Mitochondria, calcium and cell death: A deadly triad in neurodegeneration

Celsi, Fulvio; Pizzo, Paola; Brini, Marisa; Leo, Sara; Fotino, Carmen; Pinton, Paolo; Meneghesso, Gaudenzio

doi:10.1016/j.bbabio.2009.02.021

Cited by 281 publications

(209 citation statements)

References 113 publications

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“…As expected, both of these conditions lowered cell viability in control cells, confirming the notion that sustained [Ca 2+ ] mt overload enhances cell death. 44,45 More importantly, the same manipulations cause a much higher decrease of cell viability in Pat#1 cells (Figure 6d). This indicates that the decrease of mitochondrial Ca 2+ uptake in 13514A4G fibroblasts is a pro-survival compensatory mechanism in these cells.…”

Section: Resultsmentioning

confidence: 83%

Reduced mitochondrial Ca2+ transients stimulate autophagy in human fibroblasts carrying the 13514A>G mutation of the ND5 subunit of NADH dehydrogenase

et al. 2015

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Mitochondrial disorders are a group of pathologies characterized by impairment of mitochondrial function mainly due to defects of the respiratory chain and consequent organellar energetics. This affects organs and tissues that require an efficient energy supply, such as brain and skeletal muscle. They are caused by mutations in both nuclear-and mitochondrial DNA (mtDNA)-encoded genes and their clinical manifestations show a great heterogeneity in terms of age of onset and severity, suggesting that patient-specific features are key determinants of the pathogenic process. In order to correlate the genetic defect to the clinical phenotype, we used a cell culture model consisting of fibroblasts derived from patients with different mutations in the mtDNA-encoded ND5 complex I subunit and with different severities of the illness. Interestingly, we found that cells from patients with the 13514A4G mutation, who manifested a relatively late onset and slower progression of the disease, display an increased autophagic flux when compared with fibroblasts from other patients or healthy donors. We characterized their mitochondrial phenotype by investigating organelle turnover, morphology, membrane potential and Ca 2+ homeostasis, demonstrating that mitochondrial quality control through mitophagy is upregulated in 13514A4G cells. This is due to a specific downregulation of mitochondrial Ca 2+ uptake that causes the stimulation of the autophagic machinery through the AMPK signaling axis. Genetic and pharmacological manipulation of mitochondrial Ca 2+ homeostasis can revert this phenotype, but concurrently decreases cell viability. This indicates that the higher mitochondrial turnover in complex I deficient cells with this specific mutation is a pro-survival compensatory mechanism that could contribute to the mild clinical phenotype of this patient. Mitochondrial disorders include a wide range of pathological conditions characterized by defects in organelle homoeostasis and energy metabolism, in particular in the electron transport chain (ETC) complexes. They are mostly caused by mutations in nuclear-or mtDNA-encoded genes of the respiratory chain complexes leading to a variety of clinical manifestations, ranging from lesions in specific tissues, such as in Leber's hereditary optic neuropathy, to complex multisystem syndromes, such as myoclonic epilepsy with ragged-red fibers, Leigh syndrome or the mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes syndrome (MELAS). 1,2 Despite the detailed knowledge of the molecular defects in these diseases, their pathogenesis remains poorly understood. The heterogeneity of signs and symptoms depends on the diversity of the genetic background and on patient-specific compensatory mechanisms. Several studies investigated the consequences of nuclear DNA mutations on intracellular organelle physiology and Ca 2+ homeostasis. 3,4 Here we analyzed a cohort of patients with mutations in the mtDNA-encoded ND5 subunit of NADH dehydrogenase in order to correlate the clinical phenot...

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Section: Resultsmentioning

confidence: 83%

Reduced mitochondrial Ca2+ transients stimulate autophagy in human fibroblasts carrying the 13514A>G mutation of the ND5 subunit of NADH dehydrogenase

et al. 2015

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“…Previous work showed that Ca 2+ homeostasis is dysregulated in cellular models of AD, as well as in human AD brains (Berridge, Bootman & Lipp, 1998; Celsi et al., 2009; Garwood et al., 2013). Surprisingly, our data showed decreased levels of free calcium, both in mitochondria and in cytoplasm, after the addition of the Aβ peptides.…”

Section: Discussionmentioning

confidence: 99%

Carbonic anhydrase inhibition selectively prevents amyloid β neurovascular mitochondrial toxicity

et al. 2018

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SummaryMounting evidence suggests that mitochondrial dysfunction plays a causal role in the etiology and progression of Alzheimer's disease (AD). We recently showed that the carbonic anhydrase inhibitor (CAI) methazolamide (MTZ) prevents amyloid β (Aβ)‐mediated onset of apoptosis in the mouse brain. In this study, we used MTZ and, for the first time, the analog CAI acetazolamide (ATZ) in neuronal and cerebral vascular cells challenged with Aβ, to clarify their protective effects and mitochondrial molecular mechanism of action. The CAIs selectively inhibited mitochondrial dysfunction pathways induced by Aβ, without affecting metabolic function. ATZ was effective at concentrations 10 times lower than MTZ. Both MTZ and ATZ prevented mitochondrial membrane depolarization and H2O2 generation, with no effects on intracellular pH or ATP production. Importantly, the drugs did not primarily affect calcium homeostasis. This work suggests a new role for carbonic anhydrases (CAs) in the Aβ‐induced mitochondrial toxicity associated with AD and cerebral amyloid angiopathy (CAA), and paves the way to AD clinical trials for CAIs, FDA‐approved drugs with a well‐known profile of brain delivery.

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“…It has been reported recently (14) that presenilins are enriched in ER mitochondriaassociated membranes, i.e., the ER membrane domains interacting closely with mitochondria and endowed with key players of the Ca 2+ -handling machinery (15). This finding, together with the generally accepted concept that mitochondrial deficits are key events in most neurodegenerative diseases (16,17), and more specifically in AD (18, 19), led us to investigate the effect of presenilins on ER-mitochondria cross-talk.By directly measuring mitochondrial Ca 2+ dynamics, we show here that PS2, but not PS1, favors Ca 2+ transfer between ER and mitochondria, an effect reduced by PS2 down-regulation and enhanced by the expression of PS2 mutants. The most striking modification associated with PS2 expression is an increased number of contact sites between ER and mitochondria.…”

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confidence: 99%

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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.

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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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Mitochondria, calcium and cell death: A deadly triad in neurodegeneration

Cited by 281 publications

References 113 publications

Reduced mitochondrial Ca2+ transients stimulate autophagy in human fibroblasts carrying the 13514A>G mutation of the ND5 subunit of NADH dehydrogenase

Reduced mitochondrial Ca2+ transients stimulate autophagy in human fibroblasts carrying the 13514A>G mutation of the ND5 subunit of NADH dehydrogenase

Carbonic anhydrase inhibition selectively prevents amyloid β neurovascular mitochondrial toxicity

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

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Mitochondria, calcium and cell death: A deadly triad in neurodegeneration

Cited by 281 publications

References 113 publications

Reduced mitochondrial Ca2+ transients stimulate autophagy in human fibroblasts carrying the 13514A>G mutation of the ND5 subunit of NADH dehydrogenase

Reduced mitochondrial Ca2+ transients stimulate autophagy in human fibroblasts carrying the 13514A>G mutation of the ND5 subunit of NADH dehydrogenase

Carbonic anhydrase inhibition selectively prevents amyloid β neurovascular mitochondrial toxicity

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

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