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Fis1 ablation in the male germline disrupts mitochondrial morphology and mitophagy, and arrests spermatid maturation

Varuzhanyan, Grigor and Ladinsky, Mark S. and Yamashita, Shun-ichi and Abe, Manabu and Sakimura, Kenji and Kanki, Tomotake and Chan, David C. (2021) Fis1 ablation in the male germline disrupts mitochondrial morphology and mitophagy, and arrests spermatid maturation. Development, 148 (16). Art. No. dev199686. ISSN 0950-1991. PMCID PMC8380467. doi:10.1242/dev.199686.

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Male germline development involves choreographed changes to mitochondrial number, morphology and organization. Mitochondrial reorganization during spermatogenesis was recently shown to require mitochondrial fusion and fission. Mitophagy, the autophagic degradation of mitochondria, is another mechanism for controlling mitochondrial number and physiology, but its role during spermatogenesis is largely unknown. During post-meiotic spermatid development, restructuring of the mitochondrial network results in packing of mitochondria into a tight array in the sperm midpiece to fuel motility. Here, we show that disruption of mouse Fis1 in the male germline results in early spermatid arrest that is associated with increased mitochondrial content. Mutant spermatids coalesce into multinucleated giant cells that accumulate mitochondria of aberrant ultrastructure and numerous mitophagic and autophagic intermediates, suggesting a defect in mitophagy. We conclude that Fis1 regulates mitochondrial morphology and turnover to promote spermatid maturation.

Item Type:Article
Related URLs:
URLURL TypeDescription CentralArticle
Varuzhanyan, Grigor0000-0001-6165-0857
Ladinsky, Mark S.0000-0002-1036-3513
Kanki, Tomotake0000-0001-9646-5379
Chan, David C.0000-0002-0191-2154
Additional Information:© 2021. Published by The Company of Biologists Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed. Received: 06 Apr 2021; Accepted: 13 Jul 2021. We are grateful to Hsiuchen Chen for help with generating conditional Fis1 mice, for work on the early part of this project, and for overall guidance. We thank the rest of the Chan lab members for helpful discussions. We thank the Caltech Kavli Nanoscience Institute for maintenance of the TF-30 electron microscope. This work was supported by the National Institutes of Health [R35 GM127147 to D.C.C.]; a National Science Foundation Graduate Research Fellowship [DGE-1144469 to G.V.]; a National Institutes of Health Cell and Molecular Biology Training Grant [GM07616T32 to G.V.]; a Japan Society for the Promotion of Science (JSPS) KAKENHI grant [16KK0162 to S.Y.]; a JSPS KAKENHI grant [16H06276 to T.K.]; M.S.L. was supported by the National Institute of Allergy and Infectious Diseases (NIAID) (2 P50 AI150464) (awarded to Pamela J. Bjorkman, Caltech). Open access funding provided by California Institute of Technology. Deposited in PMC for immediate release. Author contributions: Conceptualization: D.C.C.; Investigation: G.V., M.S.L.; Resources: S.Y., M.A., K.S., T.K.; Writing - original draft: G.V.; Writing - review & editing: D.C.C.; Supervision: D.C.C.; Funding acquisition: D.C.C. The authors declare no competing or financial interests.
Group:Kavli Nanoscience Institute
Funding AgencyGrant Number
NIHR35 GM127147
NSF Graduate Research FellowshipDGE-1144469
NIH Predoctoral FellowshipGM07616T32
Japan Society for the Promotion of Science (JSPS)16KK0162
Japan Society for the Promotion of Science (JSPS)16H06276
NIH2 P50 AI150464
Subject Keywords:Autophagy, Mitochondrial dynamics, Mitophagy, Spermatid, Spermatogenesis, Mouse
Issue or Number:16
PubMed Central ID:PMC8380467
Record Number:CaltechAUTHORS:20210831-213708833
Persistent URL:
Official Citation:Grigor Varuzhanyan, Mark S. Ladinsky, Shun-ichi Yamashita, Manabu Abe, Kenji Sakimura, Tomotake Kanki, David C. Chan; Fis1 ablation in the male germline disrupts mitochondrial morphology and mitophagy, and arrests spermatid maturation. Development 15 August 2021; 148 (16): dev199686. doi:
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:110672
Deposited By: Tony Diaz
Deposited On:31 Aug 2021 21:49
Last Modified:07 Sep 2021 16:09

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