Melatonin prevents abnormal mitochondrial dynamics resulting from the neurotoxicity of cadmium by blocking calcium‐dependent translocation of Drp1 to the mitochondria

Abstract

Cadmium (Cd) is a persistent environmental toxin and occupational pollutant that is considered to be a potential risk factor in the development of neurodegenerative diseases. Abnormal mitochondrial dynamics are increasingly implicated in mitochondrial damage in various neurological pathologies. The aim of this study was to investigate whether the disturbance of mitochondrial dynamics contributed to Cd-induced neurotoxicity and whether melatonin has any neuroprotective properties. After cortical neurons were exposed to 10 μM cadmium chloride (CdCl2 ) for various periods (0, 3, 6, 12, and 24 hr), the morphology of their mitochondria significantly changed from the normal tubular networks into punctuated structures within 3 hr. Following this pronounced mitochondrial fragmentation, Cd treatment led to signs of mitochondrial dysfunction, including excess reactive oxygen species (ROS) production, decreased ATP content, and mitochondrial membrane potential (▵Ψm) loss. However, 1 mM melatonin pretreatment efficiently attenuated the Cd-induced mitochondrial fragmentation, which improved the turnover of mitochondrial function. In the brain tissues of rats that were intraperitoneally given 1 mg/kg CdCl2 for 7 days, melatonin also ameliorated excessive mitochondrial fragmentation and mitochondrial damage in vivo. Melatonin's protective effects were attributed to its roles in preventing cytosolic calcium ([Ca(2+) ]i ) overload, which blocked the recruitment of Drp1 from the cytoplasm to the mitochondria. Taken together, our results are the first to demonstrate that abnormal mitochondrial dynamics is involved in cadmium-induced neurotoxicity. Melatonin has significant pharmacological potential in protecting against the neurotoxicity of Cd by blocking the disbalance of mitochondrial fusion and fission.

YAP Inhibits the Apoptosis and Migration of Human Rectal Cancer Cells via Suppression of JNK-Drp1-Mitochondrial Fission-HtrA2/Omi Pathways

“…However, the molecular signals that lie downstream of the Hippo-Yap pathway in cancer remain largely uncharacterized. Our present study found that mitochondrial fission was a novel sequential signal of the Hippo-Yap pathway in RC tumorigenesis and metastasis [48]. Yap functions through its direct interaction with JNK to suppress Drp1-mediated mitochondrial fission, sustaining RC growth and metastasis.…”

“…Under normal conditions, mitochondria undergo continual fusion and fission to maintain the cellular energetic demands. A shift to excessive fission causes an increase in non-functional mitochondria debris [48], and this mitochondrial debris contains pro-apoptotic factors, such as cyt-c, Smac and HtrA2/Omi, which disrupt the balance between cellular survival and apoptosis [53]. In this study, we found that loss of Yap triggered the leakage of HtrA2/Omi from mitochondria into the cytoplasm via activation of mitochondrial fission, leading to a marked drop in anti-apoptotic proteins.…”

Effect of Mst1 on Endometriosis Apoptosis and Migration: Role of Drp1-Related Mitochondrial Fission and Parkin-Required Mitophagy

“…The cells were subsequently scraped, and the homogenates were spun at 800 x g for 5 minutes at 4°C. The supernatants were centrifuged at 10, 000 x g for 20 min at 4°C to acquire the pellets, which were spun again [6,24]. The final pellets were suspended in lysis buffer containing 1% Triton X-100 and were noted as mitochondrial-rich lysate fractions [34].…”

“…These data indicate that mitochondria homeostasis could be considered a therapeutic target for the treatment of endometriosis. Notably, recent studies show that mitochondrial dynamics, especially Drp1-related mitochondrial fission, happen at the early stage of cellular apoptosis, such as in liver cancer, cardiomyocytes and neurocytes [6,7]. Excessive mitochondrial fission initiates caspase 9-related mitochondrial apoptosis, leading to cell death [8,9].…”

SIRT3 Facilitates Amniotic Fluid Stem Cells to Repair Diabetic Nephropathy Through Protecting Mitochondrial Homeostasis by Modulation of Mitophagy

“…Then, the samples were blocked with 10% goat serum albumin (Invitrogen, USA) for 1 h at room temperature and subsequently incubated with primary antibodies overnight at 4°C [33]. After three rinses in PBS, secondary antibodies were added to the samples for 1 h at room temperature [34].…”