Mitochondria are critical cellular energy resources and are central to the life of the neuron. Mitophagy selectively clears damaged or dysfunctional mitochondria through autophagic machinery to maintain mitochondrial quality control and homeostasis. Mature neurons are postmitotic and consume substantial energy, thus require highly efficient mitophagy pathways to turn over damaged or dysfunctional mitochondria. Recent evidence indicates that mitophagy is pivotal to the pathogenesis of neurological diseases. However, more work is needed to study mitophagy pathway components as potential therapeutic targets. In this review, we briefly discuss the characteristics of nonselective autophagy and selective autophagy, including ERphagy, aggrephagy, and mitophagy. We then introduce the mechanisms of Parkin-dependent and Parkin-independent mitophagy pathways under physiological conditions. Next, we summarize the diverse repertoire of mitochondrial membrane receptors and phospholipids that mediate mitophagy. Importantly, we review the critical role of mitophagy in the pathogenesis of neurodegenerative diseases including Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. Last, we discuss recent studies considering mitophagy as a potential therapeutic target for treating neurodegenerative diseases. Together, our review may provide novel views to better understand the roles of mitophagy in neurodegenerative disease pathogenesis.

Background: A gut-microbial metabolite, trimethylamine N-oxide (TMAO), has been associated with type 2 diabetes mellitus (T2DM). Few previous prospective studies have addressed associations between the changes in TMAO and T2DM incidence. Methods: Data were derived from a longitudinal cohort conducted from 2019 to 2021 in rural areas of Fuxin County, Liaoning Province, China, and 1515 diabetes-free participants aged above 35 years were included. The concentrations of serum TMAO and its precursors were measured at two time points, namely in 2019 and 2021. TMAO and TMAO changes (ΔTMAO) were separately tested in a logistic regression model. For further examination, the odds ratios (ORs) for T2DM were calculated according to a combination of TMAO levels and ΔTMAO levels. Results: During a median follow-up of 1.85 years, 81 incident cases of T2DM (5.35%) were identified. Baseline TMAO levels exhibited a nonlinear relationship, first decreasing and then increasing, and only at the highest quartile was it associated with the risk of T2DM. The OR for T2DM in the highest quartile of serum TMAO was 3.35 (95%CI: 1.55–7.26, p = 0.002), compared with the lowest quartile. As for its precursors, only choline level was associated with T2DM risk and the OR for T2DM in the Q3 and Q4 of serum choline was 3.37 (95%CI: 1.41–8.05, p = 0.006) and 4.72 (95%CI: 1.47–15.13, p = 0.009), respectively. When considering both baseline TMAO levels and ΔTMAO over time, participants with sustained high TMAO levels demonstrated a significantly increased risk of T2DM, with a multivariable-adjusted OR of 8.68 (95%CI: 1.97, 38.34). Conclusion: Both initial serum TMAO levels and long-term serum TMAO changes were collectively and significantly associated with the occurrence of subsequent T2DM events. Interventions aimed at normalizing TMAO levels, such as adopting a healthy dietary pattern, may be particularly beneficial in T2DM prevention.

Parabens are common preservatives in personal care products, cosmetics, and medical goods. In the past few years, animal studies showed the male reproductive toxicity associated with some parabens. Yet, epidemiological studies have generated inconsistent findings and research rarely has focused on the mixture effects of the parabens. We aimed to explore the associations between individual paraben exposure as well as the mixture and semen quality parameters. A total of 795 male partners from preconception couples were included in the study. Their urine samples were analyzed for the concentrations of six parabens, namely methyl paraben (MeP), ethyl paraben (EtP), propyl paraben (PrP), butyl paraben (BuP), benzyl paraben (BzP) and heptyl paraben (HeP). Multiple linear regression models and weighted quantile sum regression (WQS) models were utilized to assess the relationships between individual paraben exposure and paraben mixture with semen quality parameters, respectively. After adjusting for covariates, exposure to a paraben mixture was significantly associated with declining sperm concentration, total sperm count, and progressive motility, among which BuP was identified as the main contributor to sperm concentration and total sperm count while MeP to progressive motility. Results from multiple linear regression models were generally in line with the WQS analysis. Our results suggest negative associations between paraben mixture and sperm concentration, total sperm count, and sperm motility among reproductive-aged men.

STUDY QUESTION: Is pre-conception exposure to parabens associated with fecundity in couples of childbearing age?SUMMARY ANSWER: Paraben exposure in female partners was associated with reduced couple fecundity and anti-Müllerian hormone (AMH) might be one of the possible mediators.WHAT IS KNOWN ALREADY: The reproductive toxicity of parabens, a class of widely used preservatives, has been suggested but evidence regarding their effects on couple fecundity is scarce.STUDY DESIGN, SIZE, DURATION: In this couple-based prospective cohort study, a total of 884 pre-conception couples who participated in the Shanghai Birth Cohort between 2013 and 2015 were included.PARTICIPANTS/MATERIALS, SETTING, METHODS: Concentrations of six parabens were measured in urine samples collected from couples. Malondialdehyde, C-reactive protein, and AMH were assessed in female partners. The outcomes included couple fecundability (time-to-pregnancy, TTP) and infertility (TTP > 12 menstrual cycles). Partner-specific and couple-based models were applied to estimate the associations. The joint effect of paraben mixture on couple fecundity was estimated by quantile-based g-computation (q-gcomp). Mediation analysis was used to assess the mediating roles of oxidative stress, inflammation and ovarian reserve.MAIN RESULTS AND THE ROLE OF CHANCE: A total of 525 couples (59.4%) conceived spontaneously. In the partner-specific model, propyl paraben (PrP), butyl paraben (BuP), and heptyl paraben (HeP) in female partners were associated with reduced fecundability (fecundability odds ratio (95% CI): 0.96 (0.94–0.98) for PrP; 0.90 (0.87–0.94) for BuP; 0.42 (0.28–0.65) for HeP) and increased risk of infertility (rate ratio (95% CI): 1.06 (1.03–1.10) for PrP; 1.14 (1.08–1.21) for BuP; 1.89 (1.26–2.83) for HeP). Similar associations were observed in the couple-based model. AMH played a significant mediation role in the association (average causal mediation effect (95% CI): 0.001 (0.0001–0.003)). Paraben exposure in male partners was not associated with couple fecundity. The joint effect of paraben mixture on couple fecundity was non-significant.LIMITATIONS, REASONS FOR CAUTION: Self-reported pregnancy and single urine sample may lead to misclassification. The mediation analysis is limited in that levels of sex hormones were not measured. The inclusion of women with irregular menstrual cycles might affect the results. It is possible that the observed association was due to reverse causation.WIDER IMPLICATIONS OF THE FINDINGS: This is the first study to assess the effects of paraben exposure on couple fecundity in Asians. Given the widespread exposure to parabens in couples of childbearing age, the present findings may have important public health implications.STUDY FUNDING/COMPETING INTEREST(S): This study was supported in part by the National Natural Science Foundation of China (41991314), the Shanghai Science and Technology Development Foundation (22YF1426700), the Science and Technology Commission of Shanghai Municipality (21410713500), and the Shanghai Municipal Health Commission (2020CXJQ01). All authors declare no conflict of interest.TRIAL REGISTRATION NUMBER: N/A.