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Mitochondrial dysfunction and axonal degeneration are early pathological features of Alzheimer's disease (AD)-affected brains. The underlying mechanisms and strategies to rescue it have not been well elucidated. Here, we evaluated axonal mitochondrial transport and function in AD subject-derived mitochondria. We analyzed mitochondrial transport and kinetics in human trans-mitochondrial "cybrid" (cytoplasmic hybrid) neuronal cells whose mitochondria were derived from platelets of patients with sporadic AD and compared these AD cybrid cell lines with cybrid cell lines whose mitochondria were derived from age-matched, cognitively normal subjects. Human AD cybrid cell lines, when induced to differentiate, developed stunted projections. Mitochondrial transport and function within neuronal processes/axons was altered in AD-derived mitochondria. Antioxidants reversed deficits in axonal mitochondrial transport and function. These findings suggest that antioxidants may be able to mitigate the consequences of AD-associated mitochondrial dysfunction. The present study provides evidence of the cause/effect of AD specific mitochondrial defects, which significantly enhances our understanding of the AD pathogenesis and exploring the effective therapeutic strategy for AD. [ABSTRACT FROM AUTHOR]

Background: 17β-hydroxysteroid dehydrogenase type 10 (HSD10) has been shown to play a protective role in cells undergoing stress. Upregulation of HSD10 under nutrient-limiting conditions leads to recovery of a homeostatic state. Across disease states, increased HSD10 levels can have a profound and varied impact, such as beneficial in Parkinson’s disease and harmful in Alzheimer’s disease. Recently, HSD10 overexpression has been observed in some prostate and bone cancers, consistently correlating with poor patient prognosis. As the role of HSD10 in cancer remains underexplored, we propose that cancer cells utilize this enzyme to promote cancer cell survival under cell death conditions. Methods: The proliferative effect of HSD10 was examined in transfected pheochromocytoma cells by growth curve analysis and a xenograft model. Fluctuations in mitochondrial bioenergetics were evaluated by electron transport chain complex enzyme activity assays and energy production. Additionally, the effect of HSD10 on pheochromocytoma resistance to cell death was investigated using TUNEL staining, MTT, and complex IV enzyme activity assays. Results: In this study, we examined the tumor-promoting effect of HSD10 in pheochromocytoma cells. Overexpression of HSD10 increased pheochromocytoma cell growth in both in vitro cell culture and an in vivo xenograft mouse model. The increases in respiratory enzymes and energy generation observed in HSD10-overexpressing cells likely supported the accelerated growth rate observed. Furthermore, cells overexpressing HSD10 were more resistant to oxidative stress-induced perturbation. Conclusions: Our findings demonstrate that overexpression of HSD10 accelerates pheochromocytoma cell growth, enhances cell respiration, and increases cellular resistance to cell death induction. This suggests that blockade of HSD10 may halt and/or prevent cancer growth, thus providing a promising novel target for cancer patients as a screening or therapeutic option. [ABSTRACT FROM AUTHOR]

Aβ binding alcohol dehydrogenase (ABAD) is an NAD-dependent mitochondrial dehydrogenase. The binding between ABAD and Aβ is likely a direct link between Aβ and mitochondrial toxicity in Alzheimer's disease. In this study, surface plasmon resonance (SPR) was employed to determine the temperature dependence of the affinity of the ABAD-Aβ interaction. A van't Hoff analysis revealed that the ABAD-Aβ association is driven by a favorable entropic change (ΔS = 300 ± 30 J mol-1 K-1) which overcomes an unfavorable enthalpy change (ΔH = 49 ± 7 kJ/mol). Therefore, hydrophobic interactions and changes in protein dynamics are the dominant driving forces of the ABAD-Aβ interaction. This is the first dissection of the entropic and enthalpic contribution to the energetics of a protein-protein interaction involving Aft. SPR confirmed the conformational changes in the ABAD-Aβ complex after Aβ binding, consistent with differences seen in the crystal structures of free ABAD and the ABAD-Aβ complex. Saturation transfer difference (STD) NMR experiments directly and unambiguously demonstrated the inhibitory effect of Aβ on the ABAD-NAD interaction. Conversely, NAD inhibits the Aβ-ABAD interaction. Binding of Aβ and binding of NAD to ABAD are likely mutually exclusive. Thus, Aβ binding induces conformational and subsequently functional changes in ABAD, which may have a role in the mechanism of Aβ toxicity in Alzheimer's disease. [ABSTRACT FROM AUTHOR]