scholarly journals Molecular Mechanisms of Leucine Zipper EF-Hand Containing Transmembrane Protein-1 Function in Health and Disease

2019 ◽  
Vol 20 (2) ◽  
pp. 286 ◽  
Author(s):  
Qi-Tong Lin ◽  
Peter Stathopulos
Keyword(s):  
Leucine Zipper ◽  
Molecular Mechanisms ◽  
Transmembrane Protein ◽  
Cell Physiology ◽  
Inner Mitochondrial Membrane ◽  
Atp Production ◽  
Transporter Protein ◽  
Mitochondrial Functions ◽  
Ef Hand ◽  
Mechanistic Basis

Mitochondrial calcium (Ca2+) uptake shapes cytosolic Ca2+ signals involved in countless cellular processes and more directly regulates numerous mitochondrial functions including ATP production, autophagy and apoptosis. Given the intimate link to both life and death processes, it is imperative that mitochondria tightly regulate intramitochondrial Ca2+ levels with a high degree of precision. Among the Ca2+ handling tools of mitochondria, the leucine zipper EF-hand containing transmembrane protein-1 (LETM1) is a transporter protein localized to the inner mitochondrial membrane shown to constitute a Ca2+/H+ exchanger activity. The significance of LETM1 to mitochondrial Ca2+ regulation is evident from Wolf-Hirschhorn syndrome patients that harbor a haplodeficiency in LETM1 expression, leading to dysfunctional mitochondrial Ca2+ handling and from numerous types of cancer cells that show an upregulation of LETM1 expression. Despite the significance of LETM1 to cell physiology and pathophysiology, the molecular mechanisms of LETM1 function remain poorly defined. In this review, we aim to provide an overview of the current understanding of LETM1 structure and function and pinpoint the knowledge gaps that need to be filled in order to unravel the underlying mechanistic basis for LETM1 function.

scholarly journals Functional reconstitution of the mitochondrial Ca2+/H+ antiporter Letm1

2013 ◽  
Vol 143 (1) ◽  
pp. 67-73 ◽  
Author(s):  
Ming-Feng Tsai ◽  
Dawei Jiang ◽  
Linlin Zhao ◽  
David Clapham ◽  
Christopher Miller
Keyword(s):  
Transport Mechanism ◽  
Turnover Rate ◽  
Leucine Zipper ◽  
Transmembrane Protein ◽  
Ruthenium Red ◽  
Mitochondrial Calcium Uniporter ◽  
Mitochondrial Inner Membrane ◽  
Calcium Uniporter ◽  
Ef Hand ◽  
Inner Membrane Protein

The leucine zipper, EF hand–containing transmembrane protein 1 (Letm1) gene encodes a mitochondrial inner membrane protein, whose depletion severely perturbs mitochondrial Ca2+ and K+ homeostasis. Here we expressed, purified, and reconstituted human Letm1 protein in liposomes. Using Ca2+ fluorophore and 45Ca2+-based assays, we demonstrate directly that Letm1 is a Ca2+ transporter, with apparent affinities of cations in the sequence of Ca2+ ≈ Mn2+ > Gd3+ ≈ La3+ > Sr2+ >> Ba2+, Mg2+, K+, Na+. Kinetic analysis yields a Letm1 turnover rate of 2 Ca2+/s and a Km of ∼25 µM. Further experiments show that Letm1 mediates electroneutral 1 Ca2+/2 H+ antiport. Letm1 is insensitive to ruthenium red, an inhibitor of the mitochondrial calcium uniporter, and CGP-37157, an inhibitor of the mitochondrial Na+/Ca2+ exchanger. Functional properties of Letm1 described here are remarkably similar to those of the H+-dependent Ca2+ transport mechanism identified in intact mitochondria.

scholarly journals Metabolic Alterations Caused by Defective Cardiolipin Remodeling in Inherited Cardiomyopathies

Life ◽  
2020 ◽  
Vol 10 (11) ◽  
pp. 277
Author(s):  
Christina Wasmus ◽  
Jan Dudek
Keyword(s):  
Heart Failure ◽  
Respiratory Chain ◽  
Mitochondrial Membrane ◽  
Molecular Mechanisms ◽  
Mitochondrial Enzymes ◽  
Inner Mitochondrial Membrane ◽  
Mitochondrial Functions ◽  
Metabolic Remodeling ◽  
Inherited Cardiomyopathies ◽  
The Impact

The heart is the most energy-consuming organ in the human body. In heart failure, the homeostasis of energy supply and demand is endangered by an increase in cardiomyocyte workload, or by an insufficiency in energy-providing processes. Energy metabolism is directly associated with mitochondrial redox homeostasis. The production of toxic reactive oxygen species (ROS) may overwhelm mitochondrial and cellular ROS defense mechanisms in case of heart failure. Mitochondria are essential cell organelles and provide 95% of the required energy in the heart. Metabolic remodeling, changes in mitochondrial structure or function, and alterations in mitochondrial calcium signaling diminish mitochondrial energy provision in many forms of cardiomyopathy. The mitochondrial respiratory chain creates a proton gradient across the inner mitochondrial membrane, which couples respiration with oxidative phosphorylation and the preservation of energy in the chemical bonds of ATP. Akin to other mitochondrial enzymes, the respiratory chain is integrated into the inner mitochondrial membrane. The tight association with the mitochondrial phospholipid cardiolipin (CL) ensures its structural integrity and coordinates enzymatic activity. This review focuses on how changes in mitochondrial CL may be associated with heart failure. Dysfunctional CL has been found in diabetic cardiomyopathy, ischemia reperfusion injury and the aging heart. Barth syndrome (BTHS) is caused by an inherited defect in the biosynthesis of cardiolipin. Moreover, a dysfunctional CL pool causes other types of rare inherited cardiomyopathies, such as Sengers syndrome and Dilated Cardiomyopathy with Ataxia (DCMA). Here we review the impact of cardiolipin deficiency on mitochondrial functions in cellular and animal models. We describe the molecular mechanisms concerning mitochondrial dysfunction as an incitement of cardiomyopathy and discuss potential therapeutic strategies.

Effect of MALAT1 in the crosstalk between nucleus and mitochondria on mitochondrial reprogramming in hepatocellular carcinoma cells.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e14711-e14711
Author(s):  
Yijing Zhao ◽  
Jiuwei Cui ◽  
Jifan Hu ◽  
Andrew R Hoffman
Keyword(s):  
Rna Binding ◽  
Transmembrane Protein ◽  
Mitochondrial Morphology ◽  
Mitochondrial Rna ◽  
Mtdna Copy Number ◽  
Mitochondria Dysfunction ◽  
Mt Dna ◽  
Apoptosis Pathway ◽  
Atp Production ◽  
Mitochondrial Functions

e14711 Background: Mitochondria-nuclear crosstalk is a bidirectional pathway of communication between mitochondria and nucleus that influences many cellular and organismal activities. This crosstalk can regulate several oncogenic pathways involved in tumorigenesis. MALAT1 (metastasis-associated lung adenocarcinoma transcript 1), a nucleus-encoded lncRNA, dysregulated in multiple human malignancies is recently found to drive mitochondria dysfunction in Mitochondria-nuclear crosstalk. Methods: RNA sequencing, “RNA reverse transcription-associated trap sequencing” (RAT-seq), RNA immunoprecipitation(RIP), fluorescence in situ hybridization (FISH), were performed to detect the position of the MALAT1, and its interaction protein and DNAs in HepG2 cell line. After silencing MALAT1 by shRNAs, Seahorse, ATP production, lysotracker staining, Western blot, and electronic microscope were used to measure metabolism, ROS amount, mitophagy, apoptosis and mitochondrial morphology of the silencing cell lines. Results: By combining mitochondrial RNA-Seq with FISH, it is surprised to discover that MALAT1 was enriched in the mitochondria of HepG2 cells. Using RAT-seq approach, MALAT1 was found to utilized it 3’-fragment to interact with multiple loci of mitochondrial DNA( D-loop, COX2, ND3, and CYTB ). The RIP and affinity RNA pulldown assays suggested that the RNA-binding protein HuR mediated the transportation of MALAT1 to the mitochondria. Also, mitochondria transmembrane protein mitochondrial carrier 2(MTCH2) is found to interacted MALAT1, suggesting that MALAT1 may through the MTCH2 to get into the inside of the mitochondria. Knockdown of MALAT1 induced multiple abnormalities in mitochondrial functions, including low OXPHOS, low ATP production, reduced mitophagy, declined mtDNA copy number, and activation of the mitochondrial apoptosis pathway. Conclusions: Together, this study greatly expands our knowledge of the nucleus-encoded lncRNA MALAT1 driving the mitochondria dysfunction. Our study establishes MALAT1 as a regulator through interacting with MT-DNA, HuR, MTCH2 protein, revealing a new regulatory mechanism of mitochondria. Many novel nucleus-encoded RNAs existing in mitochondria were identified at the first time, suggesting novel biological functions of lncRNAs, laying the foundation for further clarifying their roles.

scholarly journals Leucine zipper-EF-hand containing transmembrane protein 1 (LETM1) forms a Ca2+/H+ antiporter

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Juan Shao ◽  
Zhenglin Fu ◽  
Yanli Ji ◽  
Xiangchen Guan ◽  
Shang Guo ◽  
...  
Keyword(s):  
Leucine Zipper ◽  
Transmembrane Protein ◽  
Ef Hand

Influence of Ca2+ on mitochondrial apoptosis activation and yak meat tenderization during postmortem aging

2021 ◽  
pp. 1-12
Author(s):  
Lin-lin Wang ◽  
Lian-hong Chen ◽  
Jian Li ◽  
Rong-sheng Du ◽  
Ling Han ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Citrate Synthase ◽  
Control Group ◽  
Mitochondrial Apoptosis ◽  
Apoptosis Pathway ◽  
Atp Production ◽  
Mitochondrial Apoptosis Pathway ◽  
Mitochondrial Functions ◽  
Postmortem Aging ◽  
Meat Tenderization

The objective of this study was to investigate the underlying molecular mechanisms of mitochondrial Ca2+ homeostasis disequilibrium in mitochondrial apoptosis and its impact on yak meat tenderness. Results indicated that CaCl2 treatment significantly promoted glycolysis by increasing lactic acid level and decreasing glycogen content, pH, and ATP production (P < 0.01 and P < 0.05). The activities of Na+-K+-ATPase pump and Ca2+-ATPase pump in the early aging stage were significantly influenced by CaCl2 treatment. The activities of synchronous digital hierarchy and citrate synthase were also significantly improved by CaCl2 treatment (P < 0.01 and P < 0.05). Mitochondrial reactive oxygen species (ROS) levels were significantly higher in the CaCl2 group than in the control group (P < 0.01); at 24 h, the value in the Ca2+ group was 64.27% higher than that in the control group. Furthermore, CaCl2 treatment significantly enhanced the mitochondrial apoptosis cascade reaction and meat tenderization by improving the myofibril fragmentation index and shear force (P < 0.01). These results demonstrated that the imbalance of mitochondrial Ca2+ homeostasis played a significant role in the mitochondrial apoptosis pathway by regulating energy metabolism factors, meat intracellular environment, mitochondrial functions, and ROS-mediated oxidative stress. These conditions further improved meat tenderization during postmortem aging.

scholarly journals Physiological and Transcriptomic Responses to Nitrogen Deficiency in Neolamarckia cadamba

2021 ◽  
Vol 12 ◽  
Author(s):  
Lu Lu ◽  
Yuanyuan Zhang ◽  
Lu Li ◽  
Na Yi ◽  
Yi Liu ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Leucine Zipper ◽  
Molecular Mechanisms ◽  
Lignin Content ◽  
Nitrogen Deficiency ◽  
Essential Elements ◽  
Ammonium Transporter ◽  
Basic Leucine Zipper ◽  
Transporter Protein ◽  
Helix Loop Helix

Nitrogen (N) is one of the abundant and essential elements for plant growth and development, and N deficiency (ND) affects plants at both physiological and transcriptomic levels. Neolamarckia cadamba is a fast-growing woody plant from the Rubiaceae family. However, the physiological and molecular impacts of ND on this species have not been well investigated. Here, we studied how N. cadamba responds to ND under hydroponic conditions. In a physiological aspect, ND led to a reduction in biomass, chlorophyll content, and photosynthetic capacity. ND also impaired the assimilation of N as the activities of glutamine synthetase (GS) and nitrate reductase (NR) were decreased in the root. Interestingly, the lignin content of stem increased progressively during the ND stress. The main transcription factors, the transcription factors that are important to N regulation has been found to be upregulated, including Nodule inception-like protein 7 (NLP7), TGACG motif-binding factor 1 (TGA1), basic helix-loop-helix protein 45 (BHLH45), NAM, ATAF1,2, CUC2 (NAC) transcription factor 43 (NAC43), and basic leucine zipper pattern 44 (bZIP44). The expression of N transporters, such as nitrate transporter 2.4 (NRT2.4), ammonium transporter 3 (AMT3), and amino acid transporter protein 3 (AAP3), was also upregulated. In addition, phosphorus- and calcium-related genes such as phosphate starvation response 2 (PHR2) and cyclic nucleotide-gated ion channel 15 (CNGC15) were expressed more abundantly in response to ND stress. Our results reveal the physiological and molecular mechanisms by which woody plants respond to ND.

Regulation of OPA1-mediated mitochondrial fusion by leucine zipper/EF-hand-containing transmembrane protein-1 plays a role in apoptosis

2009 ◽  
Vol 21 (5) ◽  
pp. 767-777 ◽  
Author(s):  
Longzhen Piao ◽  
Yuwen Li ◽  
Soung Jung Kim ◽  
Kyung-Cheol Sohn ◽  
Keum-Jin Yang ◽  
...  
Keyword(s):  
Leucine Zipper ◽  
Transmembrane Protein ◽  
Mitochondrial Fusion ◽  
Ef Hand

scholarly journals Priority Strategy of Intracellular Ca2+ Homeostasis in Skeletal Muscle Fibers during the Multiple Stresses of Hibernation

Cells ◽  
2019 ◽  
Vol 9 (1) ◽  
pp. 42 ◽  
Author(s):  
Jie Zhang ◽  
Xiaoyu Li ◽  
Fazeela Ismail ◽  
Shenhui Xu ◽  
Zhe Wang ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Leucine Zipper ◽  
Binding Capacity ◽  
Transmembrane Protein ◽  
Muscle Fibers ◽  
Vital Role ◽  
Ground Squirrels ◽  
Calcium Uniporter ◽  
Skeletal Muscle Fibers ◽  
Ef Hand

Intracellular calcium (Ca2+) homeostasis plays a vital role in the preservation of skeletal muscle. In view of the well-maintained skeletal muscle found in Daurian ground squirrels (Spermophilus dauricus) during hibernation, we hypothesized that hibernators possess unique strategies of intracellular Ca2+ homeostasis. Here, cytoplasmic, sarcoplasmic reticulum (SR), and mitochondrial Ca2+ levels, as well as the potential Ca2+ regulatory mechanisms, were investigated in skeletal muscle fibers of Daurian ground squirrels at different stages of hibernation. The results showed that cytoplasmic Ca2+ levels increased in the skeletal muscle fibers during late torpor (LT) and inter-bout arousal (IBA), and partially recovered when the animals re-entered torpor (early torpor, ET). Furthermore, compared with levels in the summer active or pre-hibernation state, the activity and protein expression levels of six major Ca2+ channels/proteins were up-regulated during hibernation, including the store-operated Ca2+ entry (SOCE), ryanodine receptor 1 (RyR1), leucine zipper-EF-hand containing transmembrane protein 1 (LETM1), SR Ca2+ ATPase 1 (SERCA1), mitochondrial calcium uniporter complex (MCU complex), and calmodulin (CALM). Among these, the increased extracellular Ca2+ influx mediated by SOCE, SR Ca2+ release mediated by RyR1, and mitochondrial Ca2+ extrusion mediated by LETM1 may be triggers for the periodic elevation in cytoplasmic Ca2+ levels observed during hibernation. Furthermore, the increased SR Ca2+ uptake through SERCA1, mitochondrial Ca2+ uptake induced by MCU, and elevated free Ca2+ binding capacity mediated by CALM may be vital strategies in hibernating ground squirrels to attenuate cytoplasmic Ca2+ levels and restore Ca2+ homeostasis during hibernation. Compared with that in LT or IBA, the decreased extracellular Ca2+ influx mediated by SOCE and elevated mitochondrial Ca2+ uptake induced by MCU may be important mechanisms for the partial cytoplasmic Ca2+ recovery in ET. Overall, under extreme conditions, hibernating ground squirrels still possess the ability to maintain intracellular Ca2+ homeostasis.

Sign in / Sign up

Export Citation Format

Share Document