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Mitochondrial fusion is required for spermatogonial differentiation and meiosis

Varuzhanyan, Grigor and Rojansky, Rebecca and Sweredoski, Michael J. and Graham, Robert L. J. and Hess, Sonja and Ladinsky, Mark S. and Chan, David C. (2019) Mitochondrial fusion is required for spermatogonial differentiation and meiosis. eLife, 8 . Art. No. e51601. ISSN 2050-084X. PMCID PMC6805159. https://resolver.caltech.edu/CaltechAUTHORS:20191014-105658223

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Abstract

Differentiating cells tailor their metabolism to fulfill their specialized functions. We examined whether mitochondrial fusion is important for metabolic tailoring during spermatogenesis. Acutely after depletion of mitofusins Mfn1 and Mfn2, spermatogenesis arrests due to failure to accomplish a metabolic shift during meiosis. This metabolic shift includes increased mitochondrial content, mitochondrial elongation, and upregulation of oxidative phosphorylation (OXPHOS). With long-term mitofusin loss, all differentiating germ cell types are depleted, but proliferation of stem-like undifferentiated spermatogonia remains unaffected. Thus, compared with undifferentiated spermatogonia, differentiating spermatogonia and meiotic spermatocytes have cell physiologies that require high levels of mitochondrial fusion. Proteomics in fibroblasts reveals that mitofusin-null cells downregulate respiratory chain complexes and mitochondrial ribosomal subunits. Similarly, mitofusin depletion in immortalized spermatocytes or germ cells in vivo results in reduced OXPHOS subunits and activity. We reveal that by promoting OXPHOS, mitofusins enable spermatogonial differentiation and a metabolic shift during meiosis.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.7554/elife.51601DOIArticle
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6805159/PubMed CentralArticle
ORCID:
AuthorORCID
Varuzhanyan, Grigor0000-0001-6165-0857
Sweredoski, Michael J.0000-0003-0878-3831
Hess, Sonja0000-0002-5904-9816
Ladinsky, Mark S.0000-0002-1036-3513
Chan, David C.0000-0002-0191-2154
Additional Information:© 2019, Varuzhanyan et al. This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited. Received: 04 September 2019; Accepted: 27 September 2019; Published: 09 October 2019. We thank Hsiuchen Chen for her initial characterization of S8::Mfn1 and S8::Mfn2 mice, for help with maintaining mouse colonies, and for overall guidance throughout the project. We thank Safia Malki and Alex Bortvin for providing a detailed protocol for chromosomal spreading and with help identifying germ cell-specific markers; Prabhakara P. Reddi for providing the SP-10 antibody; and Jared Rutter for advice on studying MPC1. We thank all members of the Chan Lab for helpful discussions and for comments on the manuscript. Grigor Varuzhanyan was supported by a National Science Foundation Graduate Research Fellowship (DGE‐1144469) and a National Institutes of Health Cell and Molecular Biology Training Grant (GM07616T32). Sonja Hess and Robert LJ Graham were supported by grants from the Gordon and Betty Moore Foundation through GBMF775 and the Beckman Institute. This work was supported by NIH grants GM119388 and GM127147. The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. The authors declare no competing interests. Ethics: Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols of the California Institute of Technology. Data availability: All data generated or analyzed during this study are included in the manuscript and supporting files.
Funders:
Funding AgencyGrant Number
NSF Graduate Research FellowshipDGE‐1144469
NIH Predoctoral FellowshipGM07616T32
Gordon and Betty Moore FoundationGBMF775
Caltech Beckman InstituteUNSPECIFIED
NIHGM119388
NIHGM127147
Subject Keywords:mitochondrial fusion, mitofusins, spermatogenesis, meiosis, mitochondria
PubMed Central ID:PMC6805159
Record Number:CaltechAUTHORS:20191014-105658223
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20191014-105658223
Official Citation:Varuzhanyan et al. eLife 2019;8:e51601. DOI: https://doi.org/10.7554/eLife.51601
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:99250
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:14 Oct 2019 18:11
Last Modified:05 Nov 2019 20:46

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