From the Identification to the Dissection of the Physiological Role of the Mitochondrial Calcium Uniporter: An Ongoing Story.

The notion of mitochondria being involved in the decoding and shaping of intracellular Ca2+ signals has been circulating since the end of the 19th century. Despite that, the molecular identity of the channel that mediates Ca2+ ion transport into mitochondria remained elusive for several years. Only in the last decade, the genes and pathways responsible for the mitochondrial uptake of Ca2+ began to be cloned and characterized. The gene coding for the pore-forming unit of the mitochondrial channel was discovered exactly 10 years ago, and its product was called mitochondrial Ca2+ uniporter or MCU. Before that, only one of its regulators, the mitochondria Ca2+ uptake regulator 1, MICU1, has been described in 2010. However, in the following years, the scientific interest in mitochondrial Ca2+ signaling regulation and physiological role has increased. This shortly led to the identification of many of its components, to the description of their 3D structure, and the characterization of the uniporter contribution to tissue physiology and pathology. In this review, we will summarize the most relevant achievements in the history of mitochondrial Ca2+ studies, presenting a chronological overview of the most relevant and landmarking discoveries. Finally, we will explore the impact of mitochondrial Ca2+ signaling in the context of muscle physiology, highlighting the recent advances in understanding the role of the MCU complex in the control of muscle trophism and metabolism.

Store-Operated Calcium Entry: An Historical Overview.

Store-operated calcium entry is a mechanism of Ca2+ signaling that has evolved from theory to molecules over a period of 30 years. This brief overview summarizes the major milestones that have led to the current concepts regarding the mechanisms and regulation of this most widely encountered of calcium signaling mechanisms.

The answer is not 42.

During his long and illustrious career that now spans over 50 years David Triggle has had a major impact on biomedical science that can be linked to his research spanning the disciplines of chemistry and biology. Capitalizing on his undergraduate and postgraduate education in chemistry David's early research explored the pharmacology of adreno- and muscarinic receptors ultimately leading to studies of the cellular signaling processes that mediated the effects of receptor activation particularly with respect to calcium homeostasis. David's contributions to the identification and development of calcium channel antagonists resulted in benefits beyond the impact of such drugs in the treatment of diseases of the cardiovascular system. During David's 50+ year career many technological changes have occurred that have affected how research is conducted, funded and published and how its impact evaluated. Not all of these technological advances are necessarily positive and it is valuable to reflect on the long lasting impact of David's accomplishments with reference to such changes.

The interplay of mitochondria with calcium: an historical appraisal.

Indirect findings in the 1950s had indicated that mitochondria could accumulate Ca(2+), but only in 1961 isolated mitochondria were directly shown to take it up in a process driven by the activity of the respiratory chain or by the hydrolysis of added ATP. The uptake of Ca(2+) could be accompanied by the simultaneous uptake of inorganic phosphate, leading to the precipitation of hydroxyapatite in the matrix and to the effective buffering of the free Ca(2+) concentration in it. The uptake of Ca(2+) occurred via an electrophoretic uniporter that has been molecularly identified only recently. Ca(2+) was then released through a Na(+)/Ca(2+) exchanger that has also been identified very recently (a H(+)/Ca(2+) antiporter has also been described in some mitochondrial types). In the matrix two TCA cycle dehydrogenases and pyruvate dehydrogenase phosphate phosphatase were found to be regulated by Ca(2+), providing a rationale for the Ca(2+) cycling process. The affinity of the uptake uniporter was found to be too low to efficiently regulate Ca(2+) in the low to mid nM concentration in the cytosol. However, a number of findings showed that energy linked transport of Ca(2+) did nevertheless occur in mitochondria in situ. The enigma was solved in the 1990s, when it was found that perimitochondrial Ca(2+) pools are created by the discharge of Ca(2+) from vicinal endoplasmic reticulum stores in which the concentration of Ca(2+) is high enough to satisfy the poor affinity of the uniporter. Thus, mitochondria have now regained a key role in the regulation of cytosolic Ca(2+) (not only of their own internal Ca(2+)).

Three centuries of Eastern European and Altai lead emissions recorded in a Belukha ice core.

Human activities have significantly altered atmospheric Pb concentrations and thus, its geochemical cycle, for thousands of years. Whereas historical Pb emissions from Western Europe, North America, and Asia are well documented, there is no equivalent data for Eastern Europe. Here, we present ice-core Pb concentrations for the period 1680-1995 from Belukha glacier in the Siberian Altai, assumed to be representative of emissions in Eastern Europe and the Altai. Pb concentrations and (207)Pb/(206)Pb ratios were strongly enhanced during the period 1935-1995 due to the use of Pb additives in Russian gasoline mined in the Rudny Altai. Comparable to Western Europe and North America, Eastern European Pb emissions peaked in the 1970s. However, the subsequent downward trend in Eastern Europe was mainly caused by the economic crisis in the U.S.S.R. and not by a phase-out of leaded gasoline. Pb concentrations in the period 1680-1935, preceding the era of intensified industrialization in Russia, reflect the history of local emissions from Rudny Altai mining and related metallurgical processing primarily for the production of Russian coins. During this time, Altai ore Pb contributed about 40% of the regional atmospheric Pb.

Historical review: mitochondria and calcium: ups and downs of an unusual relationship.

The discovery of Ca(2+) transport by mitochondria is conventionally credited to De Luca and Engstrom, and Vasington and Murphy, who showed in 1961-1962 that Ca(2+) was taken up by isolated mitochondria using respiratory or ATP energy. However, contributions had already appeared in the 1950s showing - albeit indirectly - that isolated mitochondria bound Ca(2+) actively. Somehow, however, these contributions failed to attract the attention that they undoubtedly deserved. The 1961-1962 findings started the ball rolling, initiating a topic that was to have a peculiar oscillatory history. It went from peaks of great enthusiasm to valleys of essential neglect, and from there to a final (hopefully permanent) robust revival.

[Ca and P supply of ruminants in the 19th and beginning of 20th century in Middle Europe]. / Zur Ca- und P-Versorgung der Wiederkäuer im 19. und beginnenden 20. Jahrhundert in Mitteleuropa.

The present review evaluates veterinary publications about some bone diseases in ruminants till 1925. According to more than 100 publications in some regions of Germany as well as in Scandinavian and Westeuropean countries during the 19th century several cases of bone fractures in ruminants were reported, mainly in pregnant and lactating cattle and goats. From a recent point of view and after feed analyses this disease obviously was caused by a P-deficiency. Bone fractures sometimes were accompanied by licking behaviour, but in other regions pica (without severe skeletal deformations) was probably related to a Cu- or Co-deficiency. Swelling of the jaws (probably by Ca-deficiency) was exclusively described in goats. By preventive measures (feeding bone meal, P-fertilisation) bone fractures diminished in the beginning of the 20th century. After the experience in the past in ruminants bone diseases may come back, if effective preventive measures will be ignored due to the recent trends towards 'natural farming'.

Ricardo Miledi and the calcium hypothesis of neurotransmitter release.

Ricardo Miledi has made significant contributions to our basic understanding of how synapses work. Here I discuss aspects of Miledi's research that helped to establish the requirement of presynaptic calcium for neurotransmitter release, from his earliest scientific studies to his classic experiments in the squid giant synapse.