Polyamine metabolism links gut microbiota and testicular dysfunction

Background Male fertility impaired by exogenous toxins is a serious worldwide issue threatening the health of the new-born and causing infertility. However, the metabolic connection between toxic exposures and testicular dysfunction remains unclear. Results In the present study, the metabolic disorder of testicular dysfunction was investigated using triptolide-induced testicular injury in mice. We found that triptolide induced spermine deficiency resulting from disruption of polyamine biosynthesis and uptake in testis, and perturbation of the gut microbiota. Supplementation with exogenous spermine reversed triptolide-induced testicular dysfunction through increasing the expression of genes related to early and late spermatogenic events, as well as increasing the reduced number of offspring. Loss of gut microbiota by antibiotic treatment resulted in depletion of spermine levels in the intestine and potentiation of testicular injury. Testicular dysfunction in triptolide-treated mice was reversed by gut microbial transplantation from untreated mice and supplementation with polyamine-producing Parabacteroides distasonis. The protective effect of spermine during testicular injury was largely dependent on upregulation of heat shock protein 70s (HSP70s) both in vivo and in vitro. Conclusions The present study linked alterations in the gut microbiota to testicular dysfunction through disruption of polyamine metabolism. The diversity and dynamics of the gut microbiota may be considered as a therapeutic option to prevent male infertility.

Proteomic Responses to Alkali Stress in Oats and the Alleviatory Effects of Exogenous Spermine Application

Alkali stress limits plant growth and yield more strongly than salt stress and can lead to the appearance of yellow leaves; however, the reasons remain unclear. In this study, we found that (1) the down-regulation of coproporphyrinogen III oxidase, protoporphyrinogen oxidase, and Pheophorbide a oxygenase in oats under alkali stress contributes to the appearance of yellow leaves (as assessed by proteome and western blot analyses). (2) Some oat proteins that are involved in the antioxidant system, root growth, and jasmonic acid (JA) and indole-3-acetic acid (IAA) synthesis are up-regulated in response to alkalinity and help increase alkali tolerance. (3) We added exogenous spermine to oat plants to improve their alkali tolerance, which resulted in higher chlorophyll contents and plant dry weights than in plants subjected to alkaline stress alone. This was due to up-regulation of chitinase and proteins related to chloroplast structure, root growth, and the antioxidant system. Spermine addition increased sucrose utilization efficiency, and promoted carbohydrate export from leaves to roots to increase energy storage in roots. Spermine addition also increased the IAA and JA contents required for root growth.

ATP13A2-mediated endo-lysosomal polyamine export counters mitochondrial oxidative stress

Recessive loss-of-function mutations inATP13A2(PARK9) are associated with a spectrum of neurodegenerative disorders, including Parkinson’s disease (PD). We recently revealed that the late endo-lysosomal transporter ATP13A2 pumps polyamines like spermine into the cytosol, whereas ATP13A2 dysfunction causes lysosomal polyamine accumulation and rupture. Here, we investigate how ATP13A2 provides protection against mitochondrial toxins such as rotenone, an environmental PD risk factor. Rotenone promoted mitochondrial-generated superoxide (MitoROS), which was exacerbated by ATP13A2 deficiency in SH-SY5Y cells and patient-derived fibroblasts, disturbing mitochondrial functionality and inducing toxicity and cell death. Moreover, ATP13A2 knockdown induced an ATF4-CHOP-dependent stress response following rotenone exposure. MitoROS and ATF4-CHOP were blocked by MitoTEMPO, a mitochondrial antioxidant, suggesting that the impact of ATP13A2 on MitoROS may relate to the antioxidant properties of spermine. Pharmacological inhibition of intracellular polyamine synthesis with α-difluoromethylornithine (DFMO) also increased MitoROS and ATF4 when ATP13A2 was deficient. The polyamine transport activity of ATP13A2 was required for lowering rotenone/DFMO-induced MitoROS, whereas exogenous spermine quenched rotenone-induced MitoROS via ATP13A2. Interestingly, fluorescently labeled spermine uptake in the mitochondria dropped as a consequence of ATP13A2 transport deficiency. Our cellular observations were recapitulated in vivo, in aCaenorhabditis elegansstrain deficient in the ATP13A2 orthologcatp-6. These animals exhibited a basal elevated MitoROS level, mitochondrial dysfunction, and enhanced stress response regulated byatfs-1, theC. elegansortholog of ATF4, causing hypersensitivity to rotenone, which was reversible with MitoTEMPO. Together, our study reveals a conserved cell protective pathway that counters mitochondrial oxidative stress via ATP13A2-mediated lysosomal spermine export.