Recent studies on NCLX in health and diseases

Katoshevski, Tomer; Nissim, Tsipi Ben-Kasus; Sekler, Israel

doi:10.1016/j.ceca.2020.102345

Cited by 17 publications

(10 citation statements)

References 78 publications

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“…Thus, TMBIM5 appears to exert Ca 2+ /H + exchange activity, while other members of the TMBIM family act as pH-dependent Ca 2+ channels in membranes lacking a stable H + gradient (Bultynck et al, 2014;Guo et al, 2019;Li et al, 2020). Similar to the Na + /Ca 2+ exchanger NCLX (Katoshevski et al, 2021;Palty et al, 2010), TMBIM5 allows the efflux of Ca 2+ from mitochondria, raising the question why different Ca 2+ efflux routes have evolved. Although TMBIM5 is ubiquitously expressed in mice, tissue-specific demands may exist.…”

Section: Discussionmentioning

confidence: 99%

Regulation of mitochondrial proteostasis by the proton gradient

Patrón

Tarasenko

Nolte

et al. 2021

Preprint

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SummaryMitochondria adapt to different energetic demands reshaping their proteome. Mitochondrial proteases are emerging as key regulators of these adaptive processes. Here, we use a multi-proteomic approach to demonstrate regulation of the m-AAA protease AFG3L2 by the mitochondrial proton gradient, coupling mitochondrial protein turnover to the energetic status of mitochondria. We identify TMBIM5 (previously also known as GHITM or MICS1) as a Ca2+/H+ exchanger in the mitochondrial inner membrane, which binds to and inhibits the m-AAA protease. TMBIM5 ensures cell survival and respiration, allowing Ca2+ efflux from mitochondria and limiting mitochondrial hyperpolarization. Persistent hyperpolarization, however, triggers degradation of TMBIM5 and activation of the m-AAA protease. The m-AAA protease broadly remodels the mitochondrial proteome and mediates the proteolytic breakdown of respiratory complex I to confine ROS production and oxidative damage in hyperpolarized mitochondria. TMBIM5 thus integrates mitochondrial Ca2+ signaling and the energetic status of mitochondria with protein turnover rates to reshape the mitochondrial proteome and adjust the cellular metabolism.

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Section: Discussionmentioning

confidence: 99%

Regulation of mitochondrial proteostasis by the proton gradient

Patrón

Tarasenko

Nolte

et al. 2021

Preprint

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“…Partial depolarization is known to affect NCLX activity [112], posing NCLX as a possible cause of ROS production in PD. Indeed, halt in NCLX activity has been associated with increased mitochondrial Ca 2+ content and neuronal cell death in two PD-associated risk protein pathways [113,114]. As hypoxic ROS may be involved in PD progression, it would be expected that HIF-1α stabilizes during PD.…”

Section: Mitochondrial Ros Production In (Patho)physiologymentioning

confidence: 99%

Generation of Reactive Oxygen Species by Mitochondria

2021

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Reactive oxygen species (ROS) are series of chemical products originated from one or several electron reductions of oxygen. ROS are involved in physiology and disease and can also be both cause and consequence of many biological scenarios. Mitochondria are the main source of ROS in the cell and, particularly, the enzymes in the electron transport chain are the major contributors to this phenomenon. Here, we comprehensively review the modes by which ROS are produced by mitochondria at a molecular level of detail, discuss recent advances in the field involving signalling and disease, and the involvement of supercomplexes in these mechanisms. Given the importance of mitochondrial ROS, we also provide a schematic guide aimed to help in deciphering the mechanisms involved in their production in a variety of physiological and pathological settings.

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“…The NCLX transports 3Na + per Ca 2+ , but also displays Li + -dependent Ca 2+ transport [ 26 ]. The NCLX is regulated by kinase activity, mitochondrial membrane potential and proteases [ 26 , 27 ].…”

Section: Ca 2+ Signalingmentioning

confidence: 99%

Dysregulated Ca2+ Homeostasis as a Central Theme in Neurodegeneration: Lessons from Alzheimer’s Disease and Wolfram Syndrome

Callens

Loncke

Bultynck

2022

Cells

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Calcium ions (Ca2+) operate as important messengers in the cell, indispensable for signaling the underlying numerous cellular processes in all of the cell types in the human body. In neurons, Ca2+ signaling is crucial for regulating synaptic transmission and for the processes of learning and memory formation. Hence, the dysregulation of intracellular Ca2+ homeostasis results in a broad range of disorders, including cancer and neurodegeneration. A major source for intracellular Ca2+ is the endoplasmic reticulum (ER), which has close contacts with other organelles, including mitochondria. In this review, we focus on the emerging role of Ca2+ signaling at the ER–mitochondrial interface in two different neurodegenerative diseases, namely Alzheimer’s disease and Wolfram syndrome. Both of these diseases share some common hallmarks in the early stages, including alterations in the ER and mitochondrial Ca2+ handling, mitochondrial dysfunction and increased Reactive oxygen species (ROS) production. This indicates that similar mechanisms may underly these two disease pathologies and suggests that both research topics might benefit from complementary research.

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Recent studies on NCLX in health and diseases

Cited by 17 publications

References 78 publications

Regulation of mitochondrial proteostasis by the proton gradient

Regulation of mitochondrial proteostasis by the proton gradient

Generation of Reactive Oxygen Species by Mitochondria

Dysregulated Ca2+ Homeostasis as a Central Theme in Neurodegeneration: Lessons from Alzheimer’s Disease and Wolfram Syndrome

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