bims-miptne 2024-05-12 papers

bims-miptne

Biomed News

on Mitochondrial permeability transition pore-dependent necrosis

Issue of 2024‒05‒12
seven papers selected by
Oluwatobi Samuel Adegbite, University of Liverpool

The MCU and MCUb amino-terminal domains tightly interact: mechanisms for low conductance assembly of the mitochondrial calcium uniporter complex.
Mitochondrial calcium overload contributes to cannabinoid-induced paraptosis in hormone-responsive breast cancer cells.
Altered mitochondrial Ca2+ uptake in presynaptic terminals of cultured striatal and cortical neurons from the zQ175 knock-in mouse model of Huntington's disease.
Mitochondrial calcium regulation of cardiac metabolism in health and disease.
Calreticulin regulates hepatic stellate cell activation through modulating TGF-beta-induced Smad signaling.
Cardiac function is regulated by the sodium-dependent inhibition of the sodium-calcium exchanger NCX1.
The emerging role of regulated cell death in ischemia and reperfusion-induced acute kidney injury: current evidence and future perspectives.

iScience. 2024 May 17. 27(5): 109699

The MCU and MCUb amino-terminal domains tightly interact: mechanisms for low conductance assembly of the mitochondrial calcium uniporter complex.

Megan Noble, Danielle M Colussi, Murray Junop, Peter B Stathopulos.

  The mitochondrial calcium (Ca2+) uniporter (MCU) complex is regulated via integration of the MCU dominant negative beta subunit (MCUb), a low conductance paralog of the main MCU pore forming protein. The MCU amino (N)-terminal domain (NTD) also modulates channel function through cation binding to the MCU regulating acidic patch (MRAP). MCU and MCUb have high sequence similarities, yet the structural and functional roles of MCUb-NTD remain unknown. Here, we report that MCUb-NTD exhibits α-helix/β-sheet structure with a high thermal stability, dependent on protein concentration. Remarkably, MCU- and MCUb-NTDs heteromerically interact with ∼nM affinity, increasing secondary structure and stability and structurally perturbing MRAP. Further, we demonstrate MCU and MCUb co-localization is suppressed upon NTD deletion concomitant with increased mitochondrial Ca2+ uptake. Collectively, our data show that MCU:MCUb NTD tight interactions are promoted by enhanced regular structure and stability, augmenting MCU:MCUb co-localization, lowering mitochondrial Ca2+ uptake and implicating an MRAP-sensing mechanism.

Keywords:  Cell biology; Structural biology

DOI:  https://doi.org/10.1016/j.isci.2024.109699
Cell Prolif. 2024 May 09. e13650

Mitochondrial calcium overload contributes to cannabinoid-induced paraptosis in hormone-responsive breast cancer cells.

A de la Harpe, N Beukes, C Frost.

Studies have shown that natural products can induce paraptosis in tumour cell lines. Paraptosis is characterized by cytoplasmic vacuolation arising from the endoplasmic reticulum (ER) and mitochondria. The mechanism of paraptosis is unclear; however, dysregulation of Ca2+ homeostasis is believed to affect paraptosis induction. This study investigated the mechanism of cell death induced by a phytocannabinoid ratio in the MCF7 breast cancer cell line. The crystal violet assay was used to detect changes in viability and morphology changes were investigated using light and transmission electron microscopy. Various inhibitors, fluorescent staining with high-content screening, and Western blot analysis were used to investigate different cell death mechanisms. The phytocannabinoid ratio induced significant cell death and cytoplasmic vacuolation in MCF7 cells; however, no apoptosis, necrosis, autophagy, or ferroptosis was detected. Vacuolation induced by phytocannabinoid treatment was inhibited by cycloheximide, suggesting paraptosis induction. The mechanism of paraptosis induction was investigated, and it was found that treatment (1) induced ER dilation and mitochondrial swelling, (2) induced significant ER stress and mitochondrial Ca2+ overload and dysfunction, which appeared to be mediated by the voltage-dependent anion channel, and (3) significantly impaired all mitochondrial metabolic pathways. The data demonstrated that paraptosis induced by the cannabinoid ratio was mediated by Ca2+ flux from the ER to the mitochondria. These findings highlight a novel mechanism of cannabinoid-induced cell death and emphasize the anti-cancer potential of cannabinoid ratios, which exhibited enhanced effects compared to individual cannabinoids.

DOI: https://doi.org/10.1111/cpr.13650
Biochem Biophys Res Commun. 2024 Apr 26. pii: S0006-291X(24)00546-1. [Epub ahead of print]716 150010

Altered mitochondrial Ca2+ uptake in presynaptic terminals of cultured striatal and cortical neurons from the zQ175 knock-in mouse model of Huntington's disease.

Hanna Yoo, Hyokeun Park.

  Calcium (Ca2+) in mitochondria plays crucial roles in neurons including modulating metabolic processes. Moreover, excessive Ca2+ in mitochondria can lead to cell death. Thus, altered mitochondrial Ca2+ regulation has been implicated in several neurodegenerative diseases including Huntington's disease (HD). HD is a progressive hereditary neurodegenerative disorder that results from abnormally expanded cytosine-adenine-guanine trinucleotide repeats in the huntingtin gene. One neuropathological hallmark of HD is neuronal loss in the striatum and cortex. However, mechanisms underlying selective loss of striatal and cortical neurons in HD remain elusive. Here, we measured the basal Ca2+ levels and Ca2+ uptake in single presynaptic mitochondria during 100 external electrical stimuli using highly sensitive mitochondria-targeted Ca2+ indicators in cultured cortical and striatal neurons of a knock-in mouse model of HD (zQ175 mice). We observed elevated presynaptic mitochondrial Ca2+ uptake during 100 electrical stimuli in HD cortical neurons compared with wild-type (WT) cortical neurons. We also found the highly elevated presynaptic mitochondrial basal Ca2+ level and Ca2+ uptake during 100 stimuli in HD striatal neurons. The elevated presynaptic mitochondrial basal Ca2+ level in HD striatal neurons and Ca2+ uptake during stimulation in HD striatal and cortical neurons can disrupt neurotransmission and induce mitochondrial Ca2+ overload, eventually leading to neuronal death in the striatum and cortex of HD.

Keywords:  Calcium; Homeostasis; Huntington's disease; Mitochondria; Neurodegeneration; Neurodegenerative disease

DOI:  https://doi.org/10.1016/j.bbrc.2024.150010
Physiology (Bethesda). 2024 May 07.

Mitochondrial calcium regulation of cardiac metabolism in health and disease.

Enrique Balderas, Sandra Hj Lee, Neeraj K Rai, David M Mollinedo, Hannah E Duron, Dipayan Chaudhuri.

  Oxidative phosphorylation is regulated by mitochondrial calcium (Ca2+) in health and disease. In physiological states, Ca2+ enters via the mitochondrial Ca2+ uniporter and rapidly enhances NADH and ATP production. However, maintaining Ca2+ homeostasis is critical: insufficient Ca2+ impairs stress adaptation, while Ca2+ overload can trigger cell death. In this review, we delve into recent insights further defining the relationship between mitochondrial Ca2+ dynamics and oxidative phosphorylation. Our focus is on how such regulation affects cardiac function in health and disease, including heart failure, ischemia-reperfusion, arrhythmias, catecholaminergic polymorphic ventricular tachycardia, mitochondrial cardiomyopathies, Barth syndrome, and Friedreich's ataxia. Several themes emerge from recent data. First, mitochondrial Ca2+ regulation is critical for fuel substrate selection, metabolite import, and matching of ATP supply to demand. Second, mitochondrial Ca2+ regulates both the production and response to reactive oxygen species (ROS), and the balance between its pro- and antioxidant effects is key to how it contributes to physiological and pathological states. Third, Ca2+ exerts localized effects on the electron transport chain (ETC), not through traditional allosteric mechanisms, but rather indirectly. These effects hinge on specific transporters, such as the uniporter or the Na+-Ca2+ exchanger and may not be noticeable acutely, contributing differently to phenotypes depending on whether Ca2+ transporters are acutely or chronically modified. Perturbations in these novel relationships during disease states may either serve as compensatory mechanisms or exacerbate impairments in oxidative phosphorylation. Consequently, targeting mitochondrial Ca2+ holds promise as a therapeutic strategy for a variety of cardiac diseases characterized by contractile failure or arrhythmias.

Keywords:  MCU; heart failure; ischemia reperfusion injury; mitochondrial calcium transport; mitochondrial cardiomyopathy

DOI:  https://doi.org/10.1152/physiol.00014.2024
Cell Calcium. 2024 Apr 30. pii: S0143-4160(24)00053-8. [Epub ahead of print]121 102895

Calreticulin regulates hepatic stellate cell activation through modulating TGF-beta-induced Smad signaling.

Chien-Chih Chen, Li-Wen Hsu, Kuang-Den Chen, King-Wah Chiu, Chao-Pin Kung, Shu-Rong Li, Chao-Long Chen, Kuang-Tzu Huang.

  Liver fibrosis is characterized by excessive deposition of extracellular matrix (ECM) as a wound healing process. Activated hepatic stellate cells (HpSCs) are the major producer of the ECM and play a central role in liver fibrogenesis. It has been widely accepted that elimination of activated HpSCs or reversion to a quiescent state can be a feasible strategy for resolving the disease, further highlighting the urgent need for novel therapeutic targets. Calreticulin (CRT) is a molecular chaperone that normally resides in the endoplasmic reticulum (ER), important in protein folding and trafficking through the secretory pathway. CRT also plays a critical role in calcium (Ca2+) homeostasis, with its Ca2+ storage capacity. In the current study, we aimed to demonstrate its function in directing HpSC activation. In a mouse liver injury model, CRT was up-regulated in HpSCs. In cellular experiments, we further showed that this activation was through modulating the canonical TGF-β signaling. As down-regulation of CRT in HpSCs elevated intracellular Ca2+ levels through a form of Ca2+ influx, named store-operated Ca2+ entry (SOCE), we examined whether moderating SOCE affected TGF-β signaling. Interestingly, blocking SOCE had little effect on TGF-β-induced gene expression. In contrast, inhibition of ER Ca2+ release using the inositol trisphosphate receptor inhibitor 2-APB increased TGF-β signaling. Treatment with 2-APB did not alter SOCE but decreased intracellular Ca2+ at the basal level. Indeed, adjusting Ca2+ concentrations by EGTA or BAPTA-AM chelation further enhanced TGF-β-induced signaling. Our results suggest a crucial role of CRT in the liver fibrogenic process through modulating Ca2+ concentrations and TGF-β signaling in HpSCs, which may provide new information and help advance the current discoveries for liver fibrosis.

Keywords:  Calcium; Calreticulin; Hepatic stellate cells; Liver fibrosis; Store-operated calcium entry; TGF-beta

DOI:  https://doi.org/10.1016/j.ceca.2024.102895
Nat Commun. 2024 May 07. 15(1): 3831

Cardiac function is regulated by the sodium-dependent inhibition of the sodium-calcium exchanger NCX1.

Kyle Scranton, Scott John, Marina Angelini, Federica Steccanella, Soban Umar, Rui Zhang, Joshua I Goldhaber, Riccardo Olcese, Michela Ottolia.

The Na+-Ca2+ exchanger (NCX1) is the dominant Ca2+ extrusion mechanism in cardiac myocytes. NCX1 activity is inhibited by intracellular Na+ via a process known as Na+-dependent inactivation. A central question is whether this inactivation plays a physiological role in heart function. Using CRISPR/Cas9, we inserted the K229Q mutation in the gene (Slc8a1) encoding for NCX1. This mutation removes the Na+-dependent inactivation while preserving transport properties and other allosteric regulations. NCX1 mRNA levels, protein expression, and protein localization are unchanged in K229Q male mice. However, they exhibit reduced left ventricular ejection fraction and fractional shortening, while displaying a prolonged QT interval. K229Q ventricular myocytes show enhanced NCX1 activity, resulting in action potential prolongation, higher incidence of aberrant action potentials, a faster decline of Ca2+ transients, and depressed cell shortening. The results demonstrate that NCX1 Na+-dependent inactivation plays an essential role in heart function by affecting both cardiac excitability and contractility.

DOI: https://doi.org/10.1038/s41467-024-47850-z
Cell Death Discov. 2024 May 04. 10(1): 216

The emerging role of regulated cell death in ischemia and reperfusion-induced acute kidney injury: current evidence and future perspectives.

Chenning Li, Ying Yu, Shuainan Zhu, Yan Hu, Xiaomin Ling, Liying Xu, Hao Zhang, Kefang Guo.

Renal ischemia‒reperfusion injury (IRI) is one of the main causes of acute kidney injury (AKI), which is a potentially life-threatening condition with a high mortality rate. IRI is a complex process involving multiple underlying mechanisms and pathways of cell injury and dysfunction. Additionally, various types of cell death have been linked to IRI, including necroptosis, apoptosis, pyroptosis, and ferroptosis. These processes operate differently and to varying degrees in different patients, but each plays a role in the various pathological conditions of AKI. Advances in understanding the underlying pathophysiology will lead to the development of new therapeutic approaches that hold promise for improving outcomes for patients with AKI. This review provides an overview of the recent research on the molecular mechanisms and pathways underlying IRI-AKI, with a focus on regulated cell death (RCD) forms such as necroptosis, pyroptosis, and ferroptosis. Overall, targeting RCD shows promise as a potential approach to treating IRI-AKI.

DOI: https://doi.org/10.1038/s41420-024-01979-4