In the last two decades, a school of thought emerged that perceives male reproductive health, testicular function, and sperm output as a sentry for general, somatic health. Large-scale epidemiologic studies have already linked the reduced sperm count to increased risk of chronic somatic disease (e.g., cancer, cardiovascular, neurological and bone diseases), yet most of these studies have not taken full advantage of advanced andrological analysis. Altered proteostasis, i.e., the disbalance between protein synthesis and turnover, is a common denominator of many diseases, including but not limited to cancer and neurodegenerative diseases. This chapter introduces the concept of cellular proteostasis as a measure of sperm structural and functional integrity and an endpoint of varied impacts on spermiogenesis and sperm maturation, including heritability, general health, lifestyle, and occupational and environmental reprotoxic exposure. Special consideration is given to small molecule protein modifiers, sperm-binding seminal plasma proteins, zinc-interacting proteins, and redox proteins responsible for the maintenance of protein structure and the protection of spermatozoa from oxidative damage. While the main focus is on human male infertility, serious consideration is given to relevant animal models, and in particular to male food animals with extensive records of fertility from artificial insemination services. Altogether, the proteostatic biomarker discovery and validation studies set the stage for the integration of proteomics of sperm proteostasis with genomic and high throughput phenomic approaches to benefit both human and animal reproductive medicine.

Department of Obstetrics Gynecology and Women's Health University of Missouri Columbia MO USA

Department of Veterinary Sciences Faculty of Agrobiology Food and Natural Resources Czech University of Life Sciences Prague Czech Republic

Division of Animal Sciences University of Missouri Columbia MO USA

Laboratory of Reproductive Biology Institute of Biotechnology of the Czech Academy of Sciences BIOCEV Vestec Czech Republic

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Ahlering, P., Sutovsky, M., Gliedt, D., Branson, K., Miranda Vizuete, A., Sutovsky, P.: Sperm content of TXNDC8 reflects sperm chromatin structure, pregnancy establishment, and incidence of multiple births after ART. Syst Biol Reprod Med. 66, 311–321 (2020) PubMed DOI

Rubessa, M., Wheeler, M.B.: Label-free microscopy: a non-invasive new tool to assess gametes and embryo quality. Theriogenology. 150, 241–246 (2020) PubMed DOI

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Lawlor, M., Zigo, M., Kerns, K., Cho, I.K., Easley Iv, C.A., Sutovsky, P.: Spermatozoan metabolism as a non-traditional model for the study of Huntington's disease. Int. J. Mol. Sci. 23 (2022)

Buckman, C., George, T.C., Friend, S., Sutovsky, M., Miranda-Vizuete, A., Ozanon, C., Morrissey, P., Sutovsky, P.: High throughput, parallel imaging and biomarker quantification of human spermatozoa by ImageStream flow cytometry. Syst. Biol. Reprod. Med. 55, 244–251 (2009) PubMed DOI

Teixeira, D.M., Hadyme Miyague, A., Barbosa, M.A., Navarro, P.A., Raine-Fenning, N., Nastri, C.O., Martins, W.P.: Regular (ICSI) versus ultra-high magnification (IMSI) sperm selection for assisted reproduction. Cochrane Database Syst. Rev. 2, CD010167 (2020) PubMed

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Miles, E.L., O'Gorman, C., Zhao, J., Samuel, M., Walters, E., Yi, Y.J., Sutovsky, M., Prather, R.S., Wells, K.D., Sutovsky, P.: Transgenic pig carrying green fluorescent proteasomes. Proc. Natl. Acad. Sci. USA. 110, 6334–6339 (2013) PubMed DOI PMC

Zigo, M., Manaskova-Postlerova, P., Jonakova, V., Kerns, K., Sutovsky, P.: Compartmentalization of the proteasome-interacting proteins during sperm capacitation. Sci. Rep. 9, 12583 (2019) PubMed DOI PMC

Yi, Y.J., Zimmerman, S.W., Manandhar, G., Odhiambo, J.F., Kennedy, C., Jonakova, V., Manaskova-Postlerova, P., Sutovsky, M., Park, C.S., Sutovsky, P.: Ubiquitin-activating enzyme (UBA1) is required for sperm capacitation, acrosomal exocytosis and sperm-egg coat penetration during porcine fertilization. Int. J. Androl. 35, 196–210 (2012) PubMed DOI

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Yi, Y.J., Manandhar, G., Sutovsky, M., Li, R., Jonakova, V., Oko, R., Park, C.S., Prather, R.S., Sutovsky, P.: Ubiquitin C-terminal hydrolase-activity is involved in sperm acrosomal function and anti-polyspermy defense during porcine fertilization. Biol. Reprod. 77, 780–793 (2007) PubMed DOI

Thompson, W.E., Ramalho-Santos, J., Sutovsky, P.: Ubiquitination of prohibitin in mammalian sperm mitochondria: possible roles in the regulation of mitochondrial inheritance and sperm quality control. Biol. Reprod. 69, 254–260 (2003) PubMed DOI

Antelman, J., Manandhar, G., Yi, Y.J., Li, R., Whitworth, K.M., Sutovsky, M., Agca, C., Prather, R.S., Sutovsky, P.: Expression of mitochondrial transcription factor A (TFAM) during porcine gametogenesis and preimplantation embryo development. J. Cell. Physiol. 217, 529–543 (2008) PubMed DOI

Hillman, P., Ickowicz, D., Vizel, R., Breitbart, H.: Dissociation between AKAP3 and PKARII promotes AKAP3 degradation in sperm capacitation. PLoS One. 8, e68873 (2013) PubMed DOI PMC

Qu, X., Han, Y., Chen, X., Lv, Y., Zhang, Y., Cao, L., Zhang, J., Jin, Y.: Inhibition of 26S proteasome enhances AKAP3-mediated cAMP-PKA signaling during boar sperm capacitation. Anim. Reprod. Sci. 247, 107079 (2022) PubMed DOI

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