Amyloid-beta Leads to Impaired Cellular Respiration, Energy Production and Mitochondrial Electron Chain Complex Activities in Human Neuroblastoma Cells
- 1.1k Downloads
Evidence suggests that amyloid-beta (Aβ) protein is a key factor in the pathogenesis of Alzheimer’s disease (AD) and it has been recently proposed that mitochondria are involved in the biochemical pathway by which Aβ can lead to neuronal dysfunction. Here we investigated the specific effects of Aβ on mitochondrial function under physiological conditions. Mitochondrial respiratory functions and energy metabolism were analyzed in control and in human wild-type amyloid precursor protein (APP) stably transfected human neuroblastoma cells (SH-SY5Y). Mitochondrial respiratory capacity of mitochondrial electron transport chain (ETC) in vital cells was measured with a high-resolution respirometry system (Oxygraph-2k). In addition, we determined the individual activities of mitochondrial complexes I–IV that compose ETC and ATP cellular levels. While the activities of complexes I and II did not change between cell types, complex IV activity was significantly reduced in APP cells. In contrast, activity of complex III was significantly enhanced in APP cells, as compensatory response in order to balance the defect of complex IV. However, this compensatory mechanism could not prevent the strong impairment of total respiration in vital APP cells. As a result, the respiratory control ratio (state3/state4) together with ATP production decreased in the APP cells in comparison with the control cells. Chronic exposure to soluble Aβ protein may result in an impairment of energy homeostasis due to a decreased respiratory capacity of mitochondrial electron transport chain which, in turn, may accelerate neurons demise.
KeywordsMitochondria Amyloid-beta SH-SY5Y cells Respiration Electron chain Energy ATP Oxygen consumption
This research was supported by grant from the SNSF (Swiss National Science Foundation) #310000-108223 to A.E.
- Aleardi AM, Benard G, Augereau O, Malgat M, Talbot JC, Mazat JP, Letellier T, Dachary-Prigent J, Solaini GC, Rossignol R (2005) Gradual alteration of mitochondrial structure and function by beta-amyloids: importance of membrane viscosity changes, energy deprivation, reactive oxygen species production, and cytochrome c release. J Bioenerg Biomembr 37:207–225. doi: 10.1007/s10863-005-6631-3 PubMedCrossRefGoogle Scholar
- Cassarino DS, Bennett JP Jr (1999) An evaluation of the role of mitochondria in neurodegenerative diseases: mitochondrial mutations and oxidative pathology, protective nuclear responses, and cell death in neurodegeneration. Brain Res Brain Res Rev 29:1–25. doi: 10.1016/S0165-0173(98)00046-0 PubMedCrossRefGoogle Scholar
- David DC, Hauptmann S, Scherping I, Schuessel K, Keil U, Rizzu P, Ravid R, Drose S, Brandt U, Muller WE, Eckert A, Gotz J (2005) Proteomic and functional analyses reveal a mitochondrial dysfunction in P301L tau transgenic mice. J Biol Chem 280:23802–23814. doi: 10.1074/jbc.M500356200 PubMedCrossRefGoogle Scholar
- Djafarzadeh R, Kerscher S, Zwicker K, Radermacher M, Lindahl M, Schagger H, Brandt U (2000) Biophysical and structural characterization of proton-translocating NADH-dehydrogenase (complex I) from the strictly aerobic yeast Yarrowia lipolytica. Biochim Biophys Acta 1459:230–238. doi: 10.1016/S0005-2728(00)00154-7 PubMedCrossRefGoogle Scholar
- Eckert A, Hauptmann S, Scherping I, Meinhardt J, Rhein V, Drose S, Brandt U, Fandrich M, Muller WE, Gotz J (2008) Oligomeric and fibrillar species of beta-amyloid (Abeta42) both impair mitochondrial function in P301L tau transgenic mice. J Mol Med 86:1255–1267. doi: 10.1007/s00109-008-0391-6 PubMedCrossRefGoogle Scholar
- Hauptmann S, Scherping I, Drose S, Brandt U, Schulz KL, Jendrach M, Leuner K, Eckert A, Muller WE (2008) Mitochondrial dysfunction: an early event in Alzheimer pathology accumulates with age in AD transgenic mice. Neurobiol Aging. [Epub ahead of print]Google Scholar
- Keil U, Bonert A, Marques CA, Scherping I, Weyermann J, Strosznajder JB, Muller-Spahn F, Haass C, Czech C, Pradier L, Muller WE, Eckert A (2004) Amyloid beta-induced changes in nitric oxide production and mitochondrial activity lead to apoptosis. J Biol Chem 279:50310–50320. doi: 10.1074/jbc.M405600200 PubMedCrossRefGoogle Scholar
- Krahenbuhl S, Chang M, Brass EP, Hoppel CL (1991) Decreased activities of ubiquinol:ferricytochrome c oxidoreductase (complex III) and ferrocytochrome c:oxygen oxidoreductase (complex IV) in liver mitochondria from rats with hydroxycobalamin[c-lactam]-induced methylmalonic aciduria. J Biol Chem 266:20998–21003PubMedGoogle Scholar
- Lustbader JW, Cirilli M, Lin C, Xu HW, Takuma K, Wang N, Caspersen C, Chen X, Pollak S, Chaney M, Trinchese F, Liu S, Gunn-Moore F, Lue LF, Walker DG, Kuppusamy P, Zewier ZL, Arancio O, Stern D, Yan SS, Wu H (2004) ABAD directly links Abeta to mitochondrial toxicity in Alzheimer’s disease. Science 304:448–452. doi: 10.1126/science.1091230 PubMedCrossRefGoogle Scholar
- Scheuermann S, Hambsch B, Hesse L, Stumm J, Schmidt C, Beher D, Bayer TA, Beyreuther K, Multhaup G (2001) Homodimerization of amyloid precursor protein and its implication in the amyloidogenic pathway of Alzheimer’s disease. J Biol Chem 276:33923–33929. doi: 10.1074/jbc.M105410200 PubMedCrossRefGoogle Scholar