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Aluminum is a neurotoxic food contaminant. Aluminum trichloride (AlCl 3 ) causes hippocampal mitochondrial damage, leading to hippocampal injury. Damaged mitochondria can release mitochondrial reactive oxygen species (mtROS) and activate nucleotide-binding oligomerization domain-like receptor-containing 3 (NLRP3) inflammasomes and apoptosis. E3 ubiquitin ligase PARK2 (Parkin)-mediated mitophagy can attenuate mitochondrial damage. However, the role of mitophagy in AlCl 3 -induced mice hippocampal damage and its regulatory mechanism remain elusive. First, C57BL/6 N mice were treated with 0, 44.825, 89.65, and 179.3 mg/kg body weight AlCl 3 drinking water for 90 d. Apoptosis, NLRP3-inflammasome activation and mitochondrial damage were increased in AlCl 3 -induced hippocampal damage. In addition, Parkin-mediated mitophagy peaked in the middle-dose group and was slightly attenuated in the high-dose group. Subsequently, we used wild-type and Parkin knockout (Parkin -/- ) mice to investigate the AlCl 3 -induced hippocampal damage. The results showed that Parkin -/- inhibited mitophagy, and aggravated AlCl 3 -induced mitochondrial damage, NLRP3-inflammasome activation, apoptosis and hippocampal damage. Finally, we administered MitoQ (mtROS inhibitor) and MCC950 (NLRP3 inhibitor) to AlCl 3 -treated Parkin -/- mice to investigate the mechanism of Parkin-mediated mitophagy. The results showed that inhibition of mtROS and NLRP3 attenuated hippocampal NLRP3-inflammasome activation, apoptosis, and damage in AlCl 3 -treated Parkin -/- mice. These findings indicate that Parkin-mediated mitophagy protects against AlCl 3 -induced hippocampal apoptosis in mice via the mtROS-NLRP3 pathway., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Aluminium (Al) accumulates in the spleen and causes spleen apoptosis. Mitochondrial dyshomeostasis represents primary mechanisms of spleen apoptosis induced by Al. Apoptosis-inducing factor (AIF) is located in the gap of the mitochondrial membrane and can be released into the nucleus, leading to apoptosis. Phosphatase and tensin homolog (PTEN)-induced putative kinase1 (PINK1)/E3 ubiquitin ligase PARK2 (Parkin)-mediated mitophagy maintains mitochondrial homeostasis by removing damaged mitochondria, but its function in AIF-mediated spleen apoptosis induced by Al is not clear. In our study, aluminium trichloride (AlCl 3 ) was diluted in water for 90 d and administered to 75 male C57BL/6N mice at 0, 44.8, 59.8, 89.7, and 179.3 mg/kg body weight. AlCl 3 triggered PINK1/Parkin pathway-mediated mitophagy, induced AIF release and AIF-mediated spleen apoptosis. AlCl 3 was administered to sixty male C57BL/6N mice of wild type and Parkin knockout for 90 d at 0 and 179.3 mg/kg body weight. The results indicated that Parkin deficiency decreased mitophagy, aggravated mitochondrial damage, AIF release and AIF-mediated spleen apoptosis induced by AlCl 3 . According to our results, PINK1/Parkin-mediated mitophagy and AIF-mediated spleen apoptosis are caused by AlCl 3 , whereas mitophagy is protective in AIF-mediated apoptosis induced by AlCl 3 ., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Dibutyl phthalate (DBP) is a plasticizer widely used in daily production, which causes serious environmental pollution, and damage to brain, liver, kidney, and lung by producing excessive reactive oxygen species (ROS) after entering the body. DBP can also cause skeletal dysplasia, but it is unclear whether ROS is involved. In addition, overproduction of ROS can activate mitophagy, which is an important mechanism for regulating mitochondrial quality and cell homeostasis. In order to investigate whether DBP can damage MC3T3-E1 cells (osteoblast cell line) and whether ROS and mitophagy are involved, DBP toxicity experiment, Parkin gene silencing experiment, and N-acetylcysteine (NAC) intervention experiment were performed on MC3T3-E1 cells in turn. First, we found that DBP caused MC3T3-E1 cell viability decline and osteogenic dysfunction, accompanied by the overproduction of ROS and the activation of mitophagy. Then, we found that silencing Parkin expression alleviated DBP-induced apoptosis and osteogenic dysfunction of MC3T3-E1 cells. In addition, NAC treatment inhibited the PINK1/Parkin-mediated mitophagy and alleviated the apoptosis and osteogenic dysfunction of MC3T3-E1 cells caused by DBP. Our research results showed that DBP could cause MC3T3-E1 cell damage by increasing ROS to promote the PINK1/Parkin-mediated mitophagy., (© 2022 Wiley Periodicals LLC.)

Aflatoxin B 1 (AFB 1 ) can cause mitochondrial malfunction and immunosuppression in spleen. Mitochondrial damage can lead to oxidative stress and aggravate immune cell dysfunction. Phosphatase and tensin homolog (PTEN)-induced putative kinase1 (PINK1)/ E3 ubiquitin ligase PARK2 (Parkin)-mediated mitophagy can scavenge damaged mitochondria and alleviate oxidative stress to maintain cellular homeostasis. However, the role of PINK1/Parkin-mediated mitophagy in AFB 1 -induced immunosuppression in spleen is unclear. In this study, sixty male mice were sensibilized orally with AFB 1 at different concentrations [0, 0.5, 0.75, and 1 mg/kg body weight (BW)] for 28 days, and AFB 1 caused splenic structure injury and immunosuppression, also led to upregulation of PINK1/Parkin-mediated mitophagy in a dose-dependent manner. Subsequently, thirty male WT C57BL/6 N mice and thirty male Parkin knockout (Parkin -/- ) C57BL/6 N mice were sensibilized orally with AFB 1 at 0 or 1 mg/kg BW for 28 days, and Parkin -/- inhibited mitophagy and further aggravated AFB 1 -induced splenic structure injury, immunosuppression, mitochondrial damage and oxidative stress. Collectively, these results indicate that AFB 1 exposure activates PINK1/Parkin-mediated mitophagy, which protects against immunosuppression in spleen., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Aluminum (Al) is a food pollutant that has extensive deleterious effects on the liver. Our previous research proposed that E3 ubiquitin ligase PARK2 knockout (Parkin -/- ) could aggravate Al-induced liver damage by inhibiting mitophagy, during which the reactive oxygen species (ROS) content increases. Inhibition of mitophagy can activate inflammasome. But the link between Parkin-mediated mitophagy and liver inflammatory injury caused by Al, and the role of ROS in it remain unclear. In this study, we applied Al, Parkin -/- and N-acetyl-L-cysteine (NAC) to act on C57BL/6N mice to investigate them. We found that Al could induce liver inflammatory injury and Parkin -/- could aggravate it. Meanwhile, inhibition of ROS alleviated oxidative stress, mitochondrial damage, mitophagy and inflammatory injury caused by Al in Parkin -/- mice liver. These results indicated that ROS antagonized the protection of Parkin-mediated mitophagy against Al-induced liver inflammatory damage in mice., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Oxidative stress is the main mechanism of aluminum (Al) reproductive toxicity and can also lead to mitochondrial damage. Damaged mitochondria can trigger apoptosis, leading to testicular damage. PINK1 (phosphatase and tensin homolog (PTEN)-induced putative kinase1)/Parkin (E3 ubiquitin ligase PARK2)-mediated mitophagy can remove damaged mitochondria to maintain cellular homeostasis. However, its role in testicular damage caused by Al is unclear. In this study, first, 24 male wild type (WT) C57BL/6 N mice were divided into 4 groups and orally administered with 0, 44.825, 89.65, and 179.3 mg/kg body weight AlCl 3 for 90 days, respectively. We demonstrated that apoptosis and PINK1/Parkin-mediated mitophagy were activated in a dose-effect relationship in the damaged testis caused by AlCl 3 , and were most significant at 179.3 mg/kg body weight AlCl 3 . Then, 40 male WT C57BL/6 N mice and 40 male Parkin knockout (Parkin -/- ) C57BL/6 N mice were divided into 4 groups and orally administered with 0, 179.3, 0 or 179.3 mg/kg body weight AlCl 3 for 90 days, respectively. Parkin -/- inhibited mitophagy, exacerbated the growth inhibition, testicular damage, mitochondrial damage, oxidative stress, and apoptosis under AlCl 3 exposure. In general, the results reveal that AlCl 3 exposure can activate PINK1/Parkin-mediated mitophagy, and the PINK1/Parkin-mediated mitophagy plays a protective role in the testicular damage caused by AlCl 3 ., (Copyright © 2022. Published by Elsevier Inc.)

T-2 toxin can cause mitochondrial impairment and subsequent renal damage. PINK1/Parkin-mediated mitophagy can mitigate renal impairment by alleviating mitochondrial damage. Nevertheless, the impact of PINK1/Parkin-mediated mitophagy in T-2 toxin-induced renal injury remains unclear. Here, we studied the role of PINK1/Parkin-mediated mitophagy in T-2 toxin-induced nephrotoxicity. Mitochondrial damage was accompanied by NLRP3-inflammasome activation and PINK1/Parkin-mediated mitophagy in the kidney of T-2 toxin-exposed C57BL/6N mice. Knocking out Parkin inhibited the mitophagy but aggravated the structural and functional damage, NLRP3-inflammasome activation, mitochondrial damage, and apoptosis. Correlation analysis revealed that NLRP3-inflammasome activation was correlated with apoptosis. These results show that PINK1/Parkin-mediated mitophagy mitigates T-2 toxin-induced nephrotoxicity., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Aflatoxin B 1 (AFB 1 ) can cause oxidative stress leading to mitochondrial damage and subsequent liver injury. Although it is well-known that damaged mitochondria are eliminated by PINK1/Parkin-mediated mitophagy, this mechanism has not yet been characterized in the context of AFB 1 -induced liver injury. In this study, male wild-type C57BL/6N mice were divided into groups 1-4, which were then orally administered 0, 0.5, 0.75, and 1 mg/kg body weight AFB 1 for 28 d, respectively. Our results demonstrated that oxidative stress, NLRP3-inflammasome activation, and mitochondrial damage were dose-dependently augmented in AFB 1 -induced liver injury. Additionally, PINK1/Parkin-mediated mitophagy peaked in the groups that had received a mid-dose of AFB 1 (0.75 mg/kg), which was attenuated slightly in high-dose groups. Afterward, we further characterized AFB 1 -induced liver injury by comparing wild-type C57BL/6N mice with Parkin knockout (Parkin -/- ) mice. We found that the restricted mitophagy in Parkin -/- mice was associated with increased oxidative stress, NLRP3-inflammasome activation, mitochondrial damage, and liver injury. Taken together, these results indicate that PINK1/Parkin-mediated mitophagy plays an important role in attenuating AFB 1 -induced liver injury in mice., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Aluminum (Al) induces apoptosis via oxidative stress and/or mitochondrial damage. Kidney is the main organ of Al excretion, but whether Al causes apoptosis in kidney of mice remains unclear. Mitophagy maintains cell homeostasis via clearing damaged mitochondria and reducing oxidative stress, but the role in kidney damage caused by Al has also not been investigated. In this study, firstly, forty wild type (WT) male C57 mice were randomly exposed to AlCl 3 at 0, 44.825, 89.65 or 179.3 mg/kg body weight in drinking water for 90 days, respectively. Our results confirmed that Al induced apoptosis, and activated PINK1 (phosphatase and tensin homolog (PTEN)-induced putative kinase1)/Parkin (E3 ubiquitin ligase PARK2)-mediated mitophagy with the dose increased. And secondly, to further assess the role of PINK1/Parkin-mediated mitophagy in Al-induced kidney damage, twenty Parkin knockout (Parkin -/- ) mice and twenty WT mice were divided into WT group, WT + Al group, Parkin -/- group, and Parkin -/-  + Al group, and they were provided with AlCl 3 at a dose of 0 or 179.3 mg/kg body weight in drinking water for 90 days, respectively. The results showed that Parkin -/- induced more severe kidney injury caused by Al. Besides, Parkin -/- aggravated oxidative stress and apoptosis caused by Al. Overall, our findings indicate that the activation of PINK1/Parkin-mediated mitophagy protects against apoptosis in kidney damage caused by Al., (Copyright © 2022. Published by Elsevier Inc.)

Aflatoxin B 1 (AFB 1 ) is a toxic food pollutant that has extensive deleterious impacts on the kidney. Oxidative stress represents the primary mechanism of AFB 1 nephrotoxicity and can also cause mitochondrial damage. Damaged mitochondria can trigger apoptosis leading to kidney injury. PINK1/Parkin-mediated mitophagy can alleviate mitochondrial injury to maintain cellular homeostasis, however, its role in AFB 1 -induced kidney damage is unknown. To investigate the effect of PINK1/Parkin-mediated mitophagy on kidney impairment triggered by AFB 1 , 40 male wild-type (WT) C57BL/6N mice were first assigned to 4 groups and orally exposed to AFB 1 at 0, 0.5, 0.75, and 1 mg/kg body weight (BW) for 28 days. The results revealed that AFB 1 induced kidney damage, oxidative stress, mitochondrial damage, apoptosis and activated PINK1/Parkin-mediated mitophagy with a dose-dependent effect. Then, 20 male WT C57BL/6N mice and 20 male Parkin knockout (Parkin -/- ) C57BL/6N mice were assigned to 4 groups and orally exposed to AFB 1 at 0, 1, 0, and 1 mg/kg BW for 28 days. The results revealed that Parkin -/- suppressed mitophagy and exacerbated kidney damage, oxidative stress, mitochondrial damage, and apoptosis under AFB 1 exposure. The aforementioned evidences demonstrate that PINK1/Parkin-mediated mitophagy is activated by AFB 1 and protects against kidney damage in mice., (Copyright © 2022 Elsevier B.V. All rights reserved.)

The problem of excessive aluminum (Al) content in food is widespread. After Al enters the body, it can cause mineral metabolism imbalance and reactive oxygen species (ROS) overproduction, which ultimately leads to bone impairment. ROS is mainly produced in mitochondria and acts on mitochondria. Mitochondrial damage is closely related to mitophagy and apoptosis. In order to clarify whether ROS-mediated mitophagy and apoptosis are involved in Al-induced femoral impairment, forty-eight male C57BL/6 N mice were exposed to AlCl 3 (179.3 mg/kg) and/or NAC (100 mg/kg) for 90 days. Our results showed that NAC inhibited the mitophagy and apoptosis, and alleviated growth inhibition, mineral metabolism imbalance, structural damage, decreased bone mineral density and decreased bone formation factor expressions in the femora of Al-treated mice. These results suggest that ROS-mediated mitophagy and apoptosis are involved in Al-induced femoral impairment in mice, exogenous ROS clearance is a potential strategy for the treatment of Al-induced bone impairment., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Aluminum (Al) is a ubiquitous environmental metal toxicant that causes osteoblast (OB) damage which leads to Al-related bone diseases. Mitochondrial damage plays a key role in Al-related bone diseases, and while mitophagy can clear damaged mitochondria and improve OB function, the relationship between mitophagy and Al-induced OB dysfunction is unknown. To explore the role of mitophagy in Al-induced OB dysfunction in vitro, we used 2 μM carbonyl cyanide m-chlorophenylhydrazone (CCCP) and 0.4 μM Cyclosporin A (CsA) to activate and inhibit mitophagy, respectively. MC3T3-E1 cells were treated with 0 mM AlCl 3 (control group); 2 mM AlCl 3 (Al group); 2 μM CCCP (CCCP group); 2 μM CCCP and 2 mM AlCl 3 (CCCP + Al group); 0.4 μM CsA (CsA group); 0.4 μM CsA and 2 mM AlCl 3 (CsA + Al group). The results showed that Al induced ultrastructural and functional impairment of MC3T3-E1 cells. Compared to the Al group, mitophagy activation caused mitochondrial membrane potentials to collapse, up-regulated PINK1, Parkin, and LC3 expression, down-regulated p62 expression, and increased mitophagosome numbers. Mitophagy activation also reduced Al-induced oxidative stress and MC3T3-E1 cell functional damage, as seen in improvement in cell viability, cellular calcium and phosphorus contents, and collagen I, osteocalcin, and bone alkaline phosphatase gene expression. Mitophagy inhibition had the opposite effects on activation. Overall, these results show that mitophagy can protect against Al-induced OB dysfunction., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Aluminum (Al), as a common environmental pollutant, causes osteoblast (OB) dysfunction and then leads to Al-related bone diseases (ARBD). One of the mechanisms of ARBD is oxidative stress, which leads to an increase in the production of reactive oxygen species (ROS). ROS can induce mitochondrial damage, thereby inducing mitophagy and apoptosis. But whether mitophagy and apoptosis mediated by ROS, and the role of ROS in AlCl 3 -induced MC3T3-E1 cell dysfunction is still unclear. In this study, MC3T3-E1 cells used 0 mM Al (control group), 2 mM Al (Al group), 5 mM N-acetyl cysteine (NAC) (NAC group), 2 mM Al and 5 mM NAC (Al + NAC group) for 24 h. We found AlCl 3 -induced MC3T3-E1 cell dysfunction accompanied by oxidative stress, apoptosis, and mitophagy. While NAC, a ROS scavenger treatment, restored cell function and alleviated the mitophagy and apoptosis. These results suggested that mitophagy and apoptosis mediated by ROS participate in AlCl 3 -induced MC3T3-E1 cell dysfunction., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The pollution of aluminum (Al) in agricultural production and its wide application in food processing greatly increase the chance of human and animal exposure. Al can accumulate in bone and cause bone diseases by inducing oxidative stress. Mitophagy can maintain normal cell function by degrading damaged mitochondria and scavenging reactive oxygen species. However, the role of mitophagy in the bone impairment caused by Al is unknown. In this study, we demonstrated that PTEN induced putative kinase 1 (PINK1)/ E3 ubiquitin ligase PARK2 (Parkin)-mediated mitophagy was activated in the bone impairment caused by Al in vivo . Then, the Al-induced mitophagy in Parkin-deficient mice and MC3T3-E1 cells were decreased. Meanwhile, Parkin deficiency exacerbated the bone impairment, mitochondrial damage, and oxidative stress under Al exposure, both in vivo and in vitro . In general, the results reveal that Al exposure can activate PINK1/Parkin-mediated mitophagy, and the PINK1/Parkin-mediated mitophagy plays a protective role in the bone impairment caused by Al.