Mitochondrial Ca homoeostasis regulates aerobic metabolism and cell survival. Ca flux into mitochondria is mediated by the mitochondrial calcium uniporter (MCU) channel whereas Ca export is often through an electrogenic Na-Ca exchanger. Here, we report remarkable functional versatility in mitochondrial Na-Ca exchange under conditions where mitochondria are depolarised. Following physiological stimulation of cell-surface receptors, mitochondrial Na-Ca exchange initially operates in reverse mode, transporting cytosolic Ca into the matrix. As matrix Ca rises, the exchanger reverts to its forward mode state, extruding Ca. Transitions between reverse and forward modes generate repetitive oscillations in matrix Ca. We further show that reverse mode Na-Ca activity is regulated by the mitochondrial fusion protein mitofusin 2. Our results demonstrate that reversible switching between transport modes of an ion exchanger molecule generates functionally relevant oscillations in the levels of the universal Ca messenger within an organelle.
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http://dx.doi.org/10.1038/s41467-017-02638-2 | DOI Listing |
Background: While the formation of β-amyloid plaques and neurofibrillary "tau" tangles are considered hallmarks of AD pathology, therapeutic targeting of these pathways has been unsuccessful, highlighting the necessity to define the underlying molecular mechanisms driving AD progression. Previous studies from our lab demonstrated that mitochondrial calcium (Ca) overload through neuronal ablation of the mitochondrial Na/Ca exchanger (NCLX) is sufficient to trigger 'AD-like' pathology, including mitochondrial dysfunction, amyloid deposition and tau pathology, and cognitive decline. In addition, we found significant proteomic remodeling of components of the mitochondrial calcium uniporter channel (mtCU), the primary mediator of Ca uptake, in frontal cortex samples isolated post-mortem from patients diagnosed with non-familial/sporadic AD.
View Article and Find Full Text PDFSci Rep
January 2025
Marine Biotechnology Fish Nutrition and Health Division, ICAR-Central Marine Fisheries Research Institute, Ernakulam North P O, Kochi, Kerala, 682018, India.
The Indian scad, Decapterus russelli is one of the most exploited pelagic resources of India. Population genetic analyses using mitochondrial and nuclear markers indicated a lack of genetic structuring among populations from Indian waters. As this species is highly migratory, it is also important to establish the environmental influence on its population structure.
View Article and Find Full Text PDFCell Calcium
December 2024
Cardiac Signaling Center of USC, MUSC and Clemson University, 68 President St BEB 306, Charleston, SC 29425, USA. Electronic address:
Rationale & Methods: While signaling of cardiac SR by surface membrane proteins (I & I) is well studied, the regulation of mitochondrial Ca by plasmalemmal proteins remains less explored. Here we have examined the signaling of mitochondria and SR by surface-membrane calcium-transporting proteins, using genetically engineered targeted fluorescent probes, mito-GCamP6 and R-CEPIA1er.
Results: In voltage-clamped and TIRF-imaged cardiomyocytes, low Na induced SR Ca release was suppressed by short pre-exposures to ∼100 nM FCCP, suggesting mitochondrial Ca contribution to low Na triggered SR Carelease.
J Physiol
October 2024
Department of Integrative and Systems Physiology, Faculty of Medical Sciences and Life Science Innovation Center, University of Fukui, Fukui, Japan.
Previous studies demonstrated that the mitochondrial Ca uniporter MCU and the Na-Ca exchanger NCLX exist in proximity to the sarcoplasmic reticulum (SR) ryanodine receptor RyR and the Ca pump SERCA, respectively, creating a mitochondria-SR Ca interaction. However, the physiological relevance of the mitochondria-SR Ca interaction has remained unsolved. Furthermore, although mitochondrial Ca has been proposed to be an important factor regulating mitochondrial energy metabolism, by activating NADH-producing dehydrogenases, the contribution of the Ca-dependent regulatory mechanisms to cellular functions under physiological conditions has been controversial.
View Article and Find Full Text PDFPoult Sci
December 2024
College of Animal Science and Technology, Key Laboratory of Animal Origin Food Production and Safety Guarantee of Jiangsu Province, Jiangsu Collaborative Innovation Center of Meat Production and Processing, Quality and Safety Control, Nanjing Agricultural University, Nanjing, 210095, China. Electronic address:
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