Mitochondrial Perturbation in Alzheimer’s Disease and Diabetes

Mitochondria are well-known cellular organelles that play a vital role in cellular bioenergetics, heme biosynthesis, thermogenesis, calcium homeostasis, lipid catabolism, and other metabolic activities. Given the extensive role of mitochondria in cell function, mitochondrial dysfunction plays a part in many diseases, including diabetes and Alzheimer’s disease (AD). In most cases, there is overwhelming evidence that impaired mitochondrial function is a causative factor in these diseases. Studying mitochondrial function in diseased cells vs healthy cells may reveal the modified mechanisms and molecular components involved in specific disease states. In this chapter, we provide a concise overview of the major recent findings on mitochondrial abnormalities and their link to synaptic dysfunction relevant to neurodegeneration and cognitive decline in AD and diabetes. Our increased understanding of the role of mitochondrial perturbation indicates that the development of specific small molecules targeting aberrant mitochondrial function could provide therapeutic benefits for the brain in combating aging-related dementia and neurodegenerative diseases by powering up brain energy and improving synaptic function and transmission

Berberine induces caspase-independent cell death in colon tumor cells through activation of apoptosis-inducing factor

Berberine, an isoquinoline alkaloid derived from plants, is a traditional medicine for treating bacterial diarrhea and intestinal parasite infections. Although berberine has recently been shown to suppress growth of several tumor cell lines, information regarding the effect of berberine on colon tumor growth is limited. Here, we investigated the mechanisms underlying the effects of berberine on regulating the fate of colon tumor cells, specifically the immorto Min mouse colonic epithelial (IMCE) cells carrying the Apcmin mutation, and of normal colon epithelial cells, namely young adult mouse colon (YAMC) epithelial cells. Berberine decreased colon tumor colony formation in agar, and induced cell death and LDH release in a time- and concentration-dependent manner in IMCE cells. In contrast, YAMC cells were not sensitive to berberine-induced cell death. Berberine did not stimulate caspase activation, and PARP cleavage and berberine-induced cell death were not affected by a caspase inhibitor in IMCE cells. Rather, berberine stimulated a caspase-independent cell death mediator, apoptosis-inducing factor (AIF) release from mitochondria and nuclear translocation in a ROS production-dependent manner. Amelioration of berberine-stimulated ROS production or suppression of AIF expression blocked berberine-induced cell death and LDH release in IMCE cells. Furthermore, two targets of ROS production in cells, cathepsin B release from lysosomes and PARP activation were induced by berberine. Blockage of either of these pathways decreased berberine-induced AIF activation and cell death in IMCE cells. Thus, berberine-stimulated ROS production leads to cathepsin B release and PARP activation-dependent AIF activation, resulting in caspase-independent cell death in colon tumor cells. Notably, normal colon epithelial cells are less susceptible to berberine-induced cell death, which suggests the specific inhibitory effects of berberine on colon tumor cell growth

Mitochondrial Dysfunction Triggers Synaptic Deficits via Activation of p38 MAP Kinase Signaling in Differentiated Alzheimer’s Disease Trans-Mitochondrial Cybrid Cells

Loss of synapse and synaptic dysfunction contribute importantly to cognitive impairment in Alzheimer’s disease (AD). Mitochondrial dysfunction and oxidative stress are early pathological features in AD-affected brain. However, the effect of AD mitochondria on synaptogenesis remains to be determined. Using human transmitochondrial “cybrid” (cytoplasmic hybrid) neuronal cells whose mitochondria were transferred from platelets of patients with sporadic AD or age-matched non-AD subjects with relatively normal cognition, we provide the first evidence of mitochondrial dysfunction compromises synaptic development and formation of synapse in AD cybrid cells in response to chemical-induced neuronal differentiation. Compared to non-AD control cybrids, AD cybrid cells showed synaptic loss which was evidenced by a significant reduction in expression of two synaptic marker proteins: synaptophysin (presynaptic marker) and postsynaptic density protein-95, and neuronal proteins (MAP-2 and NeuN) upon neuronal differentiation. In parallel, AD-mediated synaptic deficits correlate to mitochondrial dysfunction and oxidative stress as well as activation of p38 MAP kinase. Notably, inhibition of p38 MAP kinase by pharmacological specific p38 inhibitor significantly increased synaptic density, improved mitochondrial function, and reduced oxidative stress. These results suggest that activation of p38 MAP kinase signaling pathway contributes to AD-mediated impairment in neurogenesis, possibly by inhibiting the neuronal differentiation. Our results provide new insight into the crosstalk of dysfunctional AD mitochondria to synaptic formation and maturation via activation of p38 MAP kinase. Therefore, blockade of p38 MAP kinase signal transduction could be a potential therapeutic strategy for AD by alleviating loss of synapses

Expression of hypoxia inducible factor-1α and vascular endothelial growth factor-C in human chronic periodontitis

AbstractBackground/purposeEvidence shows that there is a relationship between hypoxia and inflammatory response in periodontitis. Hypoxia-inducible factor (HIF)-1α is a major regulator of energy homeostasis and cellular adaptation to low oxygen stress. Although experimental results demonstrate an association between HIF-1α and vascular endothelial growth factor (VEGF)-C in tumor angiogenesis, the role of HIF-1α and VEGF-C in the pathogenesis of periodontitis is still ambiguous. So far, limited attention has been given to the role of hypoxia and VEGF-C in periodontitis. The present study aimed to investigate the expression and distribution of HIF-1α and VEGF-C in gingival tissue samples from patients with different stages of chronic periodontitis and healthy individuals.Materials and methodsA total of 56 samples were involved in this study, including moderate chronic periodontitis (n = 20), advanced chronic periodontitis (n = 20), and healthy control tissues (n = 16). The gingival specimens were stained with hematoxylin and eosin for histopathology. The expression of HIF-1α and VEGF-C in gingival tissues was detected by immunohistochemical staining.ResultsHIF-1α and VEGF-C were found in gingival tissues from patients with different stages of chronic periodontitis as well as healthy control tissues. HIF-1α protein was expressed mainly in the epithelial layer of gingival tissues, and VEGF-C protein was mostly located in the connective tissue papilla of gingival tissues. Compared with healthy controls, the expression of HIF-1α and VEGF-C in chronic periodontitis groups was significantly higher (P < 0.01), and the density of HIF-1α and VEGF-C in advanced chronic periodontitis group was even significantly higher than that in the moderate chronic periodontitis group (P < 0.01).ConclusionOur results suggest that the expression of HIF-1α and VEGF-C increased with severity of periodontitis. So, we conclude that HIF-1α may play an important role in the pathophysiology of human periodontitis and may be related to the function of VEGF-C during periodontitis