Amyloid precursor protein intracellular domain modulates cellular calcium homeostasis and ATP content.
Consecutive cleavages of amyloid precursor protein (APP) generate APP intracellular domain (AICD). Its cellular function is still unclear. In this study, we investigated the functional role of AICD in cellular Ca(2+) homeostasis. We could confirm previous observations that endoplasmic reticulum Ca(2+) stores contain less calcium in cells with reduced APP gamma-secretase cleavage products, increased AICD degradation, reduced AICD expression or in cells lacking APP. In addition, we observed an enhanced resting cytosolic calcium concentration under conditions where AICD is decreased or missing. In view of the reciprocal effects of Ca(2+) on mitochondria and of mitochondria on Ca(2+) homeostasis, we analysed further the cellular ATP content and the mitochondrial membrane potential. We observed a reduced ATP content and a mitochondrial hyperpolarisation in cells with reduced amounts of AICD. Blockade of mitochondrial oxidative phosphorylation chain in control cells lead to similar alterations as in cells lacking AICD. On the other hand, substrates of Complex II rescued the alteration in Ca(2+) homeostasis in cells lacking AICD. Based on these observations, our findings indicate that alterations observed in endoplasmic reticulum Ca(2+) storage in cells with reduced amounts of AICD are reciprocally linked to mitochondrial bioenergetic function.
Hamid
Runa
R
Zentrum für Neuropathologie und Prion Forschung, Ludwig Maximilians Universität, München, Germany.
Kilger
Ellen
E
Willem
Michael
M
Vassallo
Neville
N
Kostka
Markus
M
Bornhövd
Carsten
C
Reichert
Andreas S
AS
Kretzschmar
Hans A
HA
Haass
Christian
C
Herms
Jochen
J
D000255:Adenosine Triphosphate / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry* / Q000172:deficiency / Q000378:metabolism*; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D006706:Homeostasis / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D053078:Membrane Potential, Mitochondrial / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation / Q000502:physiology; D017434:Protein Structure, Tertiary / Q000502:physiology; D013997:Time Factors; D014280:Triglycerides / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000031:analogs & derivatives / Q000494:pharmacology
D016564:Amyloid beta-Protein Precursor; D004791:Enzyme Inhibitors; D007211:Indoles; D014280:Triglycerides; D005680:gamma-Aminobutyric Acid; D000255:Adenosine Triphosphate; C057077:1,2-dilinolenoyl-3-(4-aminobutyryl)propane-1,2,3-triol; D002118:Calcium; C000543:cyclopiazonic acid