Differential role of presenilin‐1 and ‐2 on mitochondrial membrane potential and oxygen consumption in mouse embryonic fibroblasts

Behbahani, Homira; Shabalina, Irina G.; Wiehager, Birgitta; Concha, Hérnan; Hultenby, Kjell; Petrovič, Nataša; Nedergaard, Jan; Winblad, Bengt; Cowburn, Richard F.; Ankarcrona, Maria

doi:10.1002/jnr.20990

Cited by 43 publications

(41 citation statements)

References 62 publications

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“…This suggests that PS2 is involved in the activation of microglia from the surveying stage. Consistent with this phenomenon, Behbahani and colleagues 41 showed that PS2 plays a role in mitochondrial membrane potential activity and cell calcium levels that may result in activity impairment. PS1 associates with microtubules and microfilaments and PS1 dysfunction may reduce cytoskeletal association.…”

mentioning

confidence: 77%

γ‐Secretase component presenilin is important for microglia β‐amyloid clearance

Farfara

Trudler

Segev-Amzaleg

et al. 2010

Annals of Neurology

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We suggest for the first time, a dual role for γ-secretase in Alzheimer's disease. One role is the cleavage of the amyloid precursor protein for pathologic β-amyloid production and the other is to regulate microglia activity that is important for clearing neurotoxic β-amyloid deposits. Further studies of γ-secretase-mediated cellular pathways in microglia may provide useful insights into the development of Alzheimer's disease and other neurodegenerative diseases, providing future avenues for therapeutic intervention.

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mentioning

confidence: 77%

γ‐Secretase component presenilin is important for microglia β‐amyloid clearance

Farfara

Trudler

Segev-Amzaleg

et al. 2010

Annals of Neurology

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“…For example, both PS1 and PS2 overexpression in WT and FAD-linked mutants decrease [Ca 2+ ] ER (6) and increase Ca 2+ leak across the ER (although to different extents), but only PS2 strongly inhibits SERCA activity (4, 6) and increases ER-mitochondria tethering. Of interest, along these lines, Behbahani et al (29) showed that mitochondrial functions are reduced significantly in cells from PS2 (but not PS1) knockout animals. This energetic deficit could depend on the reduction of ER-mitochondria Ca 2+ transfer, as elegantly demonstrated recently by Cárdenas et al (30).…”

Section: Discussionmentioning

confidence: 99%

Presenilin 2 modulates endoplasmic reticulum (ER)–mitochondria interactions and Ca ²⁺ cross-talk

Zampese¹,

Fasolato²,

Kipanyula³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

255

282

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Presenilin mutations are the main cause of familial Alzheimer's disease (FAD). Presenilins also play a key role in Ca 2+ homeostasis, and their FAD-linked mutants affect cellular Ca 2+ handling in several ways. We previously have demonstrated that FAD-linked presenilin 2 (PS2) mutants decrease the Ca 2+ content of the endoplasmic reticulum (ER) by inhibiting sarcoendoplasmic reticulum Ca 2+ -ATPase (SERCA) activity and increasing ER Ca 2+ leak. Here we focus on the effect of presenilins on mitochondrial Ca 2+ dynamics. By using genetically encoded Ca 2+ indicators specifically targeted to mitochondria (aequorin-and GFP-based probes) in SH-SY5Y cells and primary neuronal cultures, we show that overexpression or down-regulation of PS2, but not of presenilin 1 (PS1), modulates the Ca 2+ shuttling between ER and mitochondria, with its FAD mutants strongly favoring Ca 2+ transfer between the two organelles. This effect is not caused by a direct PS2 action on mitochondrial Ca 2+ -uptake machinery but rather by an increased physical interaction between ER and mitochondria that augments the frequency of Ca 2+ hot spots generated at the cytoplasmic surface of the outer mitochondrial membrane upon stimulation. This PS2 function adds further complexity to the multifaceted nature of presenilins and to their physiological role within the cell. We also discuss the importance of this additional effect of FAD-linked PS2 mutants for the understanding of FAD pathogenesis.fluorescent Ca 2+ probe | intracellular organelle tethering | fluorescence resonance energy transfer A lzheimer's disease (AD) is the most common form of dementia in developed countries. The pathogenesis of AD is still largely mysterious, and most basic research in the field is concentrated on rare genetic forms of familial AD (FAD). The majority of FAD cases are caused by point mutations in genes for two homologous proteins, presenilin 1 (PS1) and presenilin 2 (PS2), that are essential components of the γ-secretase complex responsible for the production of the amyloid β peptides (Aβ) (1).Evidence has accumulated suggesting that FAD is linked to an imbalance of cellular Ca 2+ homeostasis (see refs. 2 and 3 for recent reviews). In particular, presenilins appear to play a key role in the control of Ca 2+ concentration within the endoplasmic reticulum (ER), [Ca 2+ ] ER : (i) Several FAD-linked presenilin mutants altered the expression or sensitivity of ER Ca 2+ release channels [ryanodine receptor (RyR) and inositol 1,4,5-trisphosphate receptor (IP 3 R)] in cell lines, neurons, and brain microsomes (see ref. 4 for a recent review); (ii) the sarcoendoplasmic reticulum Ca 2+ ATPase (SERCA) has been proposed as a target of presenilins, although opposite regulatory effects have been reported (5, 6); and (iii) it has been suggested that WT presenilins, but not FAD-linked presenilin mutants, form low-conductance Ca 2+ leak channels in the ER membrane (7,8). This last finding supports the "Ca 2+ overload" hypothesis for FAD, which proposes that the reduced ER Ca 2+ leak c...

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“…Of note, both PS1 and PS2 are found enriched in the so-called mitochondria-associated membranes (MAMs), domains of close apposition between ER and mitochondria [3]. Interestingly, in PS2 KO MEF cells (but not in PS1 KO cells), mitochondrial dysfunctions have been reported, such as reduced mitochondrial membrane potential and lower respiration rate [5]. This energy deficit could indeed depend on the reduction of ER-mitochondria Ca 2+ transfer, due to a decreased organelle apposition caused by the absence of PS2.…”

Section: Characteristics Of Ca 2+ Handling By Mitochondria In Differementioning

confidence: 96%

Mitochondrial Ca2+ homeostasis: mechanism, role, and tissue specificities

Pizzo

Drago

Filadi

et al. 2012

Pflugers Arch - Eur J Physiol

133

107

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Mitochondria from every tissue are quite similar in their capability to accumulate Ca²⁺ in a process that depends on the electrical potential across the inner membrane; it is catalyzed by a gated channel (named mitochondrial Ca²⁺ uniporter), the molecular identity of which has only recently been unraveled. The release of accumulated Ca²⁺ in mitochondria from different tissues is, on the contrary, quite variable, both in terms of speed and mechanism: a Na⁺-dependent efflux in excitable cells (catalyzed by NCLX) and a H⁺/Ca²⁺ exchanger in other cells. The efficacy of mitochondrial Ca²⁺ uptake in living cells is strictly dependent on the topological arrangement of the organelles with respect to the source of Ca²⁺ flowing into the cytoplasm, i.e., plasma membrane or intracellular channels. In turn, the structural and functional relationships between mitochondria and other cellular membranes are dictated by the specific architecture of different cells. Mitochondria not only modulate the amplitude and the kinetics of local and bulk cytoplasmic Ca²⁺ changes but also depend on the Ca²⁺ signal for their own functionality, in particular for their capacity to produce ATP. In this review, we summarize the processes involved in mitochondrial Ca²⁺ handling and its integration in cell physiology, highlighting the main common characteristics as well as key differences, in different tissues.

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Differential role of presenilin‐1 and ‐2 on mitochondrial membrane potential and oxygen consumption in mouse embryonic fibroblasts

Cited by 43 publications

References 62 publications

γ‐Secretase component presenilin is important for microglia β‐amyloid clearance

γ‐Secretase component presenilin is important for microglia β‐amyloid clearance

Presenilin 2 modulates endoplasmic reticulum (ER)–mitochondria interactions and Ca ²⁺ cross-talk

Mitochondrial Ca2+ homeostasis: mechanism, role, and tissue specificities

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Differential role of presenilin‐1 and ‐2 on mitochondrial membrane potential and oxygen consumption in mouse embryonic fibroblasts

Cited by 43 publications

References 62 publications

γ‐Secretase component presenilin is important for microglia β‐amyloid clearance

γ‐Secretase component presenilin is important for microglia β‐amyloid clearance

Presenilin 2 modulates endoplasmic reticulum (ER)–mitochondria interactions and Ca 2+ cross-talk

Mitochondrial Ca2+ homeostasis: mechanism, role, and tissue specificities

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Product

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Presenilin 2 modulates endoplasmic reticulum (ER)–mitochondria interactions and Ca ²⁺ cross-talk