Infertility and Reproduction Research Program, Hunter Medical Research Institute, New Lambton Heights, NSW, Australia.
School of Environmental and Life Sciences, College of Engineering, Science and Environment, The University of Newcastle, Callaghan, New South Wales, Australia.
Antioxid Redox Signal. 2024 Aug;41(4-6):296-321. doi: 10.1089/ars.2023.0314. Epub 2024 Mar 25.
Stringent regulation of protein homeostasis pathways, under both physiological and pathological conditions, is necessary for the maintenance of proteome fidelity and optimal cell functioning. However, when challenged by endogenous or exogenous stressors, these proteostasis pathways can become dysregulated with detrimental consequences for protein fate, cell survival, and overall organism health. Most notably, there are numerous somatic pathologies associated with a loss of proteostatic regulation, including neurodegenerative disorders, type 2 diabetes, and some cancers. Lipid oxidation-derived reactive carbonyl species (RCS), such as 4-hydroxynonenal (4HNE) and malondialdehyde, are relatively underappreciated purveyors of proteostatic dysregulation, which elicit their effects the nonenzymatic post-translational modification of proteins. Emerging evidence suggests that a subset of germline proteins can serve as substrates for 4HNE modification. Among these, prevalent targets include succinate dehydrogenase, heat shock protein A2 and A-kinase anchor protein 4, all of which are intrinsically associated with fertility. Despite growing knowledge in this field, the RCS adductomes of spermatozoa and oocytes are yet to be comprehensively investigated. Furthermore, the manner by which RCS-mediated adduction impacts protein fate and drives cellular responses, such as protein aggregation, requires further examination in the germline. Given that RCS-protein adduction has been attributed a role in infertility, there has been sparked research investment into strategies to prevent lipid peroxidation in germ cells. An increased depth of knowledge regarding the mechanisms and substrates of RCS-mediated protein modification in reproductive cells may reveal important targets for the development of novel therapies to improve fertility and pregnancy outcomes for future generations.
在生理和病理条件下，严格调控蛋白质动态平衡途径对于维持蛋白质组保真度和细胞最佳功能是必要的。然而，当受到内源性或外源性应激源的挑战时，这些蛋白质动态平衡途径可能会失调，对蛋白质命运、细胞存活和整体生物体健康产生不利影响。值得注意的是，有许多与蛋白质动态平衡调节丧失相关的躯体病理学，包括神经退行性疾病、2 型糖尿病和一些癌症。
脂质氧化衍生的反应性羰基化合物（RCS），如 4-羟基壬烯醛（4HNE）和丙二醛，是相对未被充分认识的蛋白质动态平衡失调的提供者，它们通过非酶翻译后修饰蛋白质来发挥作用。新出现的证据表明，一组种系蛋白可以作为 4HNE 修饰的底物。在这些蛋白中，常见的靶标包括琥珀酸脱氢酶、热休克蛋白 A2 和 A 激酶锚蛋白 4，它们都与生育能力密切相关。
尽管在这一领域的知识不断增加，但精子和卵子的 RCS 加合物组尚未得到全面研究。此外，RCS 介导的加合物对蛋白质命运的影响方式以及驱动细胞反应（如蛋白质聚集）的方式，在生殖系中需要进一步研究。鉴于 RCS-蛋白质加合物在不孕不育中起作用，因此已经有研究投资于预防生殖细胞脂质过氧化的策略。
增加对生殖细胞中 RCS 介导的蛋白质修饰的机制和底物的深入了解，可能会为开发新的治疗方法以提高未来几代人的生育能力和妊娠结局提供重要的靶点。
