NCLX controls hepatic mitochondrial Ca extrusion and couples hormone-mediated mitochondrial Ca oscillations with gluconeogenesis.

Objective: Hepatic Ca signaling has been identified as a crucial key factor in driving gluconeogenesis. The involvement of mitochondria in hormone-induced Ca signaling and their contribution to metabolic activity remain, however, poorly understood. Moreover, the molecular mechanism governing the mitochondrial Ca efflux signaling remains unresolved.

CKII Control of Axonal Plasticity Is Mediated by Mitochondrial Ca via Mitochondrial NCLX.

Mitochondrial Ca efflux by NCLX is a critical rate-limiting step in mitochondria signaling. We previously showed that NCLX is phosphorylated at a putative Casein Kinase 2 (CKII) site, the serine 271 (S271). Here, we asked if NCLX is regulated by CKII and interrogated the physiological implications of this control.

Essential role of the mitochondrial Na/Ca exchanger NCLX in mediating PDE2-dependent neuronal survival and learning.

Impaired phosphodiesterase (PDE) function and mitochondrial Ca (i.e., [Ca]m) lead to multiple health syndromes by an unknown pathway.

ASIC1a senses lactate uptake to regulate metabolism in neurons.

Lactate is a major metabolite largely produced by astrocytes that nourishes neurons. ASIC1a, a Na and Ca-permeable channel with an extracellular proton sensing domain, is thought to be activated by lactate through chelation of divalent cations, including Ca, Mg and Zn, that block the channel pore. Here, by monitoring lactate-evoked H and Ca transport in cultured mouse cortical and hippocampal neurons, we find that stereo-selective neuronal uptake of L-lactate results in rapid intracellular acidification that triggers H extrusion to activate plasma membrane ASIC1a channels, leading to propagating Ca waves into the cytosol and mitochondria.

Recent studies on NCLX in health and diseases.

The mitochondria is a major hub for cellular Ca 2+ signaling. The identification of MCU, the mitochondrial Ca 2+ influx mediator, and the mitochondrial Ca 2+ extruder NCLX, were major breakthroughs in this field. Their identification provided novel molecular tools and animal models to interrogate their physiological function and mode of regulation.

Klotho rewires cellular metabolism of breast cancer cells through alteration of calcium shuttling and mitochondrial activity.

Klotho is a transmembrane protein, which can be shed and act as a circulating hormone and is involved in regulating cellular calcium levels and inhibition of the PI3K/AKT pathway. As a longevity hormone, it protects normal cells from oxidative stress, and as a tumor suppressor it inhibits growth of cancer cells. Mechanisms governing these differential activities have not been addressed.

ASIC1a channels regulate mitochondrial ion signaling and energy homeostasis in neurons.

Acid-sensing ion channel 1a (ASIC1a) is well-known to play a major pathophysiological role during brain ischemia linked to acute acidosis of ~pH 6, whereas its function during physiological brain activity, linked to much milder pH changes, is still poorly understood. Here, by performing live cell imaging utilizing Na and Ca sensitive and spatially specific fluorescent dyes, we investigated the role of ASIC1a in cytosolic Na and Ca signals elicited by a mild extracellular drop from pH 7.4 to 7.

Mitochondria control store-operated Ca entry through Na and redox signals.

Mitochondria exert important control over plasma membrane (PM) Orai1 channels mediating store-operated Ca entry (SOCE). Although the sensing of endoplasmic reticulum (ER) Ca stores by STIM proteins and coupling to Orai1 channels is well understood, how mitochondria communicate with Orai1 channels to regulate SOCE activation remains elusive. Here, we reveal that SOCE is accompanied by a rise in cytosolic Na that is critical in activating the mitochondrial Na/Ca exchanger (NCLX) causing enhanced mitochondrial Na uptake and Ca efflux.