
http://dx.doi.org/10.22002/D1.1393DOIVideo files for Chapter 2.
http://dx.doi.org/10.22002/D1.1394DOIVideo files for Chapter 3.
http://dx.doi.org/10.22002/D1.1624DOIVideo files for Chapter 4.
ORCID:
AuthorORCID
Varuzhanyan, Grigor0000-0001-6165-0857
Default Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:13963
Collection:CaltechTHESIS
Deposited By: Grigor Varuzhanyan
Deposited On:16 Oct 2020 15:42
Last Modified:23 Oct 2020 19:39

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