Regulation of Ca2+ exchanges and signaling in mitochondria (original) (raw)

Calcium signaling around Mitochondria Associated Membranes (MAMs)

Cell Communication and Signaling, 2011

Calcium (Ca 2+ ) homeostasis is fundamental for cell metabolism, proliferation, differentiation, and cell death. Elevation in intracellular Ca 2+ concentration is dependent either on Ca 2+ influx from the extracellular space through the plasma membrane, or on Ca 2+ release from intracellular Ca 2+ stores, such as the endoplasmic/sarcoplasmic reticulum (ER/SR). Mitochondria are also major components of calcium signalling, capable of modulating both the amplitude and the spatio-temporal patterns of Ca 2+ signals. Recent studies revealed zones of close contact between the ER and mitochondria called MAMs (Mitochondria Associated Membranes) crucial for a correct communication between the two organelles, including the selective transmission of physiological and pathological Ca 2+ signals from the ER to mitochondria. In this review, we summarize the most up-to-date findings on the modulation of intracellular Ca 2+ release and Ca 2+ uptake mechanisms. We also explore the tight interplay between ER-and mitochondria-mediated Ca 2+ signalling, covering the structural and molecular properties of the zones of close contact between these two networks.

Cytoplasmic and Mitochondrial Calcium Signaling: A Two-Way Relationship

Cold Spring Harbor Perspectives in Biology, 2019

Intracellular Ca 2+ signals are well organized in all cell types, and trigger a variety of vital physiological processes. The temporal and spatial characteristics of cytosolic Ca 2+ increases are mainly governed by the fluxes of this ion across the membrane of the endoplasmic/sarcoplasmic reticulum and the plasma membrane. However, various Ca 2+ transporters also allow for Ca 2+ exchanges between the cytoplasm and mitochondria. Increases in mitochondrial Ca 2+ stimulate the production of ATP, which allows the cells to cope with the increased energy demand created by the stimulus. Less widely appreciated is the fact that Ca 2+ handling by mitochondria also shapes cytosolic Ca 2+ signals. Indeed, the frequency, amplitude, and duration of cytosolic Ca 2+ increases can be altered by modifying the rates of Ca 2+ transport into, or from, mitochondria. In this review, we focus on the interplay between mitochondria and Ca 2+ signaling, highlighting not only the consequences of cytosolic Ca 2+ changes on mitochondrial Ca 2+ , but also how cytosolic Ca 2+ dynamics is controlled by modifications of the Ca 2+-handling properties and the metabolism of mitochondria.

Calcium uptake mechanisms of mitochondria

Biochimica et Biophysica Acta (BBA) - Bioenergetics, 2010

The ability of mitochondria to capture Ca 2+ ions has important functional implications for cells, because mitochondria shape cellular Ca 2+ signals by acting as a Ca 2+ buffer and respond to Ca 2+ elevations either by increasing the cell energy supply or by triggering the cell death program of apoptosis. A mitochondrial Ca 2+ channel known as the uniporter drives the rapid and massive entry of Ca 2+ ions into mitochondria. The uniporter operates at high, micromolar cytosolic Ca 2+ concentrations that are only reached transiently in cells, near Ca 2+ release channels. Mitochondria can also take up Ca 2+ at low, nanomolar concentrations, but this high affinity mode of Ca 2+ uptake is not well characterized. Recently, leucine-zipper-EF hand-containing transmembrane region (Letm1) was proposed to be an electrogenic 1:1 mitochondrial Ca 2+ /H + antiporter that drives the uptake of Ca 2+ into mitochondria at nanomolar cytosolic Ca 2+ concentrations. In this article, we will review the properties of the Ca 2+ import systems of mitochondria and discuss how Ca 2+ uptake via an electrogenic 1:1 Ca 2+ /H + antiport challenges our current thinking of the mitochondrial Ca 2+ uptake mechanism.

Mitochondrial dynamics and Ca2+ signaling

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, 2006

Recent data shed light on two novel aspects of the mitochondria-Ca 2+ liaison. First, it was extensively investigated how Ca 2+ handling is controlled by mitochondrial shape, and positioning; a playground also of cell death and survival regulation. On the other hand, significant progress has been made to explore how intra-and near-mitochondrial Ca 2+ signals modify mitochondrial morphology and cellular distribution. Here, we shortly summarize these advances and provide a model of Ca 2+ -mitochondria interactions.

The Ins and Outs of Mitochondrial Calcium

Circulation research, 2015

Calcium is thought to play an important role in regulating mitochondrial function. Evidence suggests that an increase in mitochondrial calcium can augment ATP production by altering the activity of calcium-sensitive mitochondrial matrix enzymes. In contrast, the entry of large amounts of mitochondrial calcium in the setting of ischemia-reperfusion injury is thought to be a critical event in triggering cellular necrosis. For many decades, the details of how calcium entered the mitochondria remained a biological mystery. In the past few years, significant progress has been made in identifying the molecular components of the mitochondrial calcium uniporter complex. Here, we review how calcium enters and leaves the mitochondria, the growing insight into the topology, stoichiometry and function of the uniporter complex, and the early lessons learned from some initial mouse models that genetically perturb mitochondrial calcium homeostasis.

Calcium and mitochondria: mechanisms and functions of a troubled relationship

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, 2004

Mitochondria promptly respond to Ca 2+ -mediated cell stimulations with a rapid accumulation of the cation into the matrix. In this article, we review (i) the basic principles of mitochondrial Ca 2+ transport, (ii) the physiological/pathological role of mitochondrial Ca 2+ uptake, (iii) the regulatory mechanisms that may operate in vivo, and (iv) the new targeted Ca 2+ probes that allowed the brediscoveryQ of these organelles in calcium signalling. D

Molecules and roles of mitochondrial calcium signaling

BioFactors, 2011

Mitochondrial Ca(2+) homeostasis is an important component of the calcium-mediated cellular response to extracellular stimuli. It controls key organelle functions, such as aerobic metabolism and the induction of apoptotic cell death, and shapes the spatiotemporal pattern of the cytosolic [Ca(2+)] increase. We here summarize both the main roles of Ca(2+) signals within mitochondria and the emerging molecular information that is starting to unravel the composition of the signaling apparatus and reveal potential pharmacological targets in this process of utmost pathophysiological relevance.

Mitochondria as all‐round players of the calcium game

The Journal of Physiology, 2000

Although it has been known for over three decades that mitochondria are endowed with a complex array of Ca¥ transporters and that key enzymes of mitochondrial metabolism are regulated by Ca¥, the possibility that physiological stimuli that raise the [Ca¥] of the cytoplasm could trigger major mitochondrial Ca¥ uptake has long been considered unlikely, based on the low affinity of the mitochondrial transporters and the limited amplitude of the cytoplasmic [Ca¥] rises. The direct measurement of mitochondrial [Ca¥] with highly selective probes has led to a complete reversion of this view, by demonstrating that, after cell stimulation, the cytoplasmic Ca¥ signal is always paralleled by a much larger rise in [Ca¥] in the mitochondrial matrix. This observation has rejuvenated the study of mitochondrial Ca¥ transport and novel, unexpected results have altered long-standing dogmas in the field of calcium signalling. Here we focus on four main topics: (i) the current knowledge of the functional properties of the Ca¥ transporters and of the thermodynamic constraints under which they operate; (ii) the occurrence of mitochondrial Ca¥ uptake in living cells and the key role of local signalling routes between the mitochondria and the Ca¥ sources; (iii) the physiological consequences of Ca¥ transport for both mitochondrial function and the modulation of the cytoplasmic Ca¥ signal; and (iv) evidence that alterations of mitochondrial Ca¥ signalling may occur in pathophysiological conditions.

Mitochondrial Ca2+ Signaling in Health, Disease and Therapy

Cells

The divalent cation calcium (Ca2+) is considered one of the main second messengers inside cells and acts as the most prominent signal in a plethora of biological processes. Its homeostasis is guaranteed by an intricate and complex system of channels, pumps, and exchangers. In this context, by regulating cellular Ca2+ levels, mitochondria control both the uptake and release of Ca2+. Therefore, at the mitochondrial level, Ca2+ plays a dual role, participating in both vital physiological processes (ATP production and regulation of mitochondrial metabolism) and pathophysiological processes (cell death, cancer progression and metastasis). Hence, it is not surprising that alterations in mitochondrial Ca2+ (mCa2+) pathways or mutations in Ca2+ transporters affect the activities and functions of the entire cell. Indeed, it is widely recognized that dysregulation of mCa2+ signaling leads to various pathological scenarios, including cancer, neurological defects and cardiovascular diseases (CV...

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

Pflügers Archiv - European Journal of Physiology, 2012

Mitochondria from every tissue are quite similar in their capability to accumulate Ca 2+ in a process that depends on the electrical potential across the inner membrane; it is catalyzed by a gated channel (named mitochondrial Ca 2+ uniporter), the molecular identity of which has only recently been unraveled. The release of accumulated Ca 2+ 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 + /Ca 2+ exchanger in other cells. The efficacy of mitochondrial Ca 2+ uptake in living cells is strictly dependent on the topological arrangement of the organelles with respect to the source of Ca 2+ 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 Ca 2+ changes but also depend on the Ca 2+ signal for their own functionality, in particular for their capacity to produce ATP. In this review, we summarize the processes involved in mitochondrial Ca 2+ handling and its integration in cell physiology, highlighting the main common characteristics as well as key differences, in different tissues. Keywords Mitochondria. Ca 2+. MCU. NCLX This article is published as part of the special issue on "Cell-specific roles of mitochondrial Ca 2+ handling."