Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.22.56 (caspase-3)
 35,750 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mitochondria constantly undergo fusion and fission that are necessary for the maintenance of organelle fidelity. However, growing evidence has shown that abnormal mitochondrial fusion and fission participate in the regulation of apoptosis. Mitochondrial fusion is able to inhibit apoptosis, whereas mitochondrial fission is involved in the initiation of apoptosis. It remains elusive as to whether mitochondrial fission can regulate DNA fragmentation during apoptosis. Mitochondrial fission is triggered by dynamin-related protein-1 (Drp1), whereas mitofusin 1 (Mfn 1) is able to induce mitochondrial fusion. Here, we report that Drp1 is required for the release of endonuclease G from mitochondria. Knockdown of Drp1 can attenuate DNA fragmentation. Our data further show that Mfn 1 prevents endonuclease G release from mitochondria and the consequent DNA fragmentation. Intriguingly, Mfn 1 could inhibit the activation of caspase-3 and caspase-9, which are necessary for endonuclease G translocation to the nucleus. Our results provide novel evidence that DNA fragmentation is regulated by the mitochondrial fission machinery.
 ...
PMID:Mitochondrial fission controls DNA fragmentation by regulating endonuclease G. 2059 82

Major depression disorder (MDD) or depression is highly prevalent in individuals with diabetes, and the depressive symptoms are more severe and less responsive to antidepressant therapies in these patients. The underlying mechanism is little understood. We hypothesized that the pathophysiology of comorbid depression was more complex than that proposed for MDD and that neural cell death played a role in the disease severity. To test this hypothesis, we generated streptozotocin (STZ)-induced diabetic mice. These mice had blood glucose levels threefold above controls and exhibited depressive phenotypes as judged by a battery of behavioral tests, thus confirming the comorbidity in mice. Immunohistological studies showed markedly increased TUNEL-positive cells in the frontal cortex and hippocampus of the comorbid mice, indicating apoptosis. This finding was supported by increased caspase-3 and decreased Bcl-2 proteins in these brain regions. In addition, the serum brain-derived neurotrophic factor (BDNF) level of comorbid mice was reduced compared with controls, further supporting the neurodegenerative change. Mechanistic analyses showed an increased expression of mitochondrial fission genes fission protein 1 (Fis1) and dynamin-related protein 1 (Drp1), and a decreased expression of mitochondrial fusion genes mitofusin 1 (Mfn1), mitofusin 2 (Mfn2) and optical atrophy 1 (Opa1). Representative assessment of the proteins Drp1 and Mfn2 mirrored the mRNA changes. The data demonstrated that neural cell death was associated with the depressive phenotype of comorbid mice and that a fission-dominant expression of genes and proteins mediating mitochondrial dynamics played a role in the hyperglycemia-induced cell death. The study provides new insight into the disease mechanism and could aid the development of novel therapeutics aimed at providing neuroprotection by modulating mitochondrial dynamics to treat comorbid depression with diabetes.
 ...
PMID:Contribution of neural cell death to depressive phenotypes of streptozotocin-induced diabetic mice. 2476 90

Changes in mitochondrial morphology and function play an important role in secondary damage after acute spinal cord injury. We recorded the time representation of mitochondrial morphology and function in rats with acute spinal cord injury. Results showed that mitochondria had an irregular shape, and increased in size. Mitochondrial cristae were disordered and mitochondrial membrane rupture was visible at 2-24 hours after injury. Fusion protein mitofusin 1 expression gradually increased, peaked at 8 hours after injury, and then decreased to its lowest level at 24 hours. Expression of dynamin-related protein 1, amitochondrial fission protein, showed the opposite kinetics. At 2-24 hours after acute spinal cord injury, malondialdehyde content, cytochrome c levels and caspase-3 expression were increased, but glutathione content, adenosine triphosphate content, Na(+)-K(+)-ATPase activity and mitochondrial membrane potential were gradually reduced. Furthermore, mitochondrial morphology altered during the acute stage of spinal cord injury. Fusion was important within the first 8 hours, but fission played a key role at 24 hours. Oxidative stress was inhibited, biological productivity was diminished, and mitochondrial membrane potential and permeability were reduced in the acute stage of injury. In summary, mitochondrial apoptosis is activated when the time of spinal cord injury is prolonged.
...
PMID:Time representation of mitochondrial morphology and function after acute spinal cord injury. 2698 Nov 3

Cadmium (Cd) is a toxic metal that is involved in apoptosis. The present study was conducted to investigate the mechanism of Cd-induced apoptosis and the protective effects of vitamin E on rat testes. Thirty-two adult Wistar rats were divided into four groups. The control group was injected with saline and three other groups received Cd, Cd+vitamin E, and vitamin E. Intraperitoneal injection was performed for 28 days. On the 29th day, the rats were slaughtered, their peritoneum was opened, and their left testis removed and weighed. The mRNA expression of apoptosis and mitochondrial dynamics genes were assessed using real-time PCR, and caspase-3/7 activation using the caspase-3/7 Assay. The groups were not significantly different in terms of testicular weight. Compared with the control group, the mRNA expression levels of Bax and caspase-9 genes increased in the rats' testes receiving Cd, the mRNA expression levels of mitofusin 1 (Mfn1) and mitofusin2 (Mfn2) genes decreased, and those of Bcl-2 remained unchanged. Vitamin E was found to significantly decrease the mRNA expression of Bax and caspase-9 genes and increase the mRNA Mfn1, Mfn2, and Bcl-2 in the rats' testes receiving Cd. The ratio of Bax/Bcl-2 and caspase-3/7 activity increased in the Cd-exposed rats compared with the control. Vitamin E remarkably attenuated the Cd-induced effects. According to the obtained results, Cd exerts its apoptotic effects through the mitochondrial pathway by increasing the ratio of Bax/Bcl-2 and activating caspases in the rats' testes, and vitamin E plays a protective role against Cd-induced apoptosis.
 ...
PMID:Protective effects of vitamin E on cadmium-induced apoptosis in rat testes. 3162 Aug 23