Autophagy, a critical element in the aging male reproductive disorders and prostate cancer: a therapeutic point of view

Abstract

Autophagy is a highly conserved, lysosome-dependent biological mechanism involved in the degradation and recycling of cellular components. There is growing evidence that autophagy is related to male reproductive biology, particularly spermatogenic and endocrinologic processes closely associated with male sexual and reproductive health. In recent decades, problems such as decreasing sperm count, erectile dysfunction, and infertility have worsened. In addition, reproductive health is closely related to overall health and comorbidity in aging men. In this review, we will outline the role of autophagy as a new player in aging male reproductive dysfunction and prostate cancer. We first provide an overview of the mechanisms of autophagy and its role in regulating male reproductive cells. We then focus on the link between autophagy and aging-related diseases. This is followed by a discussion of therapeutic strategies targeting autophagy before we end with limitations of current studies and suggestions for future developments in the field.

Keywords: Aging; Autophagy; Erectile dysfunction; Inflammaging; Male infertility; Prostate cancer.

Fig. 1

A-C) Schematic representation of three main types of autophagy process, including chaperone-mediated autophagy (A), microautophagy (B), and macroautophagy (C). HSC70: heat shock cognate 71 kDa protein; GFAP: glial fibrillary acidic protein; LAMP2A: lysosome-associated membrane protein type 2 A; ER: endoplasmic reticulum; lys-HSC70: lysosomal HSC70; AMPK: AMP-activated protein kinase; mTOR: mammalian target of rapamycin; ATG: autophagy-related proteins; ULK1: Unc-51-like kinase 1; PI3K: phosphoinositide 3-kinase; PI3P: phosphatidylinositol 3-phosphate; LC3: microtubule-associated protein 1 A/1B-light chain 3; PE: phosphatidylethanolamine

Fig. 2

Proposed role of ATG7 in acrosome biogenesis. ATG7 is involved in acrosome biogenesis by regulating the transport of proacrosomal vesicles and/or fusion with the acrosome. Germ cell-specific knockout of this gene in mouse models could result in the failure of acrosome biogenesis, which corresponds to globozoospermia in humans

Fig. 3

The involvement of autophagy in the organization of ES in Sertoli cells. The apical and basal ES are actin microfilament-rich anchoring junctions. The apical ES shapes the spermatid head, controls spermiation, and orients elongated spermatids. The basal compartment is the constructive part of the BTB. ES: ectoplasmic specialization; PDLIM1: PDZ and LIM domain 1; BTB: blood-testis barrier

Fig. 4

The role of aging-related decline of autophagy in Inflammaging. The aging process leads to a decrease in autophagy, resulting in the abnormal accumulation of proteins and dysfunctional organelles (especially mitochondria), which is one of the mechanisms that lead to Inflammaging. TNFα: tumor necrosis factor α; IL: interleukin. ↑: increase or induction; ↓: decrease or inhibition

Fig. 5

Examples of the target signaling pathways that have been studied for the treatment of ED and/or PCa. ED: erectile dysfunction; PCa: prostate cancer; PI3K: phosphoinositide 3-kinase; TSC1/2: tuberous sclerosis proteins 1 and 2; GTP: guanosine-5’-triphosphate; Rheb: Ras homolog enriched in the brain; mTORC1: mammalian target of rapamycin complex 1; AMPK: AMP-activated protein kinase; FoxO3: forkhead box O-3; SKP2: S-phase kinase-associated protein 2; CARM1: Coactivator-associated arginine methyltransferase 1; TFEB: Transcription Factor EB

Fig. 6

Examples of pharmacological drugs or therapeutical techniques researched for the treatment of PCa that primarily act through the Akt/mTOR pathway. As previously stated, autophagy is a double-edged sword because its over- or under-activation may result in cancer cell death, reduced survival, and migration. This fact has given rise to several studies on various PCa treatments. PCa: prostate cancer