Enhanced parkin levels favor ER-mitochondria crosstalk and guarantee Ca2+ transfer to sustain cell bioenergetics

Calì, Tito; Ottolini, Denis; Negro, Alessandro; Brini, Marisa

doi:10.1016/j.bbadis.2013.01.004

Cited by 197 publications

(175 citation statements)

References 68 publications

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“…According to Fick's laws, Ca 2+ will move from regions of high concentration on the ER membrane to regions of low concentration on the mitochondrial surface, forming a concentration gradient that changes with time. Einstein's diffusion equation 22 27,28 Consistent with this possibility, Csordas et al showed that RBL-2H3 cells subjected to proapoptotic stimuli respond by narrowing the MERCs cleft from 28 ± 2 to 19± 2 nm; 6 however, whether this plasticity also occurs in vivo and during physiological responses remains unknown. To gain insights on MERCs dynamics, we returned to the cryo-EM images acquired for our recent study, where we reported that MERCs double in length during fasting.…”

Section: Of Mercs Thickness and The Diffusion Laws Of Einstein And Fickmentioning

confidence: 82%

“…These data indicate that the structural plasticity of the MERC cleft accompanies changes in cell metabolism, possibly as part of an adaptive process, consistent with the notion that mitochondrial ultrastructure and bioenergetics are tightly integrated to cell physiology. [27][28][29] Impairing the remodeling of the MERC thickness might, therefore, underlie the development of those pathologies that have been linked to altered MERCs activity, such as Alzheimer's disease (AD), 30 Parkinson's disease 31 and cancer.…”

Section: Of Mercs Thickness and The Diffusion Laws Of Einstein And Fickmentioning

confidence: 99%

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The coming of age of the mitochondria–ER contact: a matter of thickness

2016

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The sites of near-contact between the mitochondrion and the endoplasmic reticulum (ER) have earned a lot of attention due to their key role in the maintenance of lipid and calcium (Ca 2+ ) homeostasis, in the initiation of autophagy and mitochondrial division, and in sensing metabolic shifts. At these sites, typically called MAMs (mitochondria-associated ER membranes) or MERCs (mitochondria-ER contacts), the organelles juxtapose at a distance that can range from~10 to~50 nm. The multifunctional role of this subcellular compartment is puzzling; further, recent studies have shown that mitochondria-ER contacts are highly plastic structures that remodel upon metabolic transitions and that their activity in controlling lipid homeostasis could be involved in Alzheimer's disease pathogenesis. This review aims at integrating the functions of this subcellular compartment to its most characterizing and unexplored structural parameter, their 'thickness': that is, the width of the cleft that separates the cytosolic face of the outer mitochondrial membrane from that of the ER. We describe and discuss the reasons why the thickness of a MERC should be considered a regulated structural parameter of the cell that defines and controls its function. Further, we propose a MERC classification that will help organize the expanding field of MERCs biology and of their role in cell physiology and human disease.

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Section: Of Mercs Thickness and The Diffusion Laws Of Einstein And Fickmentioning

confidence: 82%

Section: Of Mercs Thickness and The Diffusion Laws Of Einstein And Fickmentioning

confidence: 99%

The coming of age of the mitochondria–ER contact: a matter of thickness

2016

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“…The MCU-flag/pcDNA expression construct is described in De Stefani et al 12 The Parkin full-length expression construct is described in Cali et al 51 The MCU-flag adenovirus production is described in Raffaello et al 14 Immunofluorescence. Control and mutated fibroblasts or wt and mutated cybrids were starved (KRB for 4 h), treated with chloroquine (50 μM for 1 h), Kaempferol (20 μM for 24 or 48 h) or SB202190 (20 μM for 24 or 48 h) and transfected with Parkin, MCU or empty vector as control, as indicated.…”

Section: Methodsmentioning

confidence: 99%

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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“…[95][96][97] It may be important to address whether the microdomains of high [Ca 2+ ] at contacts between the ER and mitochondria inhibit the ubiquitination of mitochondrial targets by PARK2 and subsequently limit mitophagy, while simultaneously maintaining optimal conditions for mitochondrial Ca 2+ uptake and ATP production. Indeed a very recent study by Cali et al 98 presents evidence suggesting a role for PARK2 independent of its mitochondrial translocation, in which it promotes ER-mitochondrial tethering, Ca 2+ transfer and ATP production. PARK2 upregulation may be a mechanism to compensate for mitochondrial impairment by modulating ER-mitochondria Ca 2+ transfer.…”

Section: Camentioning

confidence: 99%