bims-mionch 2024-03-31 papers

bims-mionch

Biomed News

on Mitochondrial ion channels

Issue of 2024–03–31
twenty-two papers selected by
Gun Kim, Seoul National University

Ion channel-mediated mitochondrial volume regulation and its relationship with mitochondrial dynamics.
Nucleus-Mitochondria Contact Sites Are Associated With Asynthetic Fission in Zebrafish Skin.
Mitochondrial Dysfunction: A Key Player in Brain Aging and Diseases.
Mitochondria-Associated Membranes as Key Regulators in Cellular Homeostasis and the Potential Impact of Exercise on Insulin Resistance.
Membrane contact sites regulate vacuolar fission via sphingolipid metabolism.
Steroidogenesis Upregulation through Mitochondria-Associated Endoplasmic Reticulum Membranes and Mitochondrial Dynamics in Rat Testes: The Role of D-Aspartate.
Solute Transport through Mitochondrial Porins In Vitro and In Vivo.
Molecular Mechanism of Autophagosome-Lysosome Fusion in Mammalian Cells.
Mitochondrial Dysfunction in Advanced Maternal Aged Cumulus Cells: A Possible Link to ATP Synthase Impairment?
Viroporins Manipulate Cellular Powerhouses and Modulate Innate Immunity.
Tricarboxylic Acid Cycle Intermediates and Individual Ageing.
Potential targets for the treatment of MI: GRP75-mediated Ca2+ transfer in MAM.
Mitochondria-tau association promotes cognitive decline and hippocampal bioenergetic deficits during the aging.
The Mitochondrial Connection: The Nek Kinases' New Functional Axis in Mitochondrial Homeostasis.
Dermatologic Manifestations of Mitochondrial Dysfunction: A Review of the Literature.
Nickel induces mitochondrial damage in renal cells in vitro and in vivo through its effects on mitochondrial biogenesis, fusion, and fission.
Mitochondrial Dysfunction as a Factor of Energy Metabolism Disorders in Type 2 Diabetes Mellitus.
[Unconventional protein secretion - new perspectives in protein trafficking].
Serotonin regulation of mitochondria in kidney diseases.
Weak base drug-induced endolysosome iron dyshomeostasis controls the generation of reactive oxygen species, mitochondrial depolarization, and cytotoxicity.
Emerging mechanisms in the redox regulation of mitochondrial cytochrome c oxidase assembly and function.
Phosphorylations and Acetylations of Cytochrome c Control Mitochondrial Respiration, Mitochondrial Membrane Potential, Energy, ROS, and Apoptosis.

Channels (Austin). 2024 Dec;18(1): 2335467

Ion channel-mediated mitochondrial volume regulation and its relationship with mitochondrial dynamics.

Yujia Zhuang, Wenting Jiang, Zhe Zhao, Wencui Li, Zhiqin Deng, Jianquan Liu.

  The mitochondrion, one of the important cellular organelles, has the major function of generating adenosine triphosphate and plays an important role in maintaining cellular homeostasis, governing signal transduction, regulating membrane potential, controlling programmed cell death and modulating cell proliferation. The dynamic balance of mitochondrial volume is an important factor required for maintaining the structural integrity of the organelle and exerting corresponding functions. Changes in the mitochondrial volume are closely reflected in a series of biological functions and pathological changes. The mitochondrial volume is controlled by the osmotic balance between the cytoplasm and the mitochondrial matrix. Thus, any disruption in the influx of the main ion, potassium, into the cells can disturb the osmotic balance between the cytoplasm and the matrix, leading to water movement between these compartments and subsequent alterations in mitochondrial volume. Recent studies have shown that mitochondrial volume homeostasis is closely implicated in a variety of diseases. In this review, we provide an overview of the main influencing factors and research progress in the field of mitochondrial volume homeostasis.

Keywords:  Ion channels; cell volume regulation; mitochondrial

DOI:  https://doi.org/10.1080/19336950.2024.2335467
Contact (Thousand Oaks). 2024 Jan-Dec;7:7 25152564241239445

Nucleus-Mitochondria Contact Sites Are Associated With Asynthetic Fission in Zebrafish Skin.

Dhani Tracey-White, Matthew J Hayes.

  Rapid increase in body surface area of growing zebrafish larvae (Danio rario) is partially accomplished by asynthetic fission of superficial epithelial cells (SECs) of the skin. There are two cycles of this atypical form of cell division which is unaccompanied by DNA replication; resulting in cells with a variable DNA content. Here, electron microscopy of basal epithelium cells that give rise to these SECs in zebrafish larvae shows aggregation of mitochondria around the nucleus and the formation of nucleus-mitochondria membrane contact sites. Membrane aggregates appear in the lumen of the nuclear envelope at these sites of membrane contact in some cells, suggesting lipid turnover in this vicinity. As the epithelial cells mature and stratify, the mitochondria are engulfed by extensions arising from the nuclear envelope. The mitochondrial outer membrane fragments and mitochondria fuse with the nuclear envelope and parts of the endoplasmic reticulum. Other organelles, including the Golgi apparatus, progressively localize to a central region of the cell and lose their integrity. Thus, asynthetic fission is accompanied by an atypical pattern of organelle destruction and a prelude to this is the formation of nucleus-mitochondria membrane contact sites.

Keywords:  asynthetic fission; contact site; corneocyte; danio rerio; epidermis; keratocyte; membrane contact site; nucleus–mitochondria; site of membrane contact

DOI:  https://doi.org/10.1177/25152564241239445
Curr Issues Mol Biol. 2024 Mar 02. 46(3): 1987-2026

Mitochondrial Dysfunction: A Key Player in Brain Aging and Diseases.

Sydney Bartman, Giuseppe Coppotelli, Jaime M Ross.

  Mitochondria are thought to have become incorporated within the eukaryotic cell approximately 2 billion years ago and play a role in a variety of cellular processes, such as energy production, calcium buffering and homeostasis, steroid synthesis, cell growth, and apoptosis, as well as inflammation and ROS production. Considering that mitochondria are involved in a multitude of cellular processes, mitochondrial dysfunction has been shown to play a role within several age-related diseases, including cancers, diabetes (type 2), and neurodegenerative diseases, although the underlying mechanisms are not entirely understood. The significant increase in lifespan and increased incidence of age-related diseases over recent decades has confirmed the necessity to understand the mechanisms by which mitochondrial dysfunction impacts the process of aging and age-related diseases. In this review, we will offer a brief overview of mitochondria, along with structure and function of this important organelle. We will then discuss the cause and consequence of mitochondrial dysfunction in the aging process, with a particular focus on its role in inflammation, cognitive decline, and neurodegenerative diseases, such as Huntington's disease, Parkinson's disease, and Alzheimer's disease. We will offer insight into therapies and interventions currently used to preserve or restore mitochondrial functioning during aging and neurodegeneration.

Keywords:  aging; mitochondria; mitochondrial dysfunction; neurodegenerative diseases

DOI:  https://doi.org/10.3390/cimb46030130
Int J Mol Sci. 2024 Mar 11. pii: 3196. [Epub ahead of print]25(6):

Mitochondria-Associated Membranes as Key Regulators in Cellular Homeostasis and the Potential Impact of Exercise on Insulin Resistance.

Xi Li, Yangjun Yang, Xiaoyu Shi, Zhe Zhang, Shuzhe Ding.

  The communication between mitochondria and the endoplasmic reticulum (ER) is facilitated by a dynamic membrane structure formed by protein complexes known as mitochondria-associated membranes (MAMs). The structural and functional integrity of MAMs is crucial for insulin signal transduction, relying heavily on their regulation of intracellular calcium homeostasis, lipid homeostasis, mitochondrial quality control, and endoplasmic reticulum stress (ERS). This article reviews recent research findings, suggesting that exercise may promote the remodeling of MAMs structure and function by modulating the expression of molecules associated with their structure and function. This, in turn, restores cellular homeostasis and ultimately contributes to the amelioration of insulin resistance (IR). These insights provide additional possibilities for the study and treatment of insulin resistance-related metabolic disorders such as obesity, diabetes, fatty liver, and atherosclerosis.

Keywords:  calcium homeostasis; endoplasmic reticulum stress; exercise; insulin resistance; lipid homeostasis; mitochondria-associated membranes; mitochondrial quality control

DOI:  https://doi.org/10.3390/ijms25063196
Elife. 2024 Mar 27. pii: RP89938. [Epub ahead of print]12

Membrane contact sites regulate vacuolar fission via sphingolipid metabolism.

Kazuki Hanaoka, Kensuke Nishikawa, Atsuko Ikeda, Philipp Schlarmann, Saku Sasaki, Sotaro Fujii, Sayumi Yamashita, Aya Nakaji, Kouichi Funato.

  Membrane contact sites (MCSs) are junctures that perform important roles including coordinating lipid metabolism. Previous studies have indicated that vacuolar fission/fusion processes are coupled with modifications in the membrane lipid composition. However, it has been still unclear whether MCS-mediated lipid metabolism controls the vacuolar morphology. Here, we report that deletion of tricalbins (Tcb1, Tcb2, and Tcb3), tethering proteins at endoplasmic reticulum (ER)-plasma membrane (PM) and ER-Golgi contact sites, alters fusion/fission dynamics and causes vacuolar fragmentation in the yeast Saccharomyces cerevisiae. In addition, we show that the sphingolipid precursor phytosphingosine (PHS) accumulates in tricalbin-deleted cells, triggering the vacuolar division. Detachment of the nucleus-vacuole junction (NVJ), an important contact site between the vacuole and the perinuclear ER, restored vacuolar morphology in both cells subjected to high exogenous PHS and Tcb3-deleted cells, supporting that PHS transport across the NVJ induces vacuole division. Thus, our results suggest that vacuolar morphology is maintained by MCSs through the metabolism of sphingolipids.

Keywords:  S. cerevisiae; cell biology; membrane contact sites; sphingolipid; tricalbin; vacuolar morphology

DOI:  https://doi.org/10.7554/eLife.89938
Cells. 2024 Mar 16. pii: 523. [Epub ahead of print]13(6):

Steroidogenesis Upregulation through Mitochondria-Associated Endoplasmic Reticulum Membranes and Mitochondrial Dynamics in Rat Testes: The Role of D-Aspartate.

Debora Latino, Massimo Venditti, Sara Falvo, Giulia Grillo, Alessandra Santillo, Imed Messaoudi, Mariem Ben Rhouma, Sergio Minucci, Gabriella Chieffi Baccari, Maria Maddalena Di Fiore.

  Mitochondria-Associated Endoplasmic Reticulum Membranes (MAMs) mediate the communication between the Endoplasmic Reticulum (ER) and the mitochondria, playing a fundamental role in steroidogenesis. This study aimed to understand how D-aspartate (D-Asp), a well-known stimulator of testosterone biosynthesis and spermatogenesis, affects the mechanism of steroidogenesis in rat testes. Our results suggested that D-Asp exerts this function through MAMs, affecting lipid trafficking, calcium signaling, ER stress, and mitochondrial dynamics. After 15 days of oral administration of D-Asp to rats, there was an increase in both antioxidant enzymes (SOD and Catalase) and in the protein expression levels of ATAD3A, FACL4, and SOAT1, which are markers of lipid transfer, as well as VDAC and GRP75, which are markers of calcium signaling. Additionally, there was a decrease in protein expression levels of GRP78, a marker of aging that counteracts ER stress. The effects of D-Asp on mitochondrial dynamics strongly suggested its active role as well. It induced the expression levels of proteins involved in fusion (MFN1, MFN2, and OPA1) and in biogenesis (NRF1 and TFAM), as well as in mitochondrial mass (TOMM20), and decreased the expression level of DRP1, a crucial mitochondrial fission marker. These findings suggested D-Asp involvement in the functional improvement of mitochondria during steroidogenesis. Immunofluorescent signals of ATAD3A, MFN1/2, TFAM, and TOMM20 confirmed their localization in Leydig cells showing an intensity upgrade in D-Asp-treated rat testes. Taken together, our results demonstrate the involvement of D-Asp in the steroidogenesis of rat testes, acting at multiple stages of both MAMs and mitochondrial dynamics, opening new opportunities for future investigation in other steroidogenic tissues.

Keywords:  ER stress; biogenesis; calcium signaling; endoplasmic reticulum; fission; fusion; lipid traffic; mass; mitochondria; mitochondrial dynamics; steroidogenesis

DOI:  https://doi.org/10.3390/cells13060523
Biomolecules. 2024 Mar 04. pii: 303. [Epub ahead of print]14(3):

Solute Transport through Mitochondrial Porins In Vitro and In Vivo.

Roland Benz.

  Mitochondria are most likely descendants of strictly aerobic prokaryotes from the class Alphaproteobacteria. The mitochondrial matrix is surrounded by two membranes according to its relationship with Gram-negative bacteria. Similar to the bacterial outer membrane, the mitochondrial outer membrane acts as a molecular sieve because it also contains diffusion pores. However, it is more actively involved in mitochondrial metabolism because it plays a functional role, whereas the bacterial outer membrane has only passive sieving properties. Mitochondrial porins, also known as eukaryotic porins or voltage-dependent anion-selective channels (VDACs) control the permeability properties of the mitochondrial outer membrane. They contrast with most bacterial porins because they are voltage-dependent. They switch at relatively small transmembrane potentials of 20 to 30 mV in closed states that exhibit different permeability properties than the open state. Whereas the open state is preferentially permeable to anionic metabolites of mitochondrial metabolism, the closed states prefer cationic solutes, in particular, calcium ions. Mitochondrial porins are encoded in the nucleus, synthesized at cytoplasmatic ribosomes, and post-translationally imported through special transport systems into mitochondria. Nineteen beta strands form the beta-barrel cylinders of mitochondrial and related porins. The pores contain in addition an α-helical structure at the N-terminal end of the protein that serves as a gate for the voltage-dependence. Similarly, they bind peripheral proteins that are involved in mitochondrial function and compartment formation. This means that mitochondrial porins are localized in a strategic position to control mitochondrial metabolism. The special features of the role of mitochondrial porins in apoptosis and cancer will also be discussed in this article.

Keywords:  VDAC; apoptosis; cancer; lipid bilayer; mitochondrial metabolism; mitochondrial porin; peripheral kinases; pore structure; voltage dependence

DOI:  https://doi.org/10.3390/biom14030303
Cells. 2024 Mar 13. pii: 500. [Epub ahead of print]13(6):

Molecular Mechanism of Autophagosome-Lysosome Fusion in Mammalian Cells.

Po-Yuan Ke.

  In eukaryotes, targeting intracellular components for lysosomal degradation by autophagy represents a catabolic process that evolutionarily regulates cellular homeostasis. The successful completion of autophagy initiates the engulfment of cytoplasmic materials within double-membrane autophagosomes and subsequent delivery to autolysosomes for degradation by acidic proteases. The formation of autolysosomes relies on the precise fusion of autophagosomes with lysosomes. In recent decades, numerous studies have provided insights into the molecular regulation of autophagosome-lysosome fusion. In this review, an overview of the molecules that function in the fusion of autophagosomes with lysosomes is provided. Moreover, the molecular mechanism underlying how these functional molecules regulate autophagosome-lysosome fusion is summarized.

Keywords:  autolysosome; autophagosome; autophagosome–lysosome fusion; autophagy; lysosome

DOI:  https://doi.org/10.3390/cells13060500
Biomolecules. 2024 Feb 26. pii: 281. [Epub ahead of print]14(3):

Mitochondrial Dysfunction in Advanced Maternal Aged Cumulus Cells: A Possible Link to ATP Synthase Impairment?

Sandra Almeida-Reis, Alexandra Carvalho, Conceição Dias, Raquel Brito, Rita Silva, Teresa Almeida-Santos, João Ramalho-Santos, Ana Paula Sousa.

  Age-related changes in the mitochondrial status of human cumulus cells (hCCs) impact oocyte quality; however, the relationship between hCC mitochondrial (dys)function and reproductive aging remains poorly understood. This study aimed to establish the interplay between hCC mitochondrial dysfunction and women's reproductive potential. In this investigation, 266 women were enrolled and categorized into two groups based on their age: a young group (<35 years old) and an advanced maternal age (AMA) group (≥35 years old). Comprehensive analysis of reproductive outcomes was conducted in our population. Various mitochondrial-related parameters were analyzed across distinct subsets. Specifically, mitochondrial membrane potential (∆Ψm) and mitochondrial mass were examined in 53 samples, mtDNA content in 25 samples, protein levels in 23 samples, bioenergetic profiles using an XF24 Extracellular Flux Analyzer in 6 samples, and levels of reactive oxygen species (ROS) and adenosine triphosphate (ATP) in 39 and 43 samples, respectively. In our study, the reproductive potential of AMA women sharply decreased, as expected. Additionally, an impairment in the mitochondrial function of hCCs in older women was observed; however, no differences were found in terms of mitochondrial content. Regarding oxidative phosphorylation, metabolic profiling of hCCs from AMA women indicated a decrease in respiratory capacity, which was correlated with an age-dependent decrease in the ATP synthase (ATP5A1) protein level. However, intracellular ROS and ATP levels did not differ between groups. In conclusion, our study indicates that age-related dysfunction in hCCs is associated with impaired mitochondrial function, and, although further studies are required, ATP synthase could be relevant in this impairment.

Keywords:  ATP synthase; cumulus cells; maternal aging; mitochondria; oxidative phosphorylation

DOI:  https://doi.org/10.3390/biom14030281
Viruses. 2024 Feb 23. pii: 345. [Epub ahead of print]16(3):

Viroporins Manipulate Cellular Powerhouses and Modulate Innate Immunity.

Leticia Cedillo-Barrón, Julio García-Cordero, Giovani Visoso-Carvajal, Moisés León-Juárez.

  Viruses have a wide repertoire of molecular strategies that focus on their replication or the facilitation of different stages of the viral cycle. One of these strategies is mediated by the activity of viroporins, which are multifunctional viral proteins that, upon oligomerization, exhibit ion channel properties with mild ion selectivity. Viroporins facilitate multiple processes, such as the regulation of immune response and inflammasome activation through the induction of pore formation in various cell organelle membranes to facilitate the escape of ions and the alteration of intracellular homeostasis. Viroporins target diverse membranes (such as the cellular membrane), endoplasmic reticulum, and mitochondria. Cumulative data regarding the importance of mitochondria function in multiple processes, such as cellular metabolism, energy production, calcium homeostasis, apoptosis, and mitophagy, have been reported. The direct or indirect interaction of viroporins with mitochondria and how this interaction affects the functioning of mitochondrial cells in the innate immunity of host cells against viruses remains unclear. A better understanding of the viroporin-mitochondria interactions will provide insights into their role in affecting host immune signaling through the mitochondria. Thus, in this review, we mainly focus on descriptions of viroporins and studies that have provided insights into the role of viroporins in hijacked mitochondria.

Keywords:  inflammasome; innate immune response; mitochondria; viroporins

DOI:  https://doi.org/10.3390/v16030345
Biomolecules. 2024 Feb 22. pii: 260. [Epub ahead of print]14(3):

Tricarboxylic Acid Cycle Intermediates and Individual Ageing.

Natalia Kurhaluk.

  Anti-ageing biology and medicine programmes are a focus of genetics, molecular biology, immunology, endocrinology, nutrition, and therapy. This paper discusses metabolic therapies aimed at prolonging longevity and/or health. Individual components of these effects are postulated to be related to the energy supply by tricarboxylic acid (TCA) cycle intermediates and free radical production processes. This article presents several theories of ageing and clinical descriptions of the top markers of ageing, which define ageing in different categories; additionally, their interactions with age-related changes and diseases related to α-ketoglutarate (AKG) and succinate SC formation and metabolism in pathological states are explained. This review describes convincingly the differences in the mitochondrial characteristics of energy metabolism in animals, with different levels (high and low) of physiological reactivity of functional systems related to the state of different regulatory systems providing oxygen-dependent processes. Much attention is given to the crucial role of AKG and SC in the energy metabolism in cells related to amino acid synthesis, epigenetic regulation, cell stemness, and differentiation, as well as metabolism associated with the development of pathological conditions and, in particular, cancer cells. Another goal was to address the issue of ageing in terms of individual characteristics related to physiological reactivity. This review also demonstrated the role of the Krebs cycle as a key component of cellular energy and ageing, which is closely associated with the development of various age-related pathologies, such as cancer, type 2 diabetes, and cardiovascular or neurodegenerative diseases where the mTOR pathway plays a key role. This article provides postulates of postischaemic phenomena in an ageing organism and demonstrates the dependence of accelerated ageing and age-related pathology on the levels of AKG and SC in studies on different species (roundworm Caenorhabditis elegans, Drosophila, mice, and humans used as models). The findings suggest that this approach may also be useful to show that Krebs cycle metabolites may be involved in age-related abnormalities of the mitochondrial metabolism and may thus induce epigenetic reprogramming that contributes to the senile phenotype and degenerative diseases. The metabolism of these compounds is particularly important when considering ageing mechanisms connected with different levels of initial physiological reactivity and able to initiate individual programmed ageing, depending on the intensity of oxygen consumption, metabolic peculiarities, and behavioural reactions.

Keywords:  ageing mechanisms; anti-ageing therapy; bioenergetic mechanisms of ageing; individual ageing processes; individual physiological reactivity; tricarboxylic acid cycle intermediates

DOI:  https://doi.org/10.3390/biom14030260
Eur J Pharmacol. 2024 Mar 23. pii: S0014-2999(24)00218-8. [Epub ahead of print] 176530

Potential targets for the treatment of MI: GRP75-mediated Ca2+ transfer in MAM.

Chenyan Zhang, Bowen Liu, Jiaxing Sheng, Jia Wang, Weijie Zhu, Chen Xie, Xuan Zhou, Yuxin Zhang, Qinghai Meng, Yu Li.

  After myocardial infarction (MI), there is a notable disruption in cellular calcium ion homeostasis and mitochondrial function, which is believed to be intricately linked to endoplasmic reticulum (ER) stress. This research endeavors to elucidate the involvement of glucose regulated protein 75 (GRP75) in post-MI calcium ion homeostasis and mitochondrial function. In MI rats, symptoms of myocardial injury were accompanied by an increase in the activation of ER stress. Moreover, in oxygen-glucose deprivation (OGD)-induced cardiomyocytes, it was confirmed that inhibiting ER stress exacerbated intracellular Ca2+ disruption and cell apoptosis. Concurrently, the co-localization of GRP75 with IP3R and VDAC1 increased under ER stress in cardiomyocytes. In OGD-induced cardiomyocytes, knockdown of GRP75 not only reduced the Ca2+ levels in both the ER and mitochondria and improved the ultrastructure of cardiomyocytes, but it also increased the number of contact points between the ER and mitochondria, reducing mitochondria associated endoplasmic reticulum membrane (MAM) formation, and decreased cell apoptosis. Significantly, knockdown of GRP75 did not affect the protein expression of PERK and hypoxia-inducible factor 1α (HIF-1α). Transcriptome analysis of cardiomyocytes revealed that knockdown of GRP75 mainly influenced the molecular functions of sialyltransferase and IP3R, as well as the biosynthesis of glycosphingolipids and lactate metabolism. The complex interaction between the ER and mitochondria, driven by the GRP75 and its associated IP3R1-GRP75-VDAC1 complex, is crucial for calcium homeostasis and cardiomyocyte's adaptive response to ER stress. Modulating GRP75 could offer a strategy to regulate calcium dynamics, diminish glycolysis, and thereby mitigate cardiomyocyte apoptosis.

Keywords:  Calcium ion homeostasis; Endoplasmic reticulum stress; GRP75; Myocardial infarction

DOI:  https://doi.org/10.1016/j.ejphar.2024.176530
Free Radic Biol Med. 2024 Mar 27. pii: S0891-5849(24)00142-4. [Epub ahead of print]

Mitochondria-tau association promotes cognitive decline and hippocampal bioenergetic deficits during the aging.

Margrethe A Olesen, Eugenia Pradenas, Francisca Villavicencio-Tejo, George A Porter, Gail V W Johnson, Rodrigo A Quintanilla.

  Current studies indicate that pathological modifications of tau are associated with mitochondrial dysfunction, synaptic failure, and cognitive decline in neurological disorders and aging. We previously showed that caspase-3 cleaved tau, a relevant tau form in Alzheimer's disease (AD), affects mitochondrial bioenergetics, dynamics and synaptic plasticity by the opening of mitochondrial permeability transition pore (mPTP). Also, genetic ablation of tau promotes mitochondrial function boost and increased cognitive capacities in aging mice. However, the mechanisms and relevance of these alterations for the cognitive and mitochondrial abnormalities during aging, which is the primary risk factor for AD, has not been explored. Therefore, in this study we used aging C57BL/6 mice (2-15 and 28-month-old) to evaluate hippocampus-dependent cognitive performance and mitochondrial function. Behavioral tests revealed that aged mice (15 and 28-month-old) showed a reduced cognitive performance compared to young mice (2 month). Concomitantly, isolated hippocampal mitochondria of aged mice showed a significant decrease in bioenergetic-related functions including increases in reactive oxygen species (ROS), mitochondrial depolarization, ATP decreases, and calcium handling defects. Importantly, full-length and caspase-3 cleaved tau were preferentially present in mitochondrial fractions of 15 and 28-month-old mice. Also, aged mice (15 and 28-month-old) showed an increase in cyclophilin D (CypD), the principal regulator of mPTP opening, and a decrease in Opa-1 mitochondrial localization, indicating a possible defect in mitochondrial dynamics. Importantly, we corroborated these findings in immortalized cortical neurons expressing mitochondrial targeted full-length (GFP-T4-OMP25) and caspase-3 cleaved tau (GFP-T4C3-OMP25) which resulted in increased ROS levels and mitochondrial fragmentation, along with a decrease in Opa-1 protein expression. These results suggest that tau associates with mitochondria and this binding increases during aging. This connection may contribute to defects in mitochondrial bioenergetics and dynamics which later may conduce to cognitive decline present during aging.

Keywords:  Aging; Mitochondria; Mitochondrial permeability transition pore (mPTP); Synaptic loss; Tau

DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.03.017
Cells. 2024 Mar 07. pii: 473. [Epub ahead of print]13(6):

The Mitochondrial Connection: The Nek Kinases' New Functional Axis in Mitochondrial Homeostasis.

Fernanda L Basei, Ivan Rosa E Silva, Pedro R Firmino Dias, Camila C Ferezin, Andressa Peres de Oliveira, Luidy K Issayama, Livia A R Moura, Fernando Riback da Silva, Jörg Kobarg.

  Mitochondria provide energy for all cellular processes, including reactions associated with cell cycle progression, DNA damage repair, and cilia formation. Moreover, mitochondria participate in cell fate decisions between death and survival. Nek family members have already been implicated in DNA damage response, cilia formation, cell death, and cell cycle control. Here, we discuss the role of several Nek family members, namely Nek1, Nek4, Nek5, Nek6, and Nek10, which are not exclusively dedicated to cell cycle-related functions, in controlling mitochondrial functions. Specifically, we review the function of these Neks in mitochondrial respiration and dynamics, mtDNA maintenance, stress response, and cell death. Finally, we discuss the interplay of other cell cycle kinases in mitochondrial function and vice versa. Nek1, Nek5, and Nek6 are connected to the stress response, including ROS control, mtDNA repair, autophagy, and apoptosis. Nek4, in turn, seems to be related to mitochondrial dynamics, while Nek10 is involved with mitochondrial metabolism. Here, we propose that the participation of Neks in mitochondrial roles is a new functional axis for the Nek family.

Keywords:  Nek kinase family functions; cell cycle; cellular signaling; mitochondrial homeostasis

DOI:  https://doi.org/10.3390/cells13060473
Int J Mol Sci. 2024 Mar 14. pii: 3303. [Epub ahead of print]25(6):

Dermatologic Manifestations of Mitochondrial Dysfunction: A Review of the Literature.

Nicole Natarelli, Nimrit Gahoonia, Shaliz Aflatooni, Sahibjot Bhatia, Raja K Sivamani.

  Mitochondria are eukaryotic cellular organelles that function in energy metabolism, ROS production, and programmed cell death. Cutaneous epithelial and hair follicle dermal papilla cells are energy-rich cells that thereby may be affected by mitochondrial dysfunction and DNA mutation accumulation. In this review, we aimed to summarize the medical literature assessing dermatologic conditions and outcomes associated with mitochondrial dysfunction. A search of PubMed and Embase was performed with subsequent handsearching to retrieve additional relevant articles. Mitochondrial DNA (mtDNA) deletions, mutation accumulation, and damage are associated with phenotypic signs of cutaneous aging, hair loss, and impaired wound healing. In addition, several dermatologic conditions are associated with aberrant mitochondrial activity, such as systemic lupus erythematosus, psoriasis, vitiligo, and atopic dermatitis. Mouse model studies have better established causality between mitochondrial damage and dermatologic outcomes, with some depicting reversibility upon restoration of mitochondrial function. Mitochondrial function mediates a variety of dermatologic conditions, and mitochondrial components may be a promising target for therapeutic strategies.

Keywords:  UVR; aging; atopic dermatitis; dermatology; hair loss; lupus; mitochondria; psoriasis; vitiligo; wound healing

DOI:  https://doi.org/10.3390/ijms25063303
Chem Biol Interact. 2024 Mar 27. pii: S0009-2797(24)00121-2. [Epub ahead of print] 110975

Nickel induces mitochondrial damage in renal cells in vitro and in vivo through its effects on mitochondrial biogenesis, fusion, and fission.

Heng Yin, Xinglai Li, Chengbi Wang, Xiaocong Li, Jingbo Liu.

  Nickel (Ni) and its compounds are common, widely distributed components of hazardous waste in the chemical industry. Excessive exposure to Ni can cause kidney damage in humans and animals. We investigated the impact of Ni on renal mitochondria using in vivo and in vitro models of Ni nephrotoxicity, and explored the Ni nephrotoxic mechanism. We showed that nickel chloride (NiCl2) damaged the renal mitochondria, causing mitochondrial swelling, breakage of the mitochondrial cristae, increased levels of mitochondrial reactive oxygen species (mt-ROS), and depolarization of the mitochondrial membrane potential (MMP). The levels of the mitochondrial respiratory chain complexes I-IV were reduced in the kidneys of mice treated with NiCl2. In addition, NiCl2 treatment inhibited mitochondrial biogenesis in renal cells by down-regulating mRNA and the protein expression of TFAM, PGC-1α, and NRF1. Moreover, NiCl2 reduced the levels of the proteins involved in mitochondrial fusion, including Mfn1 and Mfn2, while significantly augmenting the levels of the proteins Fis1 and Drip1 involved in mitochondrial fission in renal cells. Taken together, these results suggested that NiCl2 inhibited mitochondrial biogenesis, suppressed mitochondrial fusion, and promoted mitochondrial fission, resulting in mitochondrial dysfunction in renal cells, ultimately causing renal injury. This study provided novel insights into the mechanisms of nephrotoxicity of Ni and new ideas for the development of targeted treatments for Ni-induced kidney injury.

Keywords:  Kidney; Mitochondria; Mitochondrial biogenesis; Mitochondrial division; Mitochondrial fusion; Nickel

DOI:  https://doi.org/10.1016/j.cbi.2024.110975
Front Biosci (Schol Ed). 2024 Mar 08. 16(1): 5

Mitochondrial Dysfunction as a Factor of Energy Metabolism Disorders in Type 2 Diabetes Mellitus.

Alexander Blagov, Ludmila Nedosugova, Tatiana Kirichenko, Vasily Sukhorukov, Alexandra Melnichenko, Alexander Orekhov.

  The pathogenesis of type 2 diabetes mellitus (T2DM) is based on the development of insulin resistance, which is a disruption to the ability of the tissues to bind to insulin, leading to a general metabolic disorder. Mitochondria are the main participants in cellular energy metabolism, meaning their dysfunction is associated with the development of insulin resistance in T2DM. Mitochondrial function is affected by insulin resistance in various tissues, including skeletal muscle and the liver, which greatly influence glucose homeostasis throughout the body. This review studies mitochondrial dysfunction in T2DM and its impact on disease progression. In addition, it considers the causes underlying the development of mitochondrial dysfunction in T2DM, including mutations in the mitochondrial genome, mitochondrial DNA methylation, and other epigenetic influences, as well as the impact of impaired mitochondrial membrane potential. New therapeutic strategies for diabetes that have been developed to target the mitochondria will also be presented.

Keywords:  glucose; insulin resistance; mitochondrial dysfunction; type 2 diabetes

DOI:  https://doi.org/10.31083/j.fbs1601005
Med Sci (Paris). 2024 Mar;40(3): 267-274

[Unconventional protein secretion - new perspectives in protein trafficking].

Morgane Denus, William Fargues, Aurore Filaquier, Éloïse Néel, Philippe Marin, Marie-Laure Parmentier, Julien Villeneuve.

The characterization of the structural and functional organization of eukaryotic cells has revealed the membrane compartments and machinery required for vesicular protein transport. Most proteins essential for intercellular communication contain an N-terminal signal sequence enabling them to be incorporated into the biosynthetic or conventional secretory pathway, in which proteins are sequentially transported through the endoplasmic reticulum (ER) and the Golgi apparatus. However, major research studies have shown the existence of alternative secretory routes that are independent of the ER-Golgi and designated as unconventional secretory pathways. These pathways involve a large number of players that may divert specific compartments from their primary function in favor of secretory roles. The comprehensive description of these processes is therefore of utmost importance to unveil how proteins secreted through these alternative pathways control cell homeostasis or contribute to disease development.

DOI: https://doi.org/10.1051/medsci/2024013
Pharmacol Res. 2024 Mar 22. pii: S1043-6618(24)00098-7. [Epub ahead of print]203 107154

Serotonin regulation of mitochondria in kidney diseases.

Kevin Hurtado, Natalie E Scholpa, Jennifer G Schnellmann, Rick G Schnellmann.

  Serotonin, while conventionally recognized as a neurotransmitter in the CNS, has recently gained attention for its role in the kidney. Specifically, serotonin is not only synthesized in the kidney, but it also regulates glomerular function, vascular resistance, and mitochondrial homeostasis. Because of serotonin's importance to mitochondrial health, this review is focused on the role of serotonin and its receptors in mitochondrial function in the context of acute kidney injury, chronic kidney disease, and diabetic kidney disease, all of which are characterized by mitochondrial dysfunction and none of which has approved pharmacological treatments. Evidence indicates that activation of certain serotonin receptors can stimulate mitochondrial biogenesis (MB) and restore mitochondrial homeostasis, resulting in improved renal function. Serotonin receptor agonists that induce MB are therefore of interest as potential therapeutic strategies for renal injury and disease. SIGNIFICANCE STATEMENT: Mitochondrial dysfunction is associated with many human renal diseases such as acute kidney injury, chronic kidney disease, and diabetic kidney disease, which are associated with increased morbidity and mortality. Unfortunately, none of these pathologies has an FDA-approved pharmacological intervention, underscoring the urgency of identifying new therapeutics for such disorders. Studies show that induction of mitochondrial biogenesis via serotonin (5-hydroxytryptamine, 5-HT) receptors reduces kidney injury markers, restores mitochondrial and renal function after kidney injury, and decreases mortality, suggesting that targeting 5-HT receptors may be a promising therapeutic avenue for mitochondrial dysfunction in kidney diseases. While numerous reviews describe the importance of mitochondria and mitochondrial quality control mechanisms in kidney disease, the relevance of 5-HT receptor-mediated mitochondrial metabolic modulation in the kidney has yet to be thoroughly explored.

Keywords:  5-HT(1F); Kidney; Kidney disease; Mitochondria; Mitochondrial biogenesis; Serotonin

DOI:  https://doi.org/10.1016/j.phrs.2024.107154
NeuroImmune Pharm Ther. 2024 Mar;3(1): 33-46

Weak base drug-induced endolysosome iron dyshomeostasis controls the generation of reactive oxygen species, mitochondrial depolarization, and cytotoxicity.

Peter W Halcrow, Darius N K Quansah, Nirmal Kumar, Rebecca L Solloway, Kayla M Teigen, Kasumi A Lee, Braelyn Liang, Jonathan D Geiger.

   Objectives: Approximately 75 % of marketed drugs have the physicochemical property of being weak bases. Weak-base drugs with relatively high pKa values enter acidic organelles including endosomes and lysosomes (endolysosomes), reside in and de-acidify endolysosomes, and induce cytotoxicity. Divalent cations within endolysosomes, including iron, are released upon endolysosome de-acidification. Endolysosomes are "master regulators of iron homeostasis", and neurodegeneration is linked to ferrous iron (Fe2+)-induced reactive oxygen species (ROS) generation via Fenton chemistry. Because endolysosome de-acidification-induced lysosome-stress responses release endolysosome Fe2+, it was crucial to determine the mechanisms by which a functionally and structurally diverse group of weak base drugs including atropine, azithromycin, fluoxetine, metoprolol, and tamoxifen influence endolysosomes and cause cell death.
Methods: Using U87MG astrocytoma and SH-SY5Y neuroblastoma cells, we conducted concentration-response relationships for 5 weak-base drugs to determine EC50 values. From these curves, we chose pharmacologically and therapeutically relevant concentrations to determine if weak-base drugs induced lysosome-stress responses by de-acidifying endolysosomes, releasing endolysosome Fe2+ in sufficient levels to increase cytosolic and mitochondria Fe2+ and ROS levels and cell death.
Results: Atropine (anticholinergic), azithromycin (antibiotic), fluoxetine (antidepressant), metoprolol (beta-adrenergic), and tamoxifen (anti-estrogen) at pharmacologically and therapeutically relevant concentrations (1) de-acidified endolysosomes, (2) decreased Fe2+ levels in endolysosomes, (3) increased Fe2+ and ROS levels in cytosol and mitochondria, (4) induced mitochondrial membrane potential depolarization, and (5) increased cell death; effects prevented by the endocytosed iron-chelator deferoxamine.
Conclusions: Weak-base pharmaceuticals induce lysosome-stress responses that may affect their safety profiles; a better understanding of weak-base drugs on Fe2+ interorganellar signaling may improve pharmacotherapeutics.

Keywords:  ADMET; cell death; endolysosome ferrous iron; mitochondrial membrane potential; reactive oxygen species; weak base drugs

DOI:  https://doi.org/10.1515/nipt-2023-0021
Biochem Soc Trans. 2024 Mar 25. pii: BST20231183. [Epub ahead of print]

Emerging mechanisms in the redox regulation of mitochondrial cytochrome c oxidase assembly and function.

Suleva Povea-Cabello, Michele Brischigliaro, Erika Fernández-Vizarra.

  In eukaryotic cells, mitochondria perform cellular respiration through a series of redox reactions ultimately reducing molecular oxygen to water. The system responsible for this process is the respiratory chain or electron transport system (ETS) composed of complexes I-IV. Due to its function, the ETS is the main source of reactive oxygen species (ROS), generating them on both sides of the mitochondrial inner membrane, i.e. the intermembrane space (IMS) and the matrix. A correct balance between ROS generation and scavenging is important for keeping the cellular redox homeostasis and other important aspects of cellular physiology. However, ROS generated in the mitochondria are important signaling molecules regulating mitochondrial biogenesis and function. The IMS contains a large number of redox sensing proteins, containing specific Cys-rich domains, that are involved in ETS complex biogenesis. The large majority of these proteins function as cytochrome c oxidase (COX) assembly factors, mainly for the handling of copper ions necessary for the formation of the redox reactive catalytic centers. A particular case of ROS-regulated COX assembly factor is COA8, whose intramitochondrial levels are increased by oxidative stress, promoting COX assembly and/or protecting the enzyme from oxidative damage. In this review, we will discuss the current knowledge concerning the role played by ROS in regulating mitochondrial activity and biogenesis, focusing on the COX enzyme and with a special emphasis on the functional role exerted by the redox sensitive Cys residues contained in the COX assembly factors.

Keywords:  complex IV; mitochondrial dysfunction; reactive oxygen species; redox signaling; respiratory chain assembly

DOI:  https://doi.org/10.1042/BST20231183
Cells. 2024 Mar 12. pii: 493. [Epub ahead of print]13(6):

Phosphorylations and Acetylations of Cytochrome c Control Mitochondrial Respiration, Mitochondrial Membrane Potential, Energy, ROS, and Apoptosis.

Paul T Morse, Tasnim Arroum, Junmei Wan, Lucynda Pham, Asmita Vaishnav, Jamie Bell, Lauren Pavelich, Moh H Malek, Thomas H Sanderson, Brian F P Edwards, Maik Hüttemann.

  Cytochrome c (Cytc) has both life-sustaining and cellular death-related functions, depending on subcellular localization. Within mitochondria, Cytc acts as a single electron carrier as part of the electron transport chain (ETC). When released into the cytosol after cellular insult, Cytc triggers the assembly of the apoptosome, committing the cell to intrinsic apoptosis. Due to these dual natures, Cytc requires strong regulation by the cell, including post-translational modifications, such as phosphorylation and acetylation. Six phosphorylation sites and three acetylation sites have been detected on Cytc in vivo. Phosphorylations at T28, S47, Y48, T49, T58, and Y97 tend to be present under basal conditions in a tissue-specific manner. In contrast, the acetylations at K8, K39, and K53 tend to be present in specific pathophysiological conditions. All of the phosphorylation sites and two of the three acetylation sites partially inhibit respiration, which we propose serves to maintain an optimal, intermediate mitochondrial membrane potential (ΔΨm) to minimize reactive oxygen species (ROS) production. Cytc phosphorylations are lost during ischemia, which drives ETC hyperactivity and ΔΨm hyperpolarization, resulting in exponential ROS production thus causing reperfusion injury following ischemia. One of the acetylation sites, K39, shows a unique behavior in that it is gained during ischemia, stimulating respiration while blocking apoptosis, demonstrating that skeletal muscle, which is particularly resilient to ischemia-reperfusion injury compared to other organs, possesses a different metabolic strategy to handle ischemic stress. The regulation of Cytc by these post-translational modifications underscores the importance of Cytc for the ETC, ΔΨm, ROS production, apoptosis, and the cell as a whole.

Keywords:  apoptosis; cytochrome c; electron transport chain; mitochondria; post-translational modifications; respiration

DOI:  https://doi.org/10.3390/cells13060493