scholarly journals LETM1: A Single Entity With Diverse Impact on Mitochondrial Metabolism and Cellular Signaling

2021 ◽  
Vol 12 ◽  
Author(s):  
Gayathri K. Natarajan ◽  
Jyotsna Mishra ◽  
Amadou K. S. Camara ◽  
Wai-Meng Kwok
Keyword(s):  
Mitochondrial Membrane ◽  
Leucine Zipper ◽  
Cellular Signaling ◽  
Multiple Roles ◽  
Cellular Respiration ◽  
Cellular Functions ◽  
Inner Mitochondrial Membrane ◽  
Cellular Processes ◽  
Ef Hand ◽  
Health And Disease

Nearly 2 decades since its discovery as one of the genes responsible for the Wolf-Hirschhorn Syndrome (WHS), the primary function of the leucine-zipper EF-hand containing transmembrane 1 (LETM1) protein in the inner mitochondrial membrane (IMM) or the mechanism by which it regulates mitochondrial Ca2+ handling is unresolved. Meanwhile, LETM1 has been associated with the regulation of fundamental cellular processes, such as development, cellular respiration and metabolism, and apoptosis. This mini-review summarizes the diversity of cellular functions impacted by LETM1 and highlights the multiple roles of LETM1 in health and disease.

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 Ethanolamine and Phosphatidylethanolamine: Partners in Health and Disease

2017 ◽  
Vol 2017 ◽  
pp. 1-18 ◽  
Author(s):  
Dhaval Patel ◽  
Stephan N. Witt
Keyword(s):  
Parkinson’S Disease ◽  
Endoplasmic Reticulum ◽  
Membrane Proteins ◽  
Total Lipid ◽  
Mammalian Cells ◽  
Mitochondrial Membrane ◽  
Inner Mitochondrial Membrane ◽  
Respiratory Complexes ◽  
Induced Stress ◽  
Health And Disease

Phosphatidylethanolamine (PE) is the second most abundant phospholipid in mammalian cells. PE comprises about 15–25% of the total lipid in mammalian cells; it is enriched in the inner leaflet of membranes, and it is especially abundant in the inner mitochondrial membrane. PE has quite remarkable activities: it is a lipid chaperone that assists in the folding of certain membrane proteins, it is required for the activity of several of the respiratory complexes, and it plays a key role in the initiation of autophagy. In this review, we focus on PE’s roles in lipid-induced stress in the endoplasmic reticulum (ER), Parkinson’s disease (PD), ferroptosis, and cancer.

scholarly journals MICU1 regulates mitochondrial cristae structure and function independent of the mitochondrial calcium uniporter channel

2019 ◽  
Author(s):  
Dhanendra Tomar ◽  
Manfred Thomas ◽  
Joanne F. Garbincius ◽  
Devin W. Kolmetzky ◽  
Oniel Salik ◽  
...  
Keyword(s):  
Mitochondrial Membrane ◽  
Mitochondrial Protein ◽  
Coiled Coil ◽  
Membrane Dynamics ◽  
Size Exclusion ◽  
Mitochondrial Calcium ◽  
Cellular Functions ◽  
Inner Mitochondrial Membrane ◽  
Cytochrome C Release ◽  
And Function

AbstractMICU1 is an EF-hand-containing mitochondrial protein that is essential for gating of the mitochondrial Ca2+ uniporter channel (mtCU) and is reported to interact directly with the pore-forming subunit, MCU and scaffold EMRE. However, using size-exclusion proteomics, we found that MICU1 exists in mitochondrial complexes lacking MCU. This suggests that MICU1 may have additional cellular functions independent of regulating mitochondrial Ca2+ uptake. To discern mtCU-independent MICU1 functions, we employed a proteomic discovery approach using BioID2-mediated proximity-based (<10nm) biotinylation and subsequent LC-MS detection. The expression of a MICU1-BioID2 fusion protein in MICU1-/- and MCU-/- cells allowed the identification of total vs. mtCU-independent MICU1 interactors. Bioinformatics identified the Mitochondrial Contact Site and Cristae Organizing System (MICOS) components MIC60 (encoded by the IMMT gene) and Coiled-coil-helix-coiled-coil helix domain containing 2 (CHCHD2) as novel MICU1 interactors, independent of the mtCU. We demonstrate that MICU1 is essential for proper proteomic organization of the MICOS complex and that MICU1 ablation results in altered cristae organization and mitochondrial ultrastructure. We hypothesize that MICU1 serves as a MICOS calcium sensor, since perturbing MICU1 is sufficient to modulate cytochrome c release independent of mitochondrial Ca2+ uptake across the inner mitochondrial membrane (IMM). Here, we provide the first experimental evidence suggesting that MICU1 regulates cellular functions independent of mitochondrial calcium uptake and may serve as a critical mediator of Ca2+-dependent signaling to modulate mitochondrial membrane dynamics and cristae organization.

scholarly journals Cadherin Signaling in Cancer and Autoimmune Diseases

2021 ◽  
Vol 22 (24) ◽  
pp. 13358
Author(s):  
Margherita Sisto ◽  
Domenico Ribatti ◽  
Sabrina Lisi
Keyword(s):  
Molecular Mechanisms ◽  
Epithelial Mesenchymal Transition ◽  
Cell Trafficking ◽  
Cellular Functions ◽  
Cytoskeletal Organization ◽  
Mesenchymal Transition ◽  
Cellular Processes ◽  
Cellular Context ◽  
Health And Disease ◽  
Mediate Cell

Cadherins mediate cell–cell adhesion through a dynamic process that is strongly dependent on the cellular context and signaling. Cadherin regulation reflects the interplay between fundamental cellular processes, including morphogenesis, proliferation, programmed cell death, surface organization of receptors, cytoskeletal organization, and cell trafficking. The variety of molecular mechanisms and cellular functions regulated by cadherins suggests that we have only scratched the surface in terms of clarifying the functions mediated by these versatile proteins. Altered cadherins expression is closely connected with tumorigenesis, epithelial–mesenchymal transition (EMT)-dependent fibrosis, and autoimmunity. We review the current understanding of how cadherins contribute to human health and disease, considering the mechanisms of cadherin involvement in diseases progression, as well as the clinical significance of cadherins as therapeutic targets.

scholarly journals Physiological and pathological roles of mitochondrial SLC25 carriers

2013 ◽  
Vol 454 (3) ◽  
pp. 371-386 ◽  
Author(s):  
Manuel Gutiérrez-Aguilar ◽  
Christopher P. Baines
Keyword(s):  
Mitochondrial Membrane ◽  
Current Knowledge ◽  
Transmembrane Helix ◽  
Building Blocks ◽  
Proper Function ◽  
Inner Mitochondrial Membrane ◽  
Health And Disease ◽  
Metabolic Reactions ◽  
Solute Carrier

The mitochondrion relies on compartmentalization of certain enzymes, ions and metabolites for the sake of efficient metabolism. In order to fulfil its activities, a myriad of carriers are properly expressed, targeted and folded in the inner mitochondrial membrane. Among these carriers, the six-transmembrane-helix mitochondrial SLC25 (solute carrier family 25) proteins facilitate transport of solutes with disparate chemical identities across the inner mitochondrial membrane. Although their proper function replenishes building blocks needed for metabolic reactions, dysfunctional SLC25 proteins are involved in pathological states. It is the purpose of the present review to cover the current knowledge on the role of SLC25 transporters in health and disease.

scholarly journals Gas Signaling Molecules and Mitochondrial Potassium Channels

2018 ◽  
Vol 19 (10) ◽  
pp. 3227 ◽  
Author(s):  
Agnieszka Walewska ◽  
Adam Szewczyk ◽  
Piotr Koprowski
Keyword(s):  
Potassium Channels ◽  
Molecular Mechanisms ◽  
Atp Synthesis ◽  
Signaling Molecules ◽  
Cellular Respiration ◽  
K Channel ◽  
Inner Mitochondrial Membrane ◽  
Beneficial Effects ◽  
Cellular Processes ◽  
Channel Inhibition

Recently, gaseous signaling molecules, such as carbon monoxide (CO), nitric oxide (NO), and hydrogen sulfide (H2S), which were previously considered to be highly toxic, have been of increasing interest due to their beneficial effects at low concentrations. These so-called gasotransmitters affect many cellular processes, such as apoptosis, proliferation, cytoprotection, oxygen sensing, ATP synthesis, and cellular respiration. It is thought that mitochondria, specifically their respiratory complexes, constitute an important target for these gases. On the other hand, increasing evidence of a cytoprotective role for mitochondrial potassium channels provides motivation for the analysis of the role of gasotransmitters in the regulation of channel function. A number of potassium channels have been shown to exhibit activity within the inner mitochondrial membrane, including ATP-sensitive potassium channels, Ca2+-activated potassium channels, voltage-gated Kv potassium channels, and TWIK-related acid-sensitive K+ channel 3 (TASK-3). The effects of these channels include the regulation of mitochondrial respiration and membrane potential. Additionally, they may modulate the synthesis of reactive oxygen species within mitochondria. The opening of mitochondrial potassium channels is believed to induce cytoprotection, while channel inhibition may facilitate cell death. The molecular mechanisms underlying the action of gasotransmitters are complex. In this review, we focus on the molecular mechanisms underlying the action of H2S, NO, and CO on potassium channels present within mitochondria.

scholarly journals LETM1 Knockdown Promotes Autophagy and Apoptosis Through AMP-Activated Protein Kinase Phosphorylation-Mediated Beclin-1/Bcl-2 Complex Dissociation in Hepatocellular Carcinoma

2021 ◽  
Vol 10 ◽  
Author(s):  
Baoyong Zhou ◽  
Changhong Yang ◽  
Xiong Yan ◽  
Zhengrong Shi ◽  
Heng Xiao ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Lines ◽  
Leucine Zipper ◽  
Beclin 1 ◽  
Inner Mitochondrial Membrane ◽  
Primary Tumors ◽  
Ef Hand ◽  
Amp Activated Protein Kinase ◽  
Kinase Phosphorylation ◽  
Mitochondrial Membrane Protein

Leucine zipper/EF hand-containing transmembrane-1 (LETM1) is an inner mitochondrial membrane protein that has been reported to be involved in many primary tumors and may regulate many biological processes. However, the biological role and molecular mechanism of LETM1 in the progression of hepatocellular carcinoma (HCC) remain largely unknown. In this study, we found that LETM1 was highly expressed in HCC tissues and cell lines and that higher LETM1 expression was associated with a lower overall survival rate in HCC patients. In addition, knockdown of LETM1 inhibited proliferation and enhanced apoptosis and autophagy in the Huh 7 and QGY-7701 liver cancer cell lines. Mechanistically, knockdown of LETM1 dissociated the Beclin-1/Bcl-2 complex through phosphorylation of AMPK and Bcl-2. These results demonstrated that LETM1 is involved in the development of HCC and could be a novel therapeutic target in HCC.

scholarly journals Role of Cardiolipin in Mitochondrial Function and Dynamics in Health and Disease: Molecular and Pharmacological Aspects

Cells ◽  
2019 ◽  
Vol 8 (7) ◽  
pp. 728 ◽  
Author(s):  
Giuseppe Paradies ◽  
Valeria Paradies ◽  
Francesca M. Ruggiero ◽  
Giuseppe Petrosillo
Keyword(s):  
Mitochondrial Function ◽  
Mitochondrial Membrane ◽  
Protein Import ◽  
Building Blocks ◽  
Inner Mitochondrial Membrane ◽  
Atp Production ◽  
Membrane Morphology ◽  
Transport Chain ◽  
Health And Disease

In eukaryotic cells, mitochondria are involved in a large array of metabolic and bioenergetic processes that are vital for cell survival. Phospholipids are the main building blocks of mitochondrial membranes. Cardiolipin (CL) is a unique phospholipid which is localized and synthesized in the inner mitochondrial membrane (IMM). It is now widely accepted that CL plays a central role in many reactions and processes involved in mitochondrial function and dynamics. Cardiolipin interacts with and is required for optimal activity of several IMM proteins, including the enzyme complexes of the electron transport chain (ETC) and ATP production and for their organization into supercomplexes. Moreover, CL plays an important role in mitochondrial membrane morphology, stability and dynamics, in mitochondrial biogenesis and protein import, in mitophagy, and in different mitochondrial steps of the apoptotic process. It is conceivable that abnormalities in CL content, composition and level of oxidation may negatively impact mitochondrial function and dynamics, with important implications in a variety of pathophysiological situations and diseases. In this review, we focus on the role played by CL in mitochondrial function and dynamics in health and diseases and on the potential of pharmacological modulation of CL through several agents in attenuating mitochondrial dysfunction.

Modulation of the calcium-activated BK-channel of the inner mitochondrial membrane by hypoxia

2007 ◽  
Vol 34 (S 2) ◽  
Author(s):  
D Siemen ◽  
Y Cheng ◽  
X Gu ◽  
P Bednarczyk ◽  
GG Haddad ◽  
...  
Keyword(s):  
Mitochondrial Membrane ◽  
Bk Channel ◽  
Inner Mitochondrial Membrane
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