bims-mionch 2024-04-07 papers

bims-mionch

Biomed News

on Mitochondrial ion channels

Issue of 2024–04–07
eightteen papers selected by
Gun Kim, Seoul National University

The ER-SURF pathway uses ER-mitochondria contact sites for protein targeting to mitochondria.
Mitochondria-associated endoplasmic reticulum membranes involve in oxidative stress-induced intestinal barrier injury and mitochondrial dysfunction under diquat exposing.
Human CCDC51 and yeast Mdm33 are functionally conserved mitochondrial inner membrane proteins that demarcate a subset of organelle fission events.
Polygonatum sibiricum polysaccharide ameliorates skeletal muscle aging via mitochondria-associated membrane-mediated calcium homeostasis regulation.
Membrane fission via transmembrane contact.
Role of mitochondria in renal ischemia-reperfusion injury.
Chronic replication stress invokes mitochondria dysfunction via impaired parkin activity.
Mitochondrial dysfunction in chronic neuroinflammatory diseases (Review).
Mitochondrial electron transport chain in macrophage reprogramming: Potential role in antibacterial immune response.
Mitochondrial quality control in non-exudative age-related macular degeneration: From molecular mechanisms to structural and functional recovery.
A genetically encoded fluorescent protein sensor for mitochondrial membrane damage detection.
An inner mitochondrial membrane microprotein from the SLC35A4 upstream ORF regulates cellular metabolism.
From powerhouse to regulator: The role of mitoepigenetics in mitochondrion-related cellular functions and human diseases.
Hypoxic adaptation of mitochondria and its impact on tumor cell function.
Transmembrane proteins with unknown function (TMEMs) as ion channels: electrophysiological properties, structure, and pathophysiological roles.
MICU1's calcium sensing beyond mitochondrial calcium uptake.
Chloride ions in health and disease.
Structural mechanisms of mitochondrial uncoupling protein 1 regulation in thermogenesis.

EMBO Rep. 2024 Apr 02.

The ER-SURF pathway uses ER-mitochondria contact sites for protein targeting to mitochondria.

Christian Koch, Svenja Lenhard, Markus Räschle, Cristina Prescianotto-Baschong, Anne Spang, Johannes M Herrmann.

  Most mitochondrial proteins are synthesized on cytosolic ribosomes and imported into mitochondria in a post-translational reaction. Mitochondrial precursor proteins which use the ER-SURF pathway employ the surface of the endoplasmic reticulum (ER) as an important sorting platform. How they reach the mitochondrial import machinery from the ER is not known. Here we show that mitochondrial contact sites play a crucial role in the ER-to-mitochondria transfer of precursor proteins. The ER mitochondria encounter structure (ERMES) and Tom70, together with Djp1 and Lam6, are part of two parallel and partially redundant ER-to-mitochondria delivery routes. When ER-to-mitochondria transfer is prevented by loss of these two contact sites, many precursors of mitochondrial inner membrane proteins are left stranded on the ER membrane, resulting in mitochondrial dysfunction. Our observations support an active role of the ER in mitochondrial protein biogenesis.

Keywords:  Contact sites; ERMES; Endoplasmic reticulum; Mitochondria; Protein import

DOI:  https://doi.org/10.1038/s44319-024-00113-w
Environ Toxicol. 2024 Apr 03.

Mitochondria-associated endoplasmic reticulum membranes involve in oxidative stress-induced intestinal barrier injury and mitochondrial dysfunction under diquat exposing.

Feiyang Gou, Fengzhou Cai, Xin Li, Qian Lin, Jiang Zhu, Minjie Yu, Shaokui Chen, Jianjun Lu, Caihong Hu.

  Many factors induced by environmental toxicants have made oxidative stress a risk factor for the intestinal barrier injury and growth restriction, which is serious health threat for human and livestock and induces significant economic loss. It is well-known that diquat-induced oxidative stress is implicated in the intestinal barrier injury. Although some studies have shown that mitochondria are the primary target organelle of diquat, the underlying mechanism remains incompletely understood. Recently, mitochondria-associated endoplasmic reticulum membranes (MAMs) have aroused increasing concerns among scholars, which participate in mitochondrial dynamics and signal transduction. In this study, we investigated whether MAMs involved in intestinal barrier injury and mitochondrial dysfunction induced by diquat-induced oxidative stress in piglets and porcine intestinal epithelial cells (IPEC-J2 cells). The results showed that diquat induced growth restriction and impaired intestinal barrier. The mitochondrial reactive oxygen species (ROS) was increased and mitochondrial membrane potential was decreased following diquat exposure. The ultrastructure of mitochondria and MAMs was also disturbed. Meanwhile, diquat upregulated endoplasmic reticulum stress marker protein and activated PERK pathway. Furthermore, loosening MAMs alleviated intestinal barrier injury, decrease of antioxidant enzyme activity and mitochondrial dysfunction induced by diquat in IPEC-J2 cells, while tightening MAMs exacerbated diquat-induced mitochondrial dysfunction. These results suggested that MAMs may be associated with the intestinal barrier injury and mitochondrial dysfunction induced by diquat in the jejunum of piglets.

Keywords:  diquat; intestinal barrier; mitochondria; mitochondria‐associated endoplasmic reticulum membranes; oxidative stress

DOI:  https://doi.org/10.1002/tox.24232
bioRxiv. 2024 Mar 22. pii: 2024.03.21.586162. [Epub ahead of print]

Human CCDC51 and yeast Mdm33 are functionally conserved mitochondrial inner membrane proteins that demarcate a subset of organelle fission events.

Alia R Edington, Olivia M Connor, Madeleine Marlar-Pavey, Jonathan R Friedman.

Mitochondria are highly dynamic double membrane-bound organelles that exist in a semi- continuous network. Mitochondrial morphology arises from the complex interplay of numerous processes, including opposing fission and fusion dynamics and the formation of highly organized cristae invaginations of the inner membrane. While extensive work has examined the mechanisms of mitochondrial fission, it remains unclear how fission is coordinated across two membrane bilayers and how mitochondrial inner membrane organization is coupled with mitochondrial fission dynamics. Previously, the yeast protein Mdm33 was implicated in facilitating fission by coordinating with inner membrane homeostasis pathways. However, Mdm33 is not conserved outside fungal species and its precise mechanistic role remains unclear. Here, we use a bioinformatic approach to identify a putative structural ortholog of Mdm33 in humans, CCDC51 (also called MITOK). We find that the mitochondrial phenotypes associated with altered CCDC51 levels implicate the protein in mitochondrial fission dynamics. Further, using timelapse microscopy, we spatially and temporally resolve Mdm33 and CCDC51 to a subset of mitochondrial fission events. Finally, we show that CCDC51 can partially rescue yeast Δ mdm33 cells, indicating the proteins are functionally analogous. Our data reveal that Mdm33/CCDC51 are conserved mediators of mitochondrial morphology and suggest the proteins play a crucial role in maintaining normal mitochondrial dynamics and organelle homeostasis.

DOI: https://doi.org/10.1101/2024.03.21.586162
Phytomedicine. 2024 Mar 24. pii: S0944-7113(24)00232-0. [Epub ahead of print]129 155567

Polygonatum sibiricum polysaccharide ameliorates skeletal muscle aging via mitochondria-associated membrane-mediated calcium homeostasis regulation.

Wenhao Chen, Zile Shen, Wenxi Dong, Guowei Huang, Dingye Yu, Weizhe Chen, Xialin Yan, Zhen Yu.

   BACKGROUND: Sarcopenia, an age-related disease, is characterized by a gradual loss of muscle mass, strength, and function. It has been linked to abnormal organelle function in myotubes, including the mitochondria and endoplasmic reticulum (ER). Recent studies revealed that mitochondria-associated membranes (MAM), the sites connecting mitochondria and the ER, may be implicated in skeletal muscle aging. In this arena, the potential of Polygonatum sibiricum polysaccharide (PSP) emerges as a beacon of hope. PSP, with its remarkable antioxidant and anti-senescence properties, is on the cusp of a therapeutic revolution, offering a promising strategy to mitigate the impacts of sarcopenia.
PURPOSE: The objective of this research is to explore the effects of PSP on age-related muscle dysfunction and the underlying mechanisms involved both in vivo and in vitro.
METHODS: In this investigation, we used in vitro experiments using D-galactose (D-gal)-induced aging in C2C12 myotubes and in vivo experiments on aged mice. Key indices were assessed, including reactive oxygen species (ROS) levels, mitochondrial function, the expression of aging-related markers, and the key proteins of mitochondria and MAM fraction. Differentially expressed genes (DEGs) related to mitochondria and ER were identified, and bioinformatic analyses were performed to explore underlying mechanisms. Muscle mass and function were determined to evaluate the quantity and quality of skeletal muscle in vivo.
RESULTS: PSP treatment effectively mitigated oxidative stress and mitochondrial malfunction caused by D-gal in C2C12 myotubes, preserving mitochondrial fitness and reducing MAM formation. Besides, PSP attenuated D-gal-induced increases in Ca2+ concentrations intracellularly by modulating the calcium-related proteins, which were also confirmed by gene ontology (GO) analysis of DEGs. In aged mice, PSP increased muscle mass and improved grip strength, hanging time, and other parameters while reducing ROS levels and increasing antioxidant enzyme activities in skeletal muscle tissue.
CONCLUSION: PSP offers protection against age-associated muscle impairments. The proposed mechanism suggests that modulation of calcium homeostasis via regulation of the MAM results in a favorable functional outcome during skeletal muscle aging. The results of this study highlight the prospect of PSP as a curative intervention for sarcopenia and affiliated pathological conditions, warranting further investigation.

Keywords:  Ca(2+) homeostasis; Mitochondria-associated membrane; Polygonatum sibiricum polysaccharide; Senescence

DOI:  https://doi.org/10.1016/j.phymed.2024.155567
Nat Commun. 2024 Mar 30. 15(1): 2793

Membrane fission via transmembrane contact.

Russell K W Spencer, Isaac Santos-Pérez, Izaro Rodríguez-Renovales, Juan Manuel Martinez Galvez, Anna V Shnyrova, Marcus Müller.

Division of intracellular organelles often correlates with additional membrane wrapping, e.g., by the endoplasmic reticulum or the outer mitochondrial membrane. Such wrapping plays a vital role in proteome and lipidome organization. However, how an extra membrane impacts the mechanics of the division has not been investigated. Here we combine fluorescence and cryo-electron microscopy experiments with self-consistent field theory to explore the stress-induced instabilities imposed by membrane wrapping in a simple double-membrane tubular system. We find that, at physiologically relevant conditions, the outer membrane facilitates an alternative pathway for the inner-tube fission through the formation of a transient contact (hemi-fusion) between both membranes. A detailed molecular theory of the fission pathways in the double membrane system reveals the topological complexity of the process, resulting both in leaky and leakless intermediates, with energies and topologies predicting physiological events.

DOI: https://doi.org/10.1038/s41467-024-47122-w
FEBS J. 2024 Apr 03.

Role of mitochondria in renal ischemia-reperfusion injury.

Ruizhen Huang, Chiyu Zhang, Zhengjie Xiang, Tao Lin, Jian Ling, Honglin Hu.

  Acute kidney injury (AKI) induced by renal ischemia-reperfusion injury (IRI) has a high morbidity and mortality, representing a worldwide problem. The kidney is an essential organ of metabolism that has high blood perfusion and is the second most mitochondria-rich organ after the heart because of the high ATP demands of its essential functions of nutrient reabsorption, acid-base and electrolyte balance, and hemodynamics. Thus, these energy-intensive cells are particularly vulnerable to mitochondrial dysfunction. As the bulk of glomerular ultrafiltrate reabsorption by proximal tubules occurs via active transport, the mitochondria of proximal tubules must be equipped for detecting and responding to fluctuations in energy availability to guarantee efficient basal metabolism. Any insults to mitochondrial quality control mechanisms may lead to biological disruption, blocking the clearance of damaged mitochondria and resulting in morphological change and tissue dysfunction. Extensive research has shown that mitochondria have pivotal roles in acute kidney disease, so in this article, we discuss the role of mitochondria, their dynamics and mitophagy in renal ischemia-reperfusion injury.

Keywords:  mitochondrial dynamics; mitochondrial fission; mitochondrial fusion; mitophagy; renal ischemia–reperfusion injury

DOI:  https://doi.org/10.1111/febs.17130
Sci Rep. 2024 Apr 03. 14(1): 7877

Chronic replication stress invokes mitochondria dysfunction via impaired parkin activity.

Tsuyoshi Kawabata, Reiko Sekiya, Shinji Goto, Tao-Sheng Li.

Replication stress is a major contributor to tumorigenesis because it provides a source of chromosomal rearrangements via recombination events. PARK2, which encodes parkin, a regulator of mitochondrial homeostasis, is located on one of the common fragile sites that are prone to rearrangement by replication stress, indicating that replication stress may potentially impact mitochondrial homeostasis. Here, we show that chronic low-dose replication stress causes a fixed reduction in parkin expression, which is associated with mitochondrial dysfunction, indicated by an increase in mtROS. Consistent with the major role of parkin in mitophagy, reduction in parkin protein expression was associated with a slight decrease in mitophagy and changes in mitochondrial morphology. In contrast, cells expressing ectopic PARK2 gene does not show mtROS increases and changes in mitochondrial morphology even after exposure to chronic replication stress, suggesting that intrinsic fragility at PARK2 loci associated with parkin reduction is responsible for mitochondrial dysfunction caused by chronic replication stress. As endogenous replication stress and mitochondrial dysfunction are both involved in multiple pathophysiology, our data support the therapeutic development of recovery of parkin expression in human healthcare.

DOI: https://doi.org/10.1038/s41598-024-58656-w
Int J Mol Med. 2024 May;pii: 47. [Epub ahead of print]53(5):

Mitochondrial dysfunction in chronic neuroinflammatory diseases (Review).

Pei Qin, Ye Sun, Liya Li.

  Chronic neuroinflammation serves a key role in the onset and progression of neurodegenerative disorders. Mitochondria serve as central regulators of neuroinflammation. In addition to providing energy to cells, mitochondria also participate in the immunoinflammatory response of neurodegenerative disorders including Alzheimer's disease, Parkinson's disease, multiple sclerosis and epilepsy, by regulating processes such as cell death and inflammasome activation. Under inflammatory conditions, mitochondrial oxidative stress, epigenetics, mitochondrial dynamics and calcium homeostasis imbalance may serve as underlying regulatory mechanisms for these diseases. Therefore, investigating mechanisms related to mitochondrial dysfunction may result in therapeutic strategies against chronic neuroinflammation and neurodegeneration. The present review summarizes the mechanisms of mitochondria in chronic neuroinflammatory diseases and the current treatment approaches that target mitochondrial dysfunction in these diseases.

Keywords:  Alzheimer's disease; Parkinson's disease; chronic neuroinflammation; epilepsy; mitochondrial dysfunction; multiple sclerosis; neurodegeneration

DOI:  https://doi.org/10.3892/ijmm.2024.5371
Curr Res Immunol. 2024 ;5 100077

Mitochondrial electron transport chain in macrophage reprogramming: Potential role in antibacterial immune response.

Manmohan Kumar, Shagun Sharma, Jai Kumar, Sailen Barik, Shibnath Mazumder.

  Macrophages restrain microbial infection and reinstate tissue homeostasis. The mitochondria govern macrophage metabolism and serve as pivot in innate immunity, thus acting as immunometabolic regulon. Metabolic pathways produce electron flows that end up in mitochondrial electron transport chain (mtETC), made of super-complexes regulating multitude of molecular and biochemical processes. Cell-intrinsic and extrinsic factors influence mtETC structure and function, impacting several aspects of macrophage immunity. These factors provide the macrophages with alternate fuel sources and metabolites, critical to gain functional competence and overcoming pathogenic stress. Mitochondrial reactive oxygen species (mtROS) and oxidative phosphorylation (OXPHOS) generated through the mtETC are important innate immune attributes, which help macrophages in mounting antibacterial responses. Recent studies have demonstrated the role of mtETC in governing mitochondrial dynamics and macrophage polarization (M1/M2). M1 macrophages are important for containing bacterial pathogens and M2 macrophages promote tissue repair and wound healing. Thus, mitochondrial bioenergetics and metabolism are intimately coupled with innate immunity. In this review, we have addressed mtETC function as innate rheostats that regulate macrophage reprogramming and innate immune responses. Advancement in this field encourages further exploration and provides potential novel macrophage-based therapeutic targets to control unsolicited inflammation.

Keywords:  Bacterial infection; Innate immunity; M1-M2 macrophages; Super-complex; mtETC; mtROS

DOI:  https://doi.org/10.1016/j.crimmu.2024.100077
Free Radic Biol Med. 2024 Apr 03. pii: S0891-5849(24)00161-8. [Epub ahead of print]

Mitochondrial quality control in non-exudative age-related macular degeneration: From molecular mechanisms to structural and functional recovery.

Hernán H Dieguez, Horacio E Romeo, Agustina Alaimo, Nathaly A Bernal Aguirre, Juan S Calanni, Juan S Adán Aréan, Silvia Alvarez, Roberta Sciurano, Ruth E Rosenstein, Damián Dorfman.

  Non-exudative age-related macular degeneration (NE-AMD) is the leading blindness cause in the elderly. Clinical and experimental evidence supports that early alterations in macular retinal pigment epithelium (RPE) mitochondria play a key role in NE-AMD-induced damage. Mitochondrial dynamics (biogenesis, fusion, fission, and mitophagy), which is under the central control of AMP-activated kinase (AMPK), in turn, determines mitochondrial quality. We have developed a NE-AMD model in C57BL/6J mice induced by unilateral superior cervical ganglionectomy (SCGx), which progressively reproduces the disease hallmarks circumscribed to the temporal region of the RPE/outer retina that exhibits several characteristics of the human macula. In this work we have studied RPE mitochondrial structure, dynamics, function, and AMPK role on these parameters' regulation at the nasal and temporal RPE from control eyes and at an early stage of experimental NE-AMD (i.e., 4 weeks post-SCGx). Although RPE mitochondrial mass was preserved, their function, which was higher at the temporal than at the nasal RPE in control eyes, was significantly decreased at 4 weeks post-SCGx at the same region. Mitochondria were bigger, more elongated, and with denser cristae at the temporal RPE from control eyes. Exclusively at the temporal RPE, SCGx severely affected mitochondrial morphology and dynamics, together with the levels of phosphorylated AMPK (p-AMPK). AMPK activation with metformin restored RPE p-AMPK levels, and mitochondrial dynamics, structure, and function at 4 weeks post-SCGx, as well as visual function and RPE/outer retina structure at 10 weeks post-SCGx. These results demonstrate a key role of the temporal RPE mitochondrial homeostasis as an early target for NE-AMD-induced damage, and that pharmacological AMPK activation could preserve mitochondrial morphology, dynamics, and function, and, consequently, avoid the functional and structural damage induced by NE-AMD.

Keywords:  AMPK; Metformin; Mitochondria dynamics; Non-exudative age-related macular degeneration; Retinal pigment epithelium

DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.03.024
Biochem Biophys Res Commun. 2024 Mar 27. pii: S0006-291X(24)00372-3. [Epub ahead of print]709 149836

A genetically encoded fluorescent protein sensor for mitochondrial membrane damage detection.

Qian Liu, Dianbing Wang, Mengmeng Cui, Min Li, Xian-En Zhang.

  Mitochondria are essential cellular organelles; detecting mitochondrial damage is crucial in cellular biology and toxicology. Compared with existing chemical probe detection methods, genetically encoded fluorescent protein sensors can directly indicate cellular and molecular events without involving exogenous reagents. In this study, we introduced a molecular sensor system, MMD-Sensor, for monitoring mitochondrial membrane damage. The sensor consists of two molecular modules. Module I is a fusion structure of the mitochondrial localization sequence (MLS), AIF cleavage site sequence (CSS), nuclear localization sequence (NLS), N-terminus of mNeonGreen and mCherry. Module II is a fusion structure of the C-terminus of mNeonGreen, NLS sequence, and mtagBFP2. Under normal condition, Module I is constrained in the inner mitochondrial membrane anchored by MLS, while Module II is restricted to the nucleus by its NLS fusion component. If the mitochondrial membrane is damaged, CSS is cut from the inner membrane, causing Module I to shift into the nucleus guided by the NLS fusion component. After Module I enters the nucleus, the N- and C-terminus of mNeonGreen meet each other and rebuild its intact 3D structure through fragment complementation and thus generates green fluorescence in the nucleus. Dynamic migration of red fluorescence from mitochondria to the nucleus and generation of green fluorescence in the nucleus indicate mitochondrial membrane damage. Using the MMD-Sensor, mitochondrial membrane damage induced by various reagents, such as uncoupling agents, ATP synthase inhibitors, monovalent cationic carriers, and ROS, in HeLa and 293T cells are directly observed and evaluated.

Keywords:  Apoptosis-inducing factor; Bimolecular fluorescence complementation; Biosensor; Genetically encoded fluorescent protein sensor; Mitochondrial membrane damage

DOI:  https://doi.org/10.1016/j.bbrc.2024.149836
J Mol Biol. 2024 Apr 03. pii: S0022-2836(24)00154-2. [Epub ahead of print] 168559

An inner mitochondrial membrane microprotein from the SLC35A4 upstream ORF regulates cellular metabolism.

Andrea L Rocha, Victor Pai, Guy Perkins, Tina Chang, Jiao Ma, Qian Chu, Joan M Vaughan, Jolene K Diedrich, Mark H Ellisman, Alan Saghatelian.

  Upstream open reading frames (uORFs) are cis-acting elements that can dynamically regulate the translation of downstream ORFs by suppressing downstream translation under basal conditions and, in some cases, increasing translation under stress conditions. Computational and empirical methods have identified uORFs in the 5'-UTRs of approximately half of all mouse and human transcripts, making uORFs one the largest regulatory elements known. Because the prevailing dogma was that eukaryotic mRNAs produce a single functional protein, the peptides and small proteins, or microproteins, encoded by uORFs are under studied. We hypothesized that a uORF in the SLC35A4 mRNA is producing a functionalmicroprotein (SLC35A4-MP) because of its conserved amino acid sequence. Through a series of biochemical and cellular experiments, we find that the 103-amino acid SLC35A4-MP is a single-pass transmembrane inner mitochondrial membrane (IMM) microprotein. The IMM contains the protein machinery crucial for cellular respiration and ATP generation, and loss of function studies with SLC35A4-MP significantly diminish maximal cellular respiration, indicating a vital role for this microprotein in cellular metabolism. The findings add to the growing list of functional microproteins and, more generally, indicate that uORFs that encode conserved microproteins are an untapped reservoir of functional microproteins.

Keywords:  cellular metabolism; inner mitochondrial membrane; microprotein; mitochondria; upstream open reading frame (uORF)

DOI:  https://doi.org/10.1016/j.jmb.2024.168559
Free Radic Biol Med. 2024 Mar 31. pii: S0891-5849(24)00162-X. [Epub ahead of print]

From powerhouse to regulator: The role of mitoepigenetics in mitochondrion-related cellular functions and human diseases.

Luigi Donato, Domenico Mordà, Concetta Scimone, Simona Alibrandi, Rosalia D'Angelo, Antonina Sidoti.

  Beyond their crucial role in energy production, mitochondria harbor a distinct genome subject to epigenetic regulation akin to that of nuclear DNA. This paper delves into the nascent but rapidly evolving fields of mitoepigenetics and mitoepigenomics, exploring the sophisticated regulatory mechanisms governing mitochondrial DNA (mtDNA). These mechanisms encompass mtDNA methylation, the influence of non-coding RNAs (ncRNAs), and post-translational modifications of mitochondrial proteins. Together, these epigenetic modifications meticulously coordinate mitochondrial gene transcription, replication, and metabolism, thereby calibrating mitochondrial function in response to the dynamic interplay of intracellular needs and environmental stimuli. Notably, the dysregulation of mitoepigenetic pathways is increasingly implicated in mitochondrial dysfunction and a spectrum of human pathologies, including neurodegenerative diseases, cancer, metabolic disorders, and cardiovascular conditions. This comprehensive review synthesizes the current state of knowledge, emphasizing recent breakthroughs and innovations in the field. It discusses the potential of high-resolution mitochondrial epigenome mapping, the diagnostic and prognostic utility of blood or tissue mtDNA epigenetic markers, and the promising horizon of mitochondrial epigenetic drugs. Furthermore, it explores the transformative potential of mitoepigenetics and mitoepigenomics in precision medicine. Exploiting a theragnostic approach to maintaining mitochondrial allostasis, this paper underscores the pivotal role of mitochondrial epigenetics in charting new frontiers in medical science.

Keywords:  Epigenetic biomarkers; Mitochondrial dysfunction; Mitochondrial therapy; Mitoepigenetics; Mitoepigenomics; Precision medicine

DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.03.025
Semin Cancer Biol. 2024 Mar 30. pii: S1044-579X(24)00022-1. [Epub ahead of print]100 28-38

Hypoxic adaptation of mitochondria and its impact on tumor cell function.

Martin Benej, Ioanna Papandreou, Nicholas C Denko.

  Mitochondria are the major sink for oxygen in the cell, consuming it during ATP production. Therefore, when environmental oxygen levels drop in the tumor, significant adaptation is required. Mitochondrial activity is also a major producer of biosynthetic precursors and a regulator of cellular oxidative and reductive balance. Because of the complex biochemistry, mitochondrial adaptation to hypoxia occurs through multiple mechanisms and has significant impact on other cellular processes such as macromolecule synthesis and gene regulation. In tumor hypoxia, mitochondria shift their location in the cell and accelerate the fission and quality control pathways. Hypoxic mitochondria also undergo significant changes to fundamental metabolic pathways of carbon metabolism and electron transport. These metabolic changes further impact the nuclear epigenome because mitochondrial metabolites are used as enzymatic substrates for modifying chromatin. This coordinated response delivers physiological flexibility and increased tumor cell robustness during the environmental stress of low oxygen.

Keywords:  Hypoxia; Mitochondria; Oxygen consumption; Reductive stress

DOI:  https://doi.org/10.1016/j.semcancer.2024.03.004
Exp Mol Med. 2024 Apr 01.

Transmembrane proteins with unknown function (TMEMs) as ion channels: electrophysiological properties, structure, and pathophysiological roles.

Hyunji Kang, C Justin Lee.

A transmembrane (TMEM) protein with an unknown function is a type of membrane-spanning protein expressed in the plasma membrane or the membranes of intracellular organelles. Recently, several TMEM proteins have been identified as functional ion channels. The structures and functions of these proteins have been extensively studied over the last two decades, starting with TMEM16A (ANO1). In this review, we provide a summary of the electrophysiological properties of known TMEM proteins that function as ion channels, such as TMEM175 (KEL), TMEM206 (PAC), TMEM38 (TRIC), TMEM87A (GolpHCat), TMEM120A (TACAN), TMEM63 (OSCA), TMEM150C (Tentonin3), and TMEM43 (Gapjinc). Additionally, we examine the unique structural features of these channels compared to those of other well-known ion channels. Furthermore, we discuss the diverse physiological roles of these proteins in lysosomal/endosomal/Golgi pH regulation, intracellular Ca2+ regulation, spatial memory, cell migration, adipocyte differentiation, and mechanical pain, as well as their pathophysiological roles in Parkinson's disease, cancer, osteogenesis imperfecta, infantile hypomyelination, cardiomyopathy, and auditory neuropathy spectrum disorder. This review highlights the potential for the discovery of novel ion channels within the TMEM protein family and the development of new therapeutic targets for related channelopathies.

DOI: https://doi.org/10.1038/s12276-024-01206-1
Biochim Biophys Acta Mol Cell Res. 2024 Mar 29. pii: S0167-4889(24)00057-0. [Epub ahead of print] 119714

MICU1's calcium sensing beyond mitochondrial calcium uptake.

Sarah D Kaye, Shanikumar Goyani, Dhanendra Tomar.

  The discovery of MICU1 as gatekeeper of mitochondrial calcium (mCa2+) entry has transformed our understanding of mCa2+ flux. Recent studies revealed an additional role of MICU1 as a Ca2+ sensor at MICOS (mitochondrial contact site and cristae organizing system). MICU1's presence at MICOS suggests its involvement in coordinating Ca2+ signaling and mitochondrial ultrastructure. Besides its role in Ca2+ regulation, MICU1 influences cellular signaling pathways including transcription, epigenetic regulation, metabolism, and cell death signaling pathways, thereby affecting human health. Here, we summarize recent findings on MICU1's canonical and noncanonical functions, and its relevance to human health and diseases.

Keywords:  Calcium; MCU; MICOS; MICU1; Mitochondria

DOI:  https://doi.org/10.1016/j.bbamcr.2024.119714
Biosci Rep. 2024 Apr 04. pii: BSR20240029. [Epub ahead of print]

Chloride ions in health and disease.

Satish K Raut, Kulwinder Singh, Shridhar Sanghvi, Veronica Loyo-Celis, Liyah Varghese, Ekam R Singh, Shubha Gururaja Rao, Harpreet Singh.

  Chloride is a key anion involved in cellular physiology by regulating its homeostasis and rheostatic processes. Changes in cellular Cl- concentration result in differential regulation of cellular functions such as transcription and translation, post-translation modifications, cell cycle and proliferation, cell volume, and pH levels. In intracellular compartments, Cl- modulates the function of lysosomes, mitochondria, endosomes, phagosomes, the nucleus, and the endoplasmic reticulum. In extracellular fluid (ECF), Cl- is present in blood/plasma, and interstitial fluid compartments. A reduction in Cl- levels in ECF can result in cell volume contraction. Cl- is the key physiological anion and is a principal compensatory ion for the movement of the major cations such as Na+, K+, and Ca2+. Over the past 25 years, we have increased our understanding of cellular signaling mediated by Cl- which has helped in understanding the molecular and metabolic changes observed in pathologies with altered Cl- levels. Here, we review the concentration of Cl- in various organs and cellular compartments, ion channels responsible for its transportation, and recent information on its physiological roles.

Keywords:  Anion transport; Chloride channels; Chloride ions; Chloride transporters; Ion homeostasis

DOI:  https://doi.org/10.1042/BSR20240029
Trends Biochem Sci. 2024 Apr 01. pii: S0968-0004(24)00071-9. [Epub ahead of print]

Structural mechanisms of mitochondrial uncoupling protein 1 regulation in thermogenesis.

Scott A Jones, Jonathan J Ruprecht, Paul G Crichton, Edmund R S Kunji.

  In mitochondria, the oxidation of nutrients is coupled to ATP synthesis by the generation of a protonmotive force across the mitochondrial inner membrane. In mammalian brown adipose tissue (BAT), uncoupling protein 1 (UCP1, SLC25A7), a member of the SLC25 mitochondrial carrier family, dissipates the protonmotive force by facilitating the return of protons to the mitochondrial matrix. This process short-circuits the mitochondrion, generating heat for non-shivering thermogenesis. Recent cryo-electron microscopy (cryo-EM) structures of human UCP1 have provided new molecular insights into the inhibition and activation of thermogenesis. Here, we discuss these structures, describing how purine nucleotides lock UCP1 in a proton-impermeable conformation and rationalizing potential conformational changes of this carrier in response to fatty acid activators that enable proton leak for thermogenesis.

Keywords:  SLC25 mitochondrial carrier family; UCP1; bioenergetics; brown adipose tissue; non-shivering thermogenesis; thermogenin

DOI:  https://doi.org/10.1016/j.tibs.2024.03.005