The molecular complexity of the Mitochondrial Calcium Uniporter

Highlights

• Mitochondria are key sensors and regulators of intracellular calcium signals.

• Calcium entry into mitochondria is mediated by the Mitochondrial Calcium Uniporter.

• The Mitochondrial Calcium Uniporter consists of pore-forming and regulatory subunits.

• The regulation of mitochondrial calcium uptake reflects tissue requirements.

• Crystallographic characterization clarified mitochondrial Ca²⁺ uptake mechanisms.

Abstract

The role of mitochondria in regulating cellular Ca²⁺ homeostasis is crucial for the understanding of different cellular functions in physiological and pathological conditions. Nevertheless, the study of this aspect was severely limited by the lack of the molecular identity of the proteins responsible for mitochondrial Ca²⁺ uptake. In 2011, the discovery of the gene encoding for the Mitochondrial Calcium Uniporter (MCU), the selective channel responsible for mitochondrial Ca²⁺ uptake, gave rise to an explosion of studies aimed to characterize the composition, the regulation of the channel and its pathophysiological roles. Here, we summarize the recent discoveries on the molecular structure and composition of the MCU complex by providing new insights into the mechanisms that regulate MCU channel activity.

Introduction

Calcium ions (Ca²⁺) are ubiquitous and versatile intracellular messengers involved in a wide array of both biological processes such as proliferation, gene transcription, aerobic metabolism, and physiological mechanisms such as muscle contraction, exocytosis and synaptic plasticity during learning and memory [1]. The original theory on the critical role of Ca²⁺ ions in controlling physiological events dates back to 1883, when Sydney Ringer discovered that saline solution prepared using tap water, containing Ca²⁺, supported the contraction of isolated frog hearts, whereas saline solution prepared using distilled water, lacking Ca²⁺, did not induce the same effect [2]. This seminal observation gave rise to the discovery of other biological processes controlled by Ca²⁺. Importantly, increases in Ca²⁺ levels can be strictly localized and play critical roles at the synaptic region and at the secretory pole of exocrine cells or at the interaction site of a lymphocyte with an antigen presenting cell, the so called immunological synapse [3]. Otherwise, local variations in intracellular calcium concentration [Ca²⁺] can diffuse throughout the cell and evoke an effect at a distant site [3]. In the majority of cell types, a spatiotemporal regulation of cytosolic Ca²⁺ concentration ([Ca²⁺]_cyt) exists. This means that the increases in [Ca²⁺]_cyt are oscillatory and the frequency of each [Ca²⁺]_cyt oscillation is precisely decoded by the cell. The spatiotemporal control of the [Ca²⁺]_cyt requires the strict cooperation between the extracellular medium ([Ca²⁺] ∼ 1 mM) and intracellular Ca²⁺ stores ([Ca²⁺] > 100 mM). Among the latter, the most important is the endoplasmic reticulum (ER) and its specialized counterpart in muscle cells, the sarcoplasmic reticulum (SR) that allow rapid release through store-resident channels [3]. Moreover, a variety of pumps, channels and buffering proteins, by generating and decoding [Ca²⁺]_cyt variations within the cell, spatiotemporally regulates [Ca²⁺]_cyt rises. Other key players in the regulation of [Ca²⁺]_cyt are mitochondria, intracellular organelles that show an enormous capacity to accumulate Ca²⁺ in the very rapid time scale of hundreds of milliseconds [4], allowing the maintenance of physiological [Ca²⁺]_cyt necessary for Ca²⁺-dependent functions. Indeed, on one hand, upon increased energy demand, mitochondrial Ca²⁺ uptake sustains cellular ATP production by positively regulating the activity of three tricarboxylic acid (TCA) cycle enzymes [3]. On the other hand, dysregulation of mitochondrial Ca²⁺ uptake leads to excessive Ca²⁺ accumulation triggering the opening of the mitochondrial permeability transition pore (mPTP), the consequent release of pro-apoptotic factors, leading to cell death [3]. Thus, the characterization of the role of mitochondria in regulating cellular Ca²⁺ homeostasis has become crucial for the understanding of many physiological events. Nevertheless, this analysis was severely limited by the lack of the molecular identity of the mitochondrial Ca²⁺ uniporter (MCU), the highly selective channel responsible for mitochondrial Ca²⁺ uptake that was discovered in 2011 [5,6]. This review article describes the molecular structure and the regulation of the components of the MCU complex.