bims-midtic 2023-07-16 papers

bims-midtic

Biomed News

on Mitochondrial dynamics and trafficking in cells

Issue of 2023‒07‒16
nineteen papers selected by
Omkar Joshi
Turku Bioscience

Mitochondrial quality control and its emerging role in the pathogenesis of diabetic kidney disease.
Mitochondria-derived cell-to-cell communication.
Immunoproteasome-specific subunit PSMB9 induction is required to regulate cellular proteostasis upon mitochondrial dysfunction.
The ELK3-DRP1 axis determines the chemosensitivity of triple-negative breast cancer cells to CDDP by regulating mitochondrial dynamics.
Defects in Mitochondrial Biogenesis Drive Mitochondrial Alterations in PINK1-deficient Human Dopamine Neurons.
Local coordination of mRNA storage and degradation near mitochondria modulates C. elegans ageing.
Metabolic flux in the driver's seat during cardiac health and disease.
A partial Drp1 knockout improves autophagy flux independent of mitochondrial function.
The role of mitochondria and mitophagy in cell senescence.
Lysosomal mitochondrial interaction promotes tumor growth in squamous cell carcinoma of the head and neck.
Fluorescence microscopy imaging of mitochondrial metabolism in cancer cells.
Mitochondria as intracellular signalling organelles. An update.
Hypoxia-reprogramed megamitochondrion contacts and engulfs lysosome to mediate mitochondrial self-digestion.
Shedding light on mitochondrial outer-membrane permeabilization and membrane potential: State of the art methods and biosensors.
A Three-Dimensional Technique for The Visualization of Mitochondrial Ultrastructural Changes in Pancreatic Cancer Cells.
Intercellular mitochondrial transfer in the brain, a new perspective for targeted treatment of central nervous system diseases.
Regulation of mitochondrial morphology and cristae architecture by the TLR4 pathway in human skeletal muscle.
The pyruvate dehydrogenase complex regulates mitophagic trafficking and protein phosphorylation.
Mitochondrial Dysfunction and Skeletal Muscle Atrophy: Causes, Mechanisms, and Treatment Strategies.

Kidney Res Clin Pract. 2023 May 22.

Mitochondrial quality control and its emerging role in the pathogenesis of diabetic kidney disease.

Jihyun Baek, Yu Ho Lee, Hye Yun Jeong, So-Young Lee.

  Most eukaryotic cells have mitochondrial networks that can change in shape, distribution, and size depending on cellular metabolic demands and environments. Mitochondrial quality control is critical for various mitochondrial functions including energy production, redox homeostasis, intracellular calcium handling, cell differentiation, proliferation, and cell death. Quality control mechanisms within mitochondria consist of antioxidant defenses, protein quality control, DNA damage repair systems, mitochondrial fusion and fission, mitophagy, and mitochondrial biogenesis. Defects in mitochondrial quality control and disruption of mitochondrial homeostasis are common characteristics of various kidney cell types under hyperglycemic conditions. Such defects contribute to diabetes-induced pathologies in renal tubular cells, podocytes, endothelial cells, and immune cells. In this review, we focus on the roles of mitochondrial quality control in diabetic kidney disease pathogenesis and discuss current research evidence and future directions.

Keywords:  Diabetic kidney disease; Endothelial cells; Immune cells; Mitochondrial quality control; Podocytes; Renal tubular cells

DOI:  https://doi.org/10.23876/j.krcp.22.233
Cell Rep. 2023 Jul 11. pii: S2211-1247(23)00739-8. [Epub ahead of print]42(7): 112728

Mitochondria-derived cell-to-cell communication.

Zahra Al Amir Dache, Alain R Thierry.

  In addition to their intracellular mobility, mitochondria and their components can exist outside the cells from which they originate. As a result, they are capable of acting on non-parental distant cells and mediate intercellular communication in physiological conditions and in a variety of pathologies. It has recently been demonstrated that this horizontal transfer governs a wide range of biological processes, such as tissue homeostasis, the rescue of injured recipient cells, and tumorigenesis. In addition, due to mitochondria's bacterial ancestry, they and their components can be recognized as damage-associated molecular patterns (DAMPs) by the immune cells, leading to inflammation. Here, we provide an overview of the most current and significant findings concerning the different structures of extracellular mitochondria and their by-products and their functions in the physiological and pathological context. This account illustrates the ongoing expansion of our understanding of mitochondria's biological role and functions in mammalian organisms.

Keywords:  CP: Cell biology; DAMP; circulating DNA; circulating mitochondria; inflammation; intercellular communication; mitochondria

DOI:  https://doi.org/10.1016/j.celrep.2023.112728
Nat Commun. 2023 07 11. 14(1): 4092

Immunoproteasome-specific subunit PSMB9 induction is required to regulate cellular proteostasis upon mitochondrial dysfunction.

Minji Kim, Remigiusz A Serwa, Lukasz Samluk, Ida Suppanz, Agata Kodroń, Tomasz M Stępkowski, Praveenraj Elancheliyan, Biniyam Tsegaye, Silke Oeljeklaus, Michal Wasilewski, Bettina Warscheid, Agnieszka Chacinska.

Perturbed cellular protein homeostasis (proteostasis) and mitochondrial dysfunction play an important role in neurodegenerative diseases, however, the interplay between these two phenomena remains unclear. Mitochondrial dysfunction leads to a delay in mitochondrial protein import, causing accumulation of non-imported mitochondrial proteins in the cytosol and challenging proteostasis. Cells respond by increasing proteasome activity and molecular chaperones in yeast and C. elegans. Here, we demonstrate that in human cells mitochondrial dysfunction leads to the upregulation of a chaperone HSPB1 and, interestingly, an immunoproteasome-specific subunit PSMB9. Moreover, PSMB9 expression is dependent on the translation elongation factor EEF1A2. These mechanisms constitute a defense response to preserve cellular proteostasis under mitochondrial stress. Our findings define a mode of proteasomal activation through the change in proteasome composition driven by EEF1A2 and its spatial regulation, and are useful to formulate therapies to prevent neurodegenerative diseases.

DOI: https://doi.org/10.1038/s41467-023-39642-8
Cell Death Discov. 2023 Jul 08. 9(1): 237

The ELK3-DRP1 axis determines the chemosensitivity of triple-negative breast cancer cells to CDDP by regulating mitochondrial dynamics.

Joo Dong Park, Hye Jung Jang, Seung Hee Choi, Gae Hoon Jo, Jin-Ho Choi, Sohyun Hwang, Wooram Park, Kyung-Soon Park.

Triple-negative breast cancer (TNBC) is the most lethal form of breast cancer. TNBC patients have higher rates of metastasis and restricted therapy options. Although chemotherapy is the conventional treatment for TNBC, the frequent occurrence of chemoresistance significantly lowers the efficacy of treatment. Here, we demonstrated that ELK3, an oncogenic transcriptional repressor that is highly expressed in TNBC, determined the chemosensitivity of two representative TNBC cell lines (MDA-MB231 and Hs578T) to cisplatin (CDDP) by regulating mitochondrial dynamics. We observed that the knockdown of ELK3 in MDA-MB231 and Hs578T rendered these cell lines more susceptible to the effects of CDDP. We further demonstrated that the chemosensitivity of TNBC cells was caused by the CDDP-mediated acceleration of mitochondrial fission, excessive mitochondrial reactive oxygen species production, and subsequent DNA damage. In addition, we identified DNM1L, a gene encoding the dynamin-related protein 1 (a major regulator of mitochondrial fission), as a direct downstream target of ELK3. Based on these results, we propose that the suppression of ELK3 expression could be used as a potential therapeutic strategy for overcoming the chemoresistance or inducing the chemosensitivity of TNBC.

DOI: https://doi.org/10.1038/s41420-023-01536-5
bioRxiv. 2023 Jun 26. pii: 2023.06.23.546087. [Epub ahead of print]

Defects in Mitochondrial Biogenesis Drive Mitochondrial Alterations in PINK1-deficient Human Dopamine Neurons.

Hu Wang, Rong Chen, Liming Xiao, Manoj Kumar, Jesús Acevedo-Cintrón, Joanna Siuda, Dariusz Koziorowski, Zbigniew K Wszolek, Valina L Dawson, Ted M Dawson.

Mutations and loss of activity in the protein kinase PINK1 play a role in the pathogenesis of Parkinson's disease (PD). PINK1 regulates many aspects of mitochondrial quality control including mitochondrial autophagy (mitophagy), fission, fusion, transport, and biogenesis. Defects in mitophagy are though to play a predominant role in the loss of dopamine (DA) neurons in PD. Here we show that, although there are defects in mitophagy in human DA neurons lacking PINK1, mitochondrial deficits induced by the absence of PINK1 are primarily due to defects in mitochondrial biogenesis. Upregulation of PARIS and the subsequent down regulation of PGC-1α accounts for the mitochondrial biogenesis defects. CRISPR/Cas9 knockdown of PARIS completely restores the mitochondrial biogenesis defects and mitochondrial function without impacting the deficits in mitophagy due to the absence of PINK1. These results highlight the importance mitochondrial biogenesis in the pathogenesis of PD due to inactivation or loss of PINK1 in human DA neurons.

DOI: https://doi.org/10.1101/2023.06.23.546087
EMBO J. 2023 Jul 10. e112446

Local coordination of mRNA storage and degradation near mitochondria modulates C. elegans ageing.

Ioanna Daskalaki, Maria Markaki, Ilias Gkikas, Nektarios Tavernarakis.

  Mitochondria are central regulators of healthspan and lifespan, yet the intricate choreography of multiple, tightly controlled steps regulating mitochondrial biogenesis remains poorly understood. Here, we uncover a pivotal role for specific elements of the 5'-3' mRNA degradation pathway in the regulation of mitochondrial abundance and function. We find that the mRNA degradation and the poly-A tail deadenylase CCR4-NOT complexes form distinct foci in somatic Caenorhabditis elegans cells that physically and functionally associate with mitochondria. Components of these two multi-subunit complexes bind transcripts of nuclear-encoded mitochondria-targeted proteins to regulate mitochondrial biogenesis during ageing in an opposite manner. In addition, we show that balanced degradation and storage of mitochondria-targeted protein mRNAs are critical for mitochondrial homeostasis, stress resistance and longevity. Our findings reveal a multifaceted role of mRNA metabolism in mitochondrial biogenesis and show that fine-tuning of mRNA turnover and local translation control mitochondrial abundance and promote longevity in response to stress and during ageing.

Keywords:  ageing; mRNA metabolism; mitochondria; protein synthesis; stress

DOI:  https://doi.org/10.15252/embj.2022112446
J Mol Cell Cardiol. 2023 Jul 12. pii: S0022-2828(23)00110-4. [Epub ahead of print]182 15-24

Metabolic flux in the driver's seat during cardiac health and disease.

E Douglas Lewandowski.

  Cardiac function is a dynamic process that must adjust efficiently to the immediate demands of physical state and activity. So too, the metabolic support of cardiac function is a dynamic process that must respond, in time, to the demands of cardiac function and viability. Flux through metabolic pathways provides chemical energy and generates signaling molecules that regulate activity among intracellular compartments to meet these demands. Thus, flux through metabolic pathways provides a dynamic mode of support of cardiomyocytes during physiological and pathophysiological challenges. Any inability of metabolic flux to keep pace with the demands of the cardiomyocyte results in progressive dysfunction that contributes to cardiac disease. Thus, the priority in maintaining and regulating flux through metabolic pathways in the cardiomyocyte cannot be understated. Great potential exists in current efforts to elucidate metabolic mechanisms as therapeutic targets for the diseased heart. As a consequence, detecting metabolic flux in the functioning myocardium of the heart, under normal and diseased conditions, is essential in elucidating the metabolic basis of contractile dysfunction. As a companion to the 2022 ISHR Research Achievement Award lecture, this review examines the use and applications of stable isotope kinetics to quantify metabolic flux through intermediary pathways and the exchange and transport of intermediates across the mitochondrial membrane and sarcolemma of intact functioning hearts in determining how these intracellular events are coordinated to support cardiac function and health. Finally, this work reviews recently demonstrated metabolic defects in diseased hearts and the potential for metabolic alleviation of heart disease.

Keywords:  Fatty acids; Glucose; Heart failure; Ischemia/Reperfusion; Isotopes; Metabolism; Mitochondria

DOI:  https://doi.org/10.1016/j.yjmcc.2023.07.004
bioRxiv. 2023 Jun 29. pii: 2023.06.29.547095. [Epub ahead of print]

A partial Drp1 knockout improves autophagy flux independent of mitochondrial function.

Rebecca Z Fan, Carolina Sportelli, Yanhao Lai, Said Salehe, Jennifer R Pinnell, Jason R Richardson, Shouqing Luo, Kim Tieu.

Dynamin-related protein 1 (Drp1) is typically known for its role in mitochondrial fission. A partial inhibition of this protein has been reported to be protective in experimental models of neurodegenerative diseases. The protective mechanism has been attributed primarily to improved mitochondrial function. Herein, we provide evidence showing that a partial Drp1-knockout improves autophagy flux independent of mitochondria. First, we characterized in cell and animal models that at low non-toxic concentrations, manganese (Mn), which causes parkinsonian-like symptoms in humans, impaired autophagy flux but not mitochondrial function and morphology. Furthermore, nigral dopaminergic neurons were more sensitive than their neighbouring GABAergic counterparts. Second, in cells with a partial Drp1-knockdown and Drp1 +/- mice, autophagy impairment induced by Mn was significantly attenuated. This study demonstrates that autophagy is a more vulnerable target than mitochondria to Mn toxicity. Furthermore, improving autophagy flux is a separate mechanism conferred by Drp1 inhibition independent of mitochondrial fission.

DOI: https://doi.org/10.1101/2023.06.29.547095
Adv Protein Chem Struct Biol. 2023 ;pii: S1876-1623(23)00043-3. [Epub ahead of print]136 93-115

The role of mitochondria and mitophagy in cell senescence.

Tayyab Ali, Fatma Hussain, Haroon Ur Rashid Kayani, Muhammad Naeem, Fozia Anjum.

  Mitochondrial malfunction and cell senescence have been defined as the hallmarks of aging. Cell senescence leads to the loss of health allied with aging. While deciphering the complex association between mitochondria and cellular senescence, it is observed that senescence has a two-faced nature being beneficial and hazardous. This duality of cellular senescence is associated with circumstantial aspects. During the process of cellular senescence, dysfunctional mitochondria are accumulated, the efficiency of the oxidative phosphorylation process declines along with the enhanced synthesis of reactive oxygen species. It is suggested that reduction in the negative consequences of senescence throughout old age might be accomplished by targeting the mitochondria as all roads lead towards mitochondria. It is unclear how perturbation of mitophagy in senescence results in the accumulation of mitochondria, impairment of mitochondrial biogenesis and onset of diseases. Understanding this complex interplay will bring about a long yet healthy lifespan. But definitely casual and specific players contribute in the initiation and conservation of the cell senescence. Variations in metabolism, quality control and dynamics of mitochondria are observed during cell aging process. Several On-target and Off-target mechanisms can also cause side effects in cellular senescence. Translational research of these mechanisms may lead to effective clinical interventions. This chapter reviews the role of mitochondria, homeostatic mechanisms and mitophagy as drivers and effectors of cell senescence along with multiple signalling pathways that lead to the initiation, maintenance, induction and suppression of cellular aging process during health and disease.

Keywords:  Autophagy; Cell senescence; Mitophagy; Signaling pathways

DOI:  https://doi.org/10.1016/bs.apcsb.2023.03.001
bioRxiv. 2023 Jun 26. pii: 2023.06.25.546311. [Epub ahead of print]

Lysosomal mitochondrial interaction promotes tumor growth in squamous cell carcinoma of the head and neck.

Avani Gopalkrishnan, Nathaniel Wang, Silvia Cruz-Rangel, Abdul Yassin- Kassab, Sruti Shiva, Chareeni Kurukulasuriya, Satdarshan P Monga, Ralph J DeBerardinis, Kirill Kiselyov, Umamaheswar Duvvuri.

Tumor growth and proliferation are regulated by numerous mechanisms. Communication between intracellular organelles has recently been shown to regulate cellular proliferation and fitness. The way lysosomes and mitochondria communicate with each other (lysosomal/mitochondrial interaction) is emerging as a major determinant of tumor proliferation and growth. About 30% of squamous carcinomas (including squamous cell carcinoma of the head and neck, SCCHN) overexpress TMEM16A, a calcium-activated chloride channel, which promotes cellular growth and negatively correlates with patient survival. TMEM16A has recently been shown to drive lysosomal biogenesis, but its impact on mitochondrial function is unclear. Here, we show that (1) patients with high TMEM16A SCCHN display increased mitochondrial content specifically complex I; (2) In vitro and in vivo models uniquely depend on mitochondrial complex I activity for growth and survival; (3) β-catenin/NRF2 signaling is a critical linchpin that drives mitochondrial biogenesis, and (4) mitochondrial complex I and lysosomal function are codependent for proliferation. Taken together, our data demonstrate that LMI drives tumor proliferation and facilitates a functional interaction between lysosomes and mitochondria. Therefore, inhibition of LMI may serve as a therapeutic strategy for patients with SCCHN.

DOI: https://doi.org/10.1101/2023.06.25.546311
Front Oncol. 2023 ;13 1152553

Fluorescence microscopy imaging of mitochondrial metabolism in cancer cells.

Monika Gooz, Eduardo N Maldonado.

  Mitochondrial metabolism is an important contributor to cancer cell survival and proliferation that coexists with enhanced glycolytic activity. Measuring mitochondrial activity is useful to characterize cancer metabolism patterns, to identify metabolic vulnerabilities and to identify new drug targets. Optical imaging, especially fluorescent microscopy, is one of the most valuable tools for studying mitochondrial bioenergetics because it provides semiquantitative and quantitative readouts as well as spatiotemporal resolution of mitochondrial metabolism. This review aims to acquaint the reader with microscopy imaging techniques currently used to determine mitochondrial membrane potential (ΔΨm), nicotinamide adenine dinucleotide (NADH), ATP and reactive oxygen species (ROS) that are major readouts of mitochondrial metabolism. We describe features, advantages, and limitations of the most used fluorescence imaging modalities: widefield, confocal and multiphoton microscopy, and fluorescent lifetime imaging (FLIM). We also discus relevant aspects of image processing. We briefly describe the role and production of NADH, NADHP, flavins and various ROS including superoxide and hydrogen peroxide and discuss how these parameters can be analyzed by fluorescent microscopy. We also explain the importance, value, and limitations of label-free autofluorescence imaging of NAD(P)H and FAD. Practical hints for the use of fluorescent probes and newly developed sensors for imaging ΔΨm, ATP and ROS are described. Overall, we provide updated information about the use of microscopy to study cancer metabolism that will be of interest to all investigators regardless of their level of expertise in the field.

Keywords:  FAD; NAD(P)H; ROS; fluorescence microscopy; mitochondrial membrane potential; mitochondrial metabolism

DOI:  https://doi.org/10.3389/fonc.2023.1152553
Cell Signal. 2023 Jul 06. pii: S0898-6568(23)00208-5. [Epub ahead of print]109 110794

Mitochondria as intracellular signalling organelles. An update.

Lucia-Doina Popov.

  Traditionally, mitochondria are known as "the powerhouse of the cell," responsible for energy (ATP) generation (by the electron transport chain, oxidative phosphorylation, the tricarboxylic acid cycle, and fatty acid ß-oxidation), and for the regulation of several metabolic processes, including redox homeostasis, calcium signalling, and cellular apoptosis. The extensive studies conducted in the last decades portray mitochondria as multifaceted signalling organelles that ultimately command cells' survival or death. Based on current knowledge, we'll outline the mitochondrial signalling to other intracellular compartments in homeostasis and pathology-related mitochondrial stress conditions here. The following topics are discussed: (i) oxidative stress and mtROS signalling in mitohormesis, (ii) mitochondrial Ca2+ signalling; (iii) the anterograde (nucleus-to-mitochondria) and retrograde (mitochondria-to-nucleus) signal transduction, (iv) the mtDNA role in immunity and inflammation, (v) the induction of mitophagy- and apoptosis - signalling cascades, (vi) the mitochondrial dysfunctions (mitochondriopathies) in cardiovascular, neurodegenerative, and malignant diseases. The novel insights into molecular mechanisms of mitochondria-mediated signalling can explain mitochondria adaptation to metabolic and environmental stresses to achieve cell survival.

Keywords:  Mitochondriopathies; Mitophagy; Oxidative stress; Signal transduction; mtDNA

DOI:  https://doi.org/10.1016/j.cellsig.2023.110794
Nat Commun. 2023 07 11. 14(1): 4105

Hypoxia-reprogramed megamitochondrion contacts and engulfs lysosome to mediate mitochondrial self-digestion.

Tianshu Hao, Jianglong Yu, Zhida Wu, Jie Jiang, Longlong Gong, Bingjun Wang, Hanze Guo, Huabin Zhao, Bin Lu, Simone Engelender, He He, Zhiyin Song.

Mitochondria are the key organelles for sensing oxygen, which is consumed by oxidative phosphorylation to generate ATP. Lysosomes contain hydrolytic enzymes that degrade misfolded proteins and damaged organelles to maintain cellular homeostasis. Mitochondria physically and functionally interact with lysosomes to regulate cellular metabolism. However, the mode and biological functions of mitochondria-lysosome communication remain largely unknown. Here, we show that hypoxia remodels normal tubular mitochondria into megamitochondria by inducing broad inter-mitochondria contacts and subsequent fusion. Importantly, under hypoxia, mitochondria-lysosome contacts are promoted, and certain lysosomes are engulfed by megamitochondria, in a process we term megamitochondria engulfing lysosome (MMEL). Both megamitochondria and mature lysosomes are required for MMEL. Moreover, the STX17-SNAP29-VAMP7 complex contributes to mitochondria-lysosome contacts and MMEL under hypoxia. Intriguingly, MMEL mediates a mode of mitochondrial degradation, which we termed mitochondrial self-digestion (MSD). Moreover, MSD increases mitochondrial ROS production. Our results reveal a mode of crosstalk between mitochondria and lysosomes and uncover an additional pathway for mitochondrial degradation.

DOI: https://doi.org/10.1038/s41467-023-39811-9
Semin Cell Dev Biol. 2023 Jul 10. pii: S1084-9521(23)00141-6. [Epub ahead of print]

Shedding light on mitochondrial outer-membrane permeabilization and membrane potential: State of the art methods and biosensors.

Nikolay Popgeorgiev, Clara Gil, Kevin Berthenet, Giulia Bertolin, Gabriel Ichim.

  Membrane structural integrity is essential for optimal mitochondrial function. These organelles produce the energy needed for all vital processes, provided their outer and inner membranes are intact. This prevents the release of mitochondrial apoptogenic factors into the cytosol and ensures intact mitochondrial membrane potential (ΔΨm) to sustain ATP production. Cell death by apoptosis is generally triggered by outer mitochondrial membrane permeabilization (MOMP), tightly coupled with loss of ΔΨ m. As these two processes are essential for both mitochondrial function and cell death, researchers have devised various techniques to assess them. Here, we discuss current methods and biosensors available for detecting MOMP and measuring ΔΨ m, focusing on their advantages and limitations and discuss what new imaging tools are needed to improve our knowledge of mitochondrial function.

Keywords:  Biosensor; MOMP; Microscopy; Mitochondrial membrane potential

DOI:  https://doi.org/10.1016/j.semcdb.2023.07.003
J Vis Exp. 2023 06 23.

A Three-Dimensional Technique for The Visualization of Mitochondrial Ultrastructural Changes in Pancreatic Cancer Cells.

Yuwei Qi, Yuhou Liu, Ye Huang, Mengqing Xiong, Shumei You, Bo Wang, Mancang Gu.

Understanding the dynamic features of the cell organelle ultrastructure, which is not only rich in unknown information but also sophisticated from a three-dimensional (3D) perspective, is critical for mechanistic studies. Electron microscopy (EM) offers good imaging depth and allows for the reconstruction of high-resolution image stacks to investigate the ultrastructural morphology of cellular organelles even at the nanometer scale; therefore, 3D reconstruction is gaining importance due to its incomparable advantages. Scanning electron microscopy (SEM) provides a high-throughput image acquisition technology that allows for reconstructing large structures in 3D from the same region of interest in consecutive slices. Therefore, the application of SEM in large-scale 3D reconstruction to restore the true 3D ultrastructure of organelles is becoming increasingly common. In this protocol, we suggest a combination of serial ultrathin section and 3D reconstruction techniques to study mitochondrial cristae in pancreatic cancer cells. The details of how these techniques are performed are described in this protocol in a step-by-step manner, including the osmium-thiocarbohydrazide-osmium (OTO) method, the serial ultrathin section imaging, and the visualization display.

DOI: https://doi.org/10.3791/65290
CNS Neurosci Ther. 2023 Jul 09.

Intercellular mitochondrial transfer in the brain, a new perspective for targeted treatment of central nervous system diseases.

Ziang Geng, Shu Guan, Siqi Wang, Zhongxue Yu, Tiancong Liu, Shaonan Du, Chen Zhu.

  AIM: Mitochondria is one of the important organelles involved in cell energy metabolism and regulation and also play a key regulatory role in abnormal cell processes such as cell stress, cell damage, and cell canceration. Recent studies have shown that mitochondria can be transferred between cells in different ways and participate in the occurrence and development of many central nervous system diseases. We aim to review the mechanism of mitochondrial transfer in the progress of central nervous system diseases and the possibility of targeted therapy.METHODS: The PubMed databank, the China National Knowledge Infrastructure databank, and Wanfang Data were searched to identify the experiments of intracellular mitochondrial transferrin central nervous system. The focus is on the donors, receptors, transfer pathways, and targeted drugs of mitochondrial transfer.
RESULTS: In the central nervous system, neurons, glial cells, immune cells, and tumor cells can transfer mitochondria to each other. Meanwhile, there are many types of mitochondrial transfer, including tunneling nanotubes, extracellular vesicles, receptor cell endocytosis, gap junction channels, and intercellular contact. A variety of stress signals, such as the release of damaged mitochondria, mitochondrial DNA, or other mitochondrial products and the elevation of reactive oxygen species, can trigger the transfer of mitochondria from donor cells to recipient cells. Concurrently, a variety of molecular pathways and related inhibitors can affect mitochondrial intercellular transfer.
CONCLUSION: This study reviews the phenomenon of intercellular mitochondrial transfer in the central nervous system and summarizes the corresponding transfer pathways. Finally, we propose targeted pathways and treatment methods that may be used to regulate mitochondrial transfer for the treatment of related diseases.

Keywords:  central nervous system; mitochondrial transfer; targeted therapy

DOI:  https://doi.org/10.1111/cns.14344
Front Cell Dev Biol. 2023 ;11 1212779

Regulation of mitochondrial morphology and cristae architecture by the TLR4 pathway in human skeletal muscle.

Mauricio Castro-Sepulveda, Mauro Tuñón-Suárez, Giovanni Rosales-Soto, Ronald Vargas-Foitzick, Louise Deldicque, Hermann Zbinden-Foncea.

  In skeletal muscle (SkM), a reduced mitochondrial elongate phenotype is associated with several metabolic disorders like type 2 diabetes mellitus (T2DM). However, the mechanisms contributing to this reduction in mitochondrial elongate phenotype in SkM have not been fully elucidated. It has recently been shown in a SkM cell line that toll-like receptor 4 (TLR4) contributes to the regulation of mitochondrial morphology. However, this has not been investigated in human SkM. Here we found that in human SkM biopsies, TLR4 protein correlated negatively with Opa1 (pro-mitochondrial fusion protein). Moreover, the incubation of human myotubes with LPS reduced mitochondrial size and elongation and induced abnormal mitochondrial cristae, which was prevented with the co-incubation of LPS with TAK242. Finally, T2DM myotubes were found to have reduced mitochondrial elongation and mitochondrial cristae density. Mitochondrial morphology, membrane structure, and insulin-stimulated glucose uptake were restored to healthy levels in T2DM myotubes treated with TAK242. In conclusion, mitochondrial morphology and mitochondrial cristae seem to be regulated by the TLR4 pathway in human SkM. Those mitochondrial alterations might potentially contribute to insulin resistance in the SkM of patients with T2DM.

Keywords:  Lipopolysaccharide; TAK242; mitochondrial dynamics; mitochondrial nanotunnels; skeletal muscle function; type 2 diabetes

DOI:  https://doi.org/10.3389/fcell.2023.1212779
Life Sci Alliance. 2023 Sep;pii: e202302149. [Epub ahead of print]6(9):

The pyruvate dehydrogenase complex regulates mitophagic trafficking and protein phosphorylation.

Panagiota Kolitsida, Vladimir Nolic, Jianwen Zhou, Michael Stumpe, Natalie M Niemi, Jörn Dengjel, Hagai Abeliovich.

The mitophagic degradation of mitochondrial matrix proteins in Saccharomyces cerevisiae was previously shown to be selective, reflecting a pre-engulfment sorting step within the mitochondrial network. This selectivity is regulated through phosphorylation of mitochondrial matrix proteins by the matrix kinases Pkp1 and Pkp2, which in turn appear to be regulated by the phosphatase Aup1/Ptc6. However, these same proteins also regulate the phosphorylation status and catalytic activity of the yeast pyruvate dehydrogenase complex, which is critical for mitochondrial metabolism. To understand the relationship between these two functions, we evaluated the role of the pyruvate dehydrogenase complex in mitophagic selectivity. Surprisingly, we identified a novel function of the complex in regulating mitophagic selectivity, which is independent of its enzymatic activity. Our data support a model in which the pyruvate dehydrogenase complex directly regulates the activity of its associated kinases and phosphatases. This regulatory interaction then determines the phosphorylation state of mitochondrial matrix proteins and their mitophagic fates.

DOI: https://doi.org/10.26508/lsa.202302149
Mitochondrion. 2023 Jul 12. pii: S1567-7249(23)00066-1. [Epub ahead of print]

Mitochondrial Dysfunction and Skeletal Muscle Atrophy: Causes, Mechanisms, and Treatment Strategies.

Gokhan Burcin Kubat, Esmaa Bouhamida, Oner Ulger, Ibrahim Turkel, Gaia Pedriali, Daniela Ramaccini, Ozgur Ekinci, Berkay Ozerklig, Ozbeyen Atalay, Simone Patergnani, Beyza Nur Sahin, Giampaolo Morciano, Meltem Tuncer, Elena Tremoli, Paolo Pinton.

  Skeletal muscle, which accounts for approximately 40% of total body weight, is one of the most dynamic and plastic tissues in the human body and plays a vital role in movement, posture and force production. More than just a component of the locomotor system, skeletal muscle functions as an endocrine organ capable of producing and secreting hundreds of bioactive molecules. Therefore, maintaining healthy skeletal muscles is crucial for supporting overall body health. Various pathological conditions, such as prolonged immobilization, cachexia, aging, drug-induced toxicity, and cardiovascular diseases (CVDs), can disrupt the balance between muscle protein synthesis and degradation, leading to skeletal muscle atrophy. Mitochondrial dysfunction is a major contributing mechanism to skeletal muscle atrophy, as it plays crucial roles in various biological processes, including energy production, metabolic flexibility, maintenance of redox homeostasis, and regulation of apoptosis. In this review, we critically examine recent knowledge regarding the causes of muscle atrophy (disuse, cachexia, aging, etc.) and its contribution to CVDs. Additionally, we highlight the mitochondrial signaling pathways involvement to skeletal muscle atrophy, such as the ubiquitin-proteasome system, autophagy and mitophagy, mitochondrial fission-fusion, and mitochondrial biogenesis. Furthermore, we discuss current strategies, including exercise, mitochondria-targeted antioxidants, in vivo transfection of PGC-1α, and the potential use of mitochondrial transplantation as a possible therapeutic approach.

Keywords:  Skeletal muscle atrophy; cardiovascular diseases; exercise; mitochondria; mitochondrial transplantation

DOI:  https://doi.org/10.1016/j.mito.2023.07.003