It has been firmly established that the rapid uptake of Ca2+ by mitochondria from a wide range of sources is mediated by a uniporter which permits transport of the ion down its electrochemical gradient. Several mechanisms of Ca2+ efflux from mitochondria have also been extensively discussed in the literature. Energized mitochondria must expend a significant amount of energy to transport Ca2+ against its electrochemical gradient from the matrix space to the external space. Two separate mechanisms have been found to mediate this outward transport: a Ca2+/nNa+ exchanger and a Na(+)-independent efflux mechanism. These efflux mechanisms are considered from the perspective of available energy. In addition, a reversible Ca2(+)-induced increase in inner membrane permeability can also occur. The induction of this permeability transition is characterized by swelling of the mitochondria, leakiness to small ions such as K+, Mg2+, and Ca2+, and loss of the mitochondrial membrane potential. It has been suggested that the permeability transition and its reversal may also function as a mitochondrial Ca2+ efflux mechanism under some conditions. The characteristics of each of these mechanisms are discussed, as well as their possible physiological functions.

Mechanisms by which mitochondria transport calcium.

The identification of intramitochondrial free calcium ([Ca2+
m) as a primary metabolic mediator [see Hansford (this volume) and Gunter, T. E., Gunter, K. K., Sheu, S.-S., and Gavin, C. E. (1994)Am. J. Physiol.
267, C313–C339, for reviews] has emphasized the importance of understanding the characteristics of those mechanisms that control [Ca2+]m. In this review, we attempt to update the descriptions of the mechanisms that mediate the transport of Ca2+ across the mitochondrial inner membrane, emphasizing the energetics of each mechanism. New concepts within this field are reviewed and some older concepts are discussed more completely than in earlier reviews. The mathematical forms of the membrane potential dependence and concentration dependence of the uniporter are interpolated in such a way as to display the convenience of consideringV
max to be an explicit function of the membrane potential. Recent evidence for a transient rapid conductance state of the uniporter is discussed. New evidence concerning the energetics and stoichiometries of both Na+-dependent and Na+-independent efflux mechanisms is reviewed. Explicit mathematical expressions are used to describe the energetics of the system and the kinetics of transport via each Ca2+ transport mechanism.

Transport of calcium by mitochondria.

The heavy metal lead is a widely deposited environmental toxicant known to impact numerous physiological systems, including the reproductive, neurological, hepatic, renal, and immune systems. Studies illustrating the capacity of lead to impair immune function and/or host resistance to disease date back to at least the 1960s. However, it has only been in recent years that lead has been recognized among a new category of immunotoxicants-those that dramatically shift immune functional capacity while producing only modest changes to immune cell populations and lymphoid organs. These relatively noncytotoxic immunomodulating chemicals and drugs represent the immunotoxic hazards most difficult to identify and problematic for risk assessment using historic approaches. As a result, such environmental factors are also among the most likely to contribute to chronic immune-related disease at relevant exposure levels. This review considers the animal and human evidence that lead exposure can produce a stark shift in immune functional capacity with a skewing predicted to elevate the risk of atopic and certain autoimmune diseases. At the same time, host defenses against infectious agents and cancer may be reduced. Age-based exposure studies also suggest that levels of blood lead previously thought to be safe, that is, below 10 microg/dl, may be associated with later life immune alterations.

Lead and immune function.

Lanthanum belongs to the group of elements known as "lanthanons," which also includes cerium, europium, promethium, and thulium. It is the most electropositive element of the rare earth group, is uniformly trivalent, and is similar in its chemical properties to the alkaline earth elements. The effects of this element and its compounds on cellular systems are of considerable interest because of their increasing use in industry and as a substitute or antagonist for calcium in a variety of cellular reactions. Lanthanum is also being employed extensively in studying anatomical barriers, membrane structure, and subcellular transport systems, particularly the calcium pathway.

Effects of lanthanum in cellular systems - A review

Scintillator based radiation detectors readout by SiPMs successively break records in their reached time resolution. Nevertheless, new challenges in time of flight positron emission tomography (TOF-PET) and high energy physics are setting unmatched goals in the 10 ps range. Recently it was shown that high frequency (HF) readout of SiPMs significantly improves the measured single photon time resolution (SPTR), allowing to evaluate the intrinsic performance of large area devices; e.g. FBK NUV-HD SiPMs of [Formula: see text] mm2 area and 40 [Formula: see text]m single photon avalanche diode (SPAD) size achieve 90 ps FWHM. In TOF-PET such readout allows to lower the leading edge detection threshold, so that the fastest photons produced in the crystal can be utilized. This is of utmost importance if a high SPTR and prompt Cherenkov light generated by the hot-recoil electron upon 511 keV photo-absorption should improve timing. This paper shows that high-frequency bipolar transistor readout of state-of-the-art SiPMs coupled to high-performance scintillators can substantially improve the best achievable coincidence time resolution (CTR) in TOF-PET. In this context a CTR of 158 [Formula: see text] 3 ps FWHM with [Formula: see text] mm3 BGO crystals coupled to FBK SiPMs is achieved. This faint Cherenkov signal is as well present in standard LSO scintillators, which together with low SPTR values (<90 ps FWHM) improves the CTR of [Formula: see text] mm3 LSO:Ce:Ca coupled to FBK NUV-HD [Formula: see text] mm2 with 25 [Formula: see text]m SPAD size to 61 [Formula: see text] 2 ps FWHM using HF-electronics, as compared to 73 [Formula: see text] 2 ps when readout by the NINO front-end ASIC. When coupling the LSO:Ce:Ca crystals to FBK NUV-HD SiPMs of [Formula: see text] mm2 and 40 [Formula: see text]m SPAD size, using HF-electronics, a CTR of even 58 [Formula: see text] 3 ps for [Formula: see text] mm3 and 98 [Formula: see text] 3 ps for [Formula: see text] mm3 is achieved. This new experimental data will allow to further discuss the timing limits in scintillator-based detectors.

https://iopscience.iop.org/article/10.1088/1361-6560/aafd52/pdf

High-frequency SiPM readout advances measured coincidence time resolution limits in TOF-PET.

Toxicologically significant amounts of inorganic lead were added to rat brain mitochondrial preparations that did not contain EDTA or Pi. The binding of the lead to the mitochondria was measured by anodic stripping voltometry. In the presence of lead, the respiratory control ratios decreased, implying a decrease in the degree of dependence of respiration on a phosphate acceptor. Nucleotide contents were also measured, and in the presence of inorganic lead the actual amounts of ATP formed from ADP were found to be significantly decreased as well.

Effect of inorganic lead on rat brain mitochondrial respiration and energy production.

Effect of low-level lead exposure on antibody-dependent and natural killer cell-mediated cytotoxicity

The effect of chronic low-level lead (Pb2+) ingestion on the metabolic pathways leading to the acetyl moiety of acetylcholine (ACh) was examined. Cerebral cortex slices, prepared from untreated or Pb2+-exposed rats (600 ppm lead acetate in the drinking water for 20 days), were incubated in Krebs-Ringer bicarbonate buffer with 10 mM glucose and tracer amounts of [6-3H]glucose and either [6-14C]glucose or [3-14C] beta-hydroxybutyrate. Altering the concentration of Pb2+ in the drinking water produced a dose-related increase in blood and brain lead levels. When tissue from Pb2+-exposed rats was incubated with mixed-label glucose, incorporation into lacate, citrate, and ACh was considerably decreased, although no changes occurred in the 3H/14C rations. Similar effects of Pb2+ were found when 14C-labeled beta-hydroxybutyrate was substituted for the [14C]glucose. It appears from these data that Pb2+ exerts a generalized effect on energy metabolism and not on a specific step in glucose metabolism. The impairment of glucose metabolism may explain partially the Pb2+-induced changes observed in cholinergic function.

Effect of chronic lead ingestion by rats on glucose metabolism and acetylcholine synthesis in cerebral cortex slices.

In this paper we report on a new silicon photomultiplier (SPM) architecture with additional signal output. This additional output has very fast single photo electron response (~2 ns FWTM). This new device can be easily integrated into legacy systems by providing the ability to operate as a normal SPM with Anode readout or in new designs with an additional fast output. As result the rise time of timing signal for LYSO scintillator coupled to this new fast SPM is about 2ns, compared with typical 20-40ns for SPM’s anode signal. This enables coincidence-timing performance improvements for SPM devices, from 300 ps (Coincidence Resolved Time – CRT FWHM) to better than 250ps (CRT FWHM) coincidence timing resolution for SM series devices. Furthermore, use of the fast terminal allows for a wide range of leading thresholds without large degradation of CRT as compared with standard terminal. In this paper we will demonstrate that providing ability to detect first photon events provides significantly better CRT, comparable to large PDE improvement.

Kevin J. O'Neill

Papers

Effect of inorganic lead on rat brain mitochondrial respiration and energy production.

Effect of low-level lead exposure on antibody-dependent and natural killer cell-mediated cytotoxicity

Effect of chronic lead ingestion by rats on glucose metabolism and acetylcholine synthesis in cerebral cortex slices.

SensL New Fast Timing Silicon Photomultiplier

Uptake of inorganic lead in vitro by isolated mitochondria and tissue slices of rat renal cortex