bims-mikwok 2024-05-05 papers

bims-mikwok

Biomed News

on Mitochondrial quality control

Issue of 2024‒05‒05
24 papers selected by
Gavin McStay, Liverpool John Moores University

A dynamin superfamily-like pseudoenzyme coordinates with MICOS to promote cristae architecture.
Mitochondrial transfer mediates endothelial cell engraftment through mitophagy.
PARKIN is not required to sustain OXPHOS function in adult mammalian tissues.
Mitochondrial dynamics, quality control and mtDNA in Alcohol-associated liver disease and liver cancer.
Mitochondrial stress response and myogenic differentiation.
Socialized mitochondria: mitonuclear crosstalk in stress.
Mitochondrial dynamics: updates and perspectives.
Follistatin-like protein 1 attenuates doxorubicin-induced cardiomyopathy by inhibiting MsrB2-mediated mitophagy.
The crosstalk between mitochondrial quality control and metal-dependent cell death.
[Pathogenesis of myelodysplastic syndromes by excessive mitochondrial fragmentation].
Tobacco toxins trigger bone marrow mesenchymal stem cells aging by inhibiting mitophagy.
Predicting mitophagy-related genes and unveiling liver endothelial cell heterogeneity in hepatic ischemia-reperfusion injury.
Mitochondrially-associated actin waves maintain organelle homeostasis and equitable inheritance.
QiDongNing induces lung cancer cell apoptosis via triggering P53/DRP1-mediated mitochondrial fission.
The mechanism of mitochondrial autophagy regulating Clathrin-mediated endocytosis in epilepsy.
Quantitative Assessment of Mitochondrial Morphology and Electrophysiological Function in the Diabetic Heart.
Small-molecule Molephantin induces apoptosis and mitophagy flux blockage through ROS production in glioblastoma.
Pharmacological mechanism of natural antidepressants: The role of mitochondrial quality control.
TROP2 promotes PINK1-mediated mitophagy and apoptosis to accelerate the progression of senile chronic obstructive pulmonary disease by up-regulating DRP1 expression.
SIRT1 regulates mitochondrial fission to alleviate high altitude hypoxia inducedcardiac dysfunction in rats via the PGC-1α-DRP1/FIS1/MFF pathway.
BMAL1 alleviates myocardial damage in sepsis by activating SIRT1 signaling and promoting mitochondrial autophagy.
Molecular crosstalk and putative mechanisms underlying mitochondrial quality control: The hidden link with methylmercury-induced cognitive impairment.
Asiatic Acid Alleviates Lipopolysaccharide-Induced Acute Myocardial Injury by Promoting Mitophagy and Regulating Mitochondrial Dynamics in Broilers.
A Role of ROS-dependent Defects in Mitochondrial Dynamic and Autophagy in Carbon Black Nanoparticle-mediated Myocardial Cell Damage.

Curr Biol. 2024 Apr 24. pii: S0960-9822(24)00468-8. [Epub ahead of print]

A dynamin superfamily-like pseudoenzyme coordinates with MICOS to promote cristae architecture.

Abhishek Kumar, Mehmet Oguz Gok, Kailey N Nguyen, Olivia M Connor, Michael L Reese, Jeremy G Wideman, Sergio A Muñoz-Gómez, Jonathan R Friedman.

  Mitochondrial cristae architecture is crucial for optimal respiratory function of the organelle. Cristae shape is maintained in part by the mitochondrial contact site and cristae organizing system (MICOS) complex. While MICOS is required for normal cristae morphology, the precise mechanistic role of each of the seven human MICOS subunits, and how the complex coordinates with other cristae-shaping factors, has not been fully determined. Here, we examine the MICOS complex in Schizosaccharomyces pombe, a minimal model whose genome only encodes for four core subunits. Using an unbiased proteomics approach, we identify a poorly characterized inner mitochondrial membrane protein that interacts with MICOS and is required to maintain cristae morphology, which we name Mmc1. We demonstrate that Mmc1 works in concert with MICOS to promote normal mitochondrial morphology and respiratory function. Mmc1 is a distant relative of the dynamin superfamily of proteins (DSPs), GTPases, which are well established to shape and remodel membranes. Similar to DSPs, Mmc1 self-associates and forms high-molecular-weight assemblies. Interestingly, however, Mmc1 is a pseudoenzyme that lacks key residues required for GTP binding and hydrolysis, suggesting that it does not dynamically remodel membranes. These data are consistent with the model that Mmc1 stabilizes cristae architecture by acting as a scaffold to support cristae ultrastructure on the matrix side of the inner membrane. Our study reveals a new class of proteins that evolved early in fungal phylogeny and is required for the maintenance of cristae architecture. This highlights the possibility that functionally analogous proteins work with MICOS to establish cristae morphology in metazoans.

Keywords:  MICOS; cristae; dynamin; fission yeast; membrane remodeling; mitochondria; pseudoenzyme

DOI:  https://doi.org/10.1016/j.cub.2024.04.028
Nature. 2024 May 01.

Mitochondrial transfer mediates endothelial cell engraftment through mitophagy.

Ruei-Zeng Lin, Gwang-Bum Im, Allen Chilun Luo, Yonglin Zhu, Xuechong Hong, Joseph Neumeyer, Hong-Wen Tang, Norbert Perrimon, Juan M Melero-Martin.

Ischaemic diseases such as critical limb ischaemia and myocardial infarction affect millions of people worldwide1. Transplanting endothelial cells (ECs) is a promising therapy in vascular medicine, but engrafting ECs typically necessitates co-transplanting perivascular supporting cells such as mesenchymal stromal cells (MSCs), which makes clinical implementation complicated2,3. The mechanisms that enable MSCs to facilitate EC engraftment remain elusive. Here we show that, under cellular stress, MSCs transfer mitochondria to ECs through tunnelling nanotubes, and that blocking this transfer impairs EC engraftment. We devised a strategy to artificially transplant mitochondria, transiently enhancing EC bioenergetics and enabling them to form functional vessels in ischaemic tissues without the support of MSCs. Notably, exogenous mitochondria did not integrate into the endogenous EC mitochondrial pool, but triggered mitophagy after internalization. Transplanted mitochondria co-localized with autophagosomes, and ablation of the PINK1-Parkin pathway negated the enhanced engraftment ability of ECs. Our findings reveal a mechanism that underlies the effects of mitochondrial transfer between mesenchymal and endothelial cells, and offer potential for a new approach for vascular cell therapy.

DOI: https://doi.org/10.1038/s41586-024-07340-0
NPJ Parkinsons Dis. 2024 Apr 29. 10(1): 93

PARKIN is not required to sustain OXPHOS function in adult mammalian tissues.

Roberta Filograna, Jule Gerlach, Hae-Na Choi, Giovanni Rigoni, Michela Barbaro, Mikael Oscarson, Seungmin Lee, Katarina Tiklova, Markus Ringnér, Camilla Koolmeister, Rolf Wibom, Sara Riggare, Inger Nennesmo, Thomas Perlmann, Anna Wredenberg, Anna Wedell, Elisa Motori, Per Svenningsson, Nils-Göran Larsson.

Loss-of-function variants in the PRKN gene encoding the ubiquitin E3 ligase PARKIN cause autosomal recessive early-onset Parkinson's disease (PD). Extensive in vitro and in vivo studies have reported that PARKIN is involved in multiple pathways of mitochondrial quality control, including mitochondrial degradation and biogenesis. However, these findings are surrounded by substantial controversy due to conflicting experimental data. In addition, the existing PARKIN-deficient mouse models have failed to faithfully recapitulate PD phenotypes. Therefore, we have investigated the mitochondrial role of PARKIN during ageing and in response to stress by employing a series of conditional Parkin knockout mice. We report that PARKIN loss does not affect oxidative phosphorylation (OXPHOS) capacity and mitochondrial DNA (mtDNA) levels in the brain, heart, and skeletal muscle of aged mice. We also demonstrate that PARKIN deficiency does not exacerbate the brain defects and the pro-inflammatory phenotype observed in mice carrying high levels of mtDNA mutations. To rule out compensatory mechanisms activated during embryonic development of Parkin-deficient mice, we generated a mouse model where loss of PARKIN was induced in adult dopaminergic (DA) neurons. Surprisingly, also these mice did not show motor impairment or neurodegeneration, and no major transcriptional changes were found in isolated midbrain DA neurons. Finally, we report a patient with compound heterozygous PRKN pathogenic variants that lacks PARKIN and has developed PD. The PARKIN deficiency did not impair OXPHOS activities or induce mitochondrial pathology in skeletal muscle from the patient. Altogether, our results argue that PARKIN is dispensable for OXPHOS function in adult mammalian tissues.

DOI: https://doi.org/10.1038/s41531-024-00707-0
Hepatology. 2024 Apr 29.

Mitochondrial dynamics, quality control and mtDNA in Alcohol-associated liver disease and liver cancer.

Xiaowen Ma, Mengwei Niu, Hong-Min Ni, Wen-Xing Ding.

Mitochondria are intracellular organelles responsible for energy production, glucose and lipid metabolism, cell death, cell proliferation, and innate immune response. Mitochondria are highly dynamic organelles that constantly undergo fission, fusion, and intracellular trafficking, as well as degradation and biogenesis. Mitochondrial dysfunction has been implicated in a variety of chronic liver diseases including alcohol-associated liver disease (ALD), metabolic dysfunction-associated steatohepatitis (MASH), and hepatocellular carcinoma (HCC). In this review, we provide a detailed overview of mitochondrial dynamics, mitophagy, and mtDNA-mediated innate immune response, and how dysregulation of these mitochondrial processes affects the pathogenesis of ALD and HCC. Mitochondrial dynamics and mtDNA-mediated innate immune response may thereby represent an attractive therapeutic target for ameliorating ALD and alcohol-associated HCC.

DOI: https://doi.org/10.1097/HEP.0000000000000910
Front Cell Dev Biol. 2024 ;12 1381417

Mitochondrial stress response and myogenic differentiation.

Fu Lin, Liankun Sun, Yu Zhang, Weinan Gao, Zihan Chen, Yanan Liu, Kai Tian, Xuyu Han, Ruize Liu, Yang Li, Luyan Shen.

  Regeneration and repair are prerequisites for maintaining effective function of skeletal muscle under high energy demands, and myogenic differentiation is one of the key steps in the regeneration and repair process. A striking feature of the process of myogenic differentiation is the alteration of mitochondria in number and function. Mitochondrial dysfunction can activate a number of transcriptional, translational and post-translational programmes and pathways to maintain cellular homeostasis under different types and degrees of stress, either through its own signaling or through constant signaling interactions with the nucleus and cytoplasm, a process known as the mitochondrial stress responses (MSRs). It is now believed that mitochondrial dysfunction is closely associated with a variety of muscle diseases caused by reduced levels of myogenic differentiation, suggesting the possibility that MSRs are involved in messaging during myogenic differentiation. Also, MSRs may be involved in myogenesis by promoting bioenergetic remodeling and assisting myoblast survival during myogenic differentiation. In this review, we will take MSRs as an entry point to explore its concrete regulatory mechanisms during myogenic differentiation, with a perspective to provide a theoretical basis for the treatment and repair of related muscle diseases.

Keywords:  ISR; UPRmt; apoptosis; mitochondrial biogenesis; mitochondrial fusion and fission; mitophagy; myogenic differentiation

DOI:  https://doi.org/10.3389/fcell.2024.1381417
Exp Mol Med. 2024 May 01.

Socialized mitochondria: mitonuclear crosstalk in stress.

Kyung Hwa Kim, Cho Bi Lee.

Traditionally, mitochondria are considered sites of energy production. However, recent studies have suggested that mitochondria are signaling organelles that are involved in intracellular interactions with other organelles. Remarkably, stressed mitochondria appear to induce a beneficial response that restores mitochondrial function and cellular homeostasis. These mitochondrial stress-centered signaling pathways have been rapidly elucidated in multiple organisms. In this review, we examine current perspectives on how mitochondria communicate with the rest of the cell, highlighting mitochondria-to-nucleus (mitonuclear) communication under various stresses. Our understanding of mitochondria as signaling organelles may provide new insights into disease susceptibility and lifespan extension.

DOI: https://doi.org/10.1038/s12276-024-01211-4
Sci Rep. 2024 04 30. 14(1): 9936

Mitochondrial dynamics: updates and perspectives.

Kezhong Zhang, Ježek Petr.

DOI: https://doi.org/10.1038/s41598-024-59998-1
Mol Cell Biochem. 2024 May 02.

Follistatin-like protein 1 attenuates doxorubicin-induced cardiomyopathy by inhibiting MsrB2-mediated mitophagy.

Linhe Lu, Yalan Shao, Nisha Wang, Xiang Xiong, Mengen Zhai, Jiayou Tang, Yang Liu, Jian Yang, Lifang Yang.

  Doxorubicin (DOX) is a potent chemotherapeutic drug; however, its clinical use is limited due to its cardiotoxicity. Mitochondrial dysfunction plays a vital role in the pathogenesis of DOX-induced cardiomyopathy. Follistatin-like protein 1 (FSTL1) is a potent cardiokine that protects the heart from diverse cardiac diseases, such as myocardial infarction, cardiac ischemia/reperfusion injury, and heart failure. However, its role in DOX-induced cardiomyopathy is unclear. Therefore, the present study investigated whether administering recombinant FSTL1 could mitigate DOX-induced cardiomyopathy and clarified the underlying molecular mechanisms. FSTL1 treatment attenuated DOX-induced cardiac dysfunction, cardiac fibrosis, and cellular apoptosis by inhibiting excess mitochondrial matrix protein methionine sulfoxide reductase B2 (MsrB2)-mediated mitophagy. Furthermore, FSTL1 administration reduced the expression of apoptotic proteins, including MsrB2, Bax, caspase 3, mitochondrial Parkin, and LC3-II, increased myocardial ATP content, and decreased cardiac malondialdehyde levels, thus protecting mitochondrial function against DOX-induced cardiac injury. Furthermore, FSTL1 treatment protected the contractile properties of adult cardiomyocytes against DOX-induced injury in vitro. Furthermore, carbonyl cyanide m-chlorophenylhydrazone, a mitophagy inducer, impaired the protective effects of FSTL1 in DOX-treated H9c2 cardiomyocytes. In conclusion, these results show that FSTL1 is a novel therapeutic agent against DOX-induced cardiotoxicity that improves mitochondrial function and decreases mitophagy.

Keywords:  Cardiotoxicity; Doxorubicin; FSTL1; Mitophagy; MsrB2

DOI:  https://doi.org/10.1007/s11010-024-04955-9
Cell Death Dis. 2024 Apr 27. 15(4): 299

The crosstalk between mitochondrial quality control and metal-dependent cell death.

Qi-Yuan Zhou, Chao Ren, Jing-Yan Li, Lu Wang, Yu Duan, Ren-Qi Yao, Ying-Ping Tian, Yong-Ming Yao.

Mitochondria are the centers of energy and material metabolism, and they also serve as the storage and dispatch hubs of metal ions. Damage to mitochondrial structure and function can cause abnormal levels and distribution of metal ions, leading to cell dysfunction and even death. For a long time, mitochondrial quality control pathways such as mitochondrial dynamics and mitophagy have been considered to inhibit metal-induced cell death. However, with the discovery of new metal-dependent cell death including ferroptosis and cuproptosis, increasing evidence shows that there is a complex relationship between mitochondrial quality control and metal-dependent cell death. This article reviews the latest research results and mechanisms of crosstalk between mitochondrial quality control and metal-dependent cell death in recent years, as well as their involvement in neurodegenerative diseases, tumors and other diseases, in order to provide new ideas for the research and treatment of related diseases.

DOI: https://doi.org/10.1038/s41419-024-06691-w
Rinsho Ketsueki. 2024 ;65(4): 249-254

[Pathogenesis of myelodysplastic syndromes by excessive mitochondrial fragmentation].

Yoshihiro Hayashi.

  Myelodysplastic syndromes (MDS) are a group of heterogenous hematopoietic stem cell (HSC) malignancies characterized by ineffective hematopoiesis in which clonal progenitor expansion occurs alongside impaired myelopoiesis. Inflammatory signaling activation due to dysregulated innate immunity is also a hallmark of MDS pathogenesis. We recently established a useful preclinical tool that recapitulates bona fide MDS phenotypes and gene expression profiles based on previously unreported co-mutations discovered during our clinical surveillance of mutations in patients with MDS. Notably, we focused unbiased transcriptome analysis on determining the distinct underlying mediators of MDS etiology, and identified excessive mitochondrial fission-mediated fragmentation in mutant HSCs and progenitors (HSC/Ps). We confirmed excessive mitochondrial fragmentation in HSC/Ps obtained from patients with MDS regardless of the mutational profile. Importantly, in vivo pharmacological inhibition of mitochondrial fission significantly attenuated inflammatory signaling activation, dysplasia formation and ineffective hematopoiesis phenotype, and prolonged survival of MDS mice, suggesting that excessive mitochondrial fragmentation could be a fundamental trigger of MDS pathogenesis. These findings provide new insights into the mechanistic basis of ineffective hematopoiesis, and a clue for targeting bone marrow failure caused by ineffective hematopoiesis in MDS.

Keywords:  Ineffective hematopoiesis; Innate immunity; Mitochondrial fragmentation; Myelodysplastic syndromes

DOI:  https://doi.org/10.11406/rinketsu.65.249
Ecotoxicol Environ Saf. 2024 Apr 26. pii: S0147-6513(24)00468-8. [Epub ahead of print]277 116392

Tobacco toxins trigger bone marrow mesenchymal stem cells aging by inhibiting mitophagy.

Kai Xiang, Mingxing Ren, Fengyi Liu, Yuzhou Li, Ping He, Xuerui Gong, Tao Chen, Tianli Wu, Ziyu Huang, Hui She, Kehao Liu, Zheng Jing, Sheng Yang.

  Smoking disrupts bone homeostasis and serves as an independent risk factor for the development and progression of osteoporosis. Tobacco toxins inhibit the proliferation and osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs), promote BMSCs aging and exhaustion, but the specific mechanisms are not yet fully understood. Herein, we successfully established a smoking-related osteoporosis (SROP) model in rats and mice through intraperitoneal injection of cigarette smoke extract (CSE), which significantly reduced bone density and induced aging and inhibited osteogenic differentiation of BMSCs both in vivo and in vitro. Bioinformatics analysis and in vitro experiments confirmed that CSE disrupts mitochondrial homeostasis through oxidative stress and inhibition of mitophagy. Furthermore, we discovered that CSE induced BMSCs aging by upregulating phosphorylated AKT, which in turn inhibited the expression of FOXO3a and the Pink1/Parkin pathway, leading to the suppression of mitophagy and the accumulation of damaged mitochondria. MitoQ, a mitochondrial-targeted antioxidant and mitophagy agonist, was effective in reducing CSE-induced mitochondrial oxidative stress, promoting mitophagy, significantly downregulating the expression of aging markers in BMSCs, restoring osteogenic differentiation, and alleviating bone loss and autophagy levels in CSE-exposed mice. In summary, our results suggest that BMSCs aging caused by the inhibition of mitophagy through the AKT/FOXO3a/Pink1/Parkin axis is a key mechanism in smoking-related osteoporosis.

Keywords:  Aging; Bone marrow mesenchymal stem cells; Cigarette smoke extract; Mitophagy; Osteoporosis

DOI:  https://doi.org/10.1016/j.ecoenv.2024.116392
Front Immunol. 2024 ;15 1370647

Predicting mitophagy-related genes and unveiling liver endothelial cell heterogeneity in hepatic ischemia-reperfusion injury.

Bochen Pan, Xuan Ma, Shihuan Zhou, Xiaoling Cheng, Jianwei Fang, Qiuyun Yi, Yuke Li, Song Li, Jiawei Yang.

  Background: Hepatic Ischemia-Reperfusion Injury (HIRI) is a major complication in liver transplants and surgeries, significantly affecting postoperative outcomes. The role of mitophagy, essential for removing dysfunctional mitochondria and maintaining cellular balance, remains unclear in HIRI.Methods: To unravel the role of mitophagy-related genes (MRGs) in HIRI, we assembled a comprehensive dataset comprising 44 HIRI samples alongside 44 normal control samples from the Gene Expression Omnibus (GEO) database for this analysis. Using Random Forests and Support Vector Machines - Recursive Feature Elimination (SVM-RFE), we pinpointed eight pivotal genes and developed a logistic regression model based on these findings. Further, we employed consensus cluster analysis for classifying HIRI patients according to their MRG expression profiles and conducted weighted gene co-expression network analysis (WGCNA) to identify clusters of genes that exhibit high correlation within different modules. Additionally, we conducted single-cell RNA sequencing data analysis to explore insights into the behavior of MRGs within the HIRI.
Results: We identified eight key genes (FUNDC1, VDAC1, MFN2, PINK1, CSNK2A2, ULK1, UBC, MAP1LC3B) with distinct expressions between HIRI and controls, confirmed by PCR validation. Our diagnostic model, based on these genes, accurately predicted HIRI outcomes. Analysis revealed a strong positive correlation of these genes with monocytic lineage and a negative correlation with B and T cells. HIRI patients were divided into three subclusters based on MRG profiles, with WGCNA uncovering highly correlated gene modules. Single-cell analysis identified two types of endothelial cells with different MRG scores, indicating their varied roles in HIRI.
Conclusions: Our study highlights the critical role of MRGs in HIRI and the heterogeneity of endothelial cells. We identified the macrophage migration inhibitory factor (MIF) and cGAS-STING (GAS) pathways as regulators of mitophagy's impact on HIRI. These findings advance our understanding of mitophagy in HIRI and set the stage for future research and therapeutic developments.

Keywords:  bioinformatic analysis; endothelial cells; hepatic ischemia reperfusion injury; immune infiltration; mitophagy

DOI:  https://doi.org/10.3389/fimmu.2024.1370647
Curr Opin Cell Biol. 2024 Apr 30. pii: S0955-0674(24)00043-7. [Epub ahead of print]88 102364

Mitochondrially-associated actin waves maintain organelle homeostasis and equitable inheritance.

Stephen M Coscia, Andrew S Moore, Yvette C Wong, Erika L F Holzbaur.

First identified in dividing cells as revolving clusters of actin filaments, these are now understood as mitochondrially-associated actin waves that are active throughout the cell cycle. These waves are formed from the polymerization of actin onto a subset of mitochondria. Within minutes, this F-actin depolymerizes while newly formed actin filaments assemble onto neighboring mitochondria. In interphase, actin waves locally fragment the mitochondrial network, enhancing mitochondrial content mixing to maintain organelle homeostasis. In dividing cells actin waves spatially mix mitochondria in the mother cell to ensure equitable partitioning of these organelles between daughter cells. Progress has been made in understanding the consequences of actin cycling as well as the underlying molecular mechanisms, but many questions remain, and here we review these elements. Also, we draw parallels between mitochondrially-associated actin cycling and cortical actin waves. These dynamic systems highlight the remarkable plasticity of the actin cytoskeleton.

DOI: https://doi.org/10.1016/j.ceb.2024.102364
J Cell Mol Med. 2024 May;28(9): e18353

QiDongNing induces lung cancer cell apoptosis via triggering P53/DRP1-mediated mitochondrial fission.

Rongzhen Ding, Yichao Wang, Ling Xu, Shuliu Sang, Guanjin Wu, Wenxiao Yang, Yilu Zhang, Chengyan Wang, Ao Qi, Haiping Xie, Yi Liu, Aiguo Dai, Lijing Jiao.

  Non-small-cell lung cancer (NSCLC) is a major cause of worldwide cancer death, posing a challenge for effective treatment. Our previous findings showed that Chinese herbal medicine (CHM) QiDongNing (QDN) could upregulate the expression of p53 and trigger cell apoptosis in NSCLC. Here, our objective was to investigate the mechanisms of QDN-induced apoptosis enhancement. We chose A549 and NCI-H460 cells for validation in vitro, and LLC cells were applied to form a subcutaneous transplantation tumour model for validation in more depth. Our findings indicated that QDN inhibited multiple biological behaviours, including cell proliferation, cloning, migration, invasion and induction of apoptosis. We further discovered that QDN increased the pro-apoptotic BAX while inhibiting the anti-apoptotic Bcl2. QDN therapy led to a decline in adenosine triphosphate (ATP) and a rise in reactive oxygen species (ROS). Furthermore, QDN elevated the levels of the tumour suppressor p53 and the mitochondrial division factor DRP1 and FIS1, and decreased the mitochondrial fusion molecules MFN1, MFN2, and OPA1. The results were further verified by rescue experiments, the p53 inhibitor Pifithrin-α and the mitochondrial division inhibitor Mdivi1 partially inhibited QDN-induced apoptosis and mitochondrial dysfunction, whereas overexpression of p53 rather increased the efficacy of the therapy. Additionally, QDN inhibited tumour growth with acceptable safety in vivo. In conclusion, QDN induced apoptosis via triggering p53/DRP1-mediated mitochondrial fission in NSCLC cells.

Keywords:  QiDongNing; apoptosis; lung cancer; mitochondrial fission; p53

DOI:  https://doi.org/10.1111/jcmm.18353
Epilepsia Open. 2024 May 03.

The mechanism of mitochondrial autophagy regulating Clathrin-mediated endocytosis in epilepsy.

Xuejiao Zhou, Yu Yang, Zhenzhen Tai, Haiqing Zhang, Juan Yang, Zhong Luo, Zucai Xu.

  OBJECTIVE: The objective of this study is to determine whether inhibition of mitophagy affects seizures through Clathrin-mediated endocytosis (CME).METHODS: Pentylenetetrazol (PTZ) was intraperitoneally injected daily to establish a chronic PTZ-kindled seizure. The Western blot (WB) was used to compare the differences in Parkin protein expression between the epilepsy group and the control group. Immunofluorescence was used to detect the expression of MitoTracker and LysoTracker. Transferrin-Alexa488 (Tf-A488) was injected into the hippocampus of mice. We evaluated the effect of 3-methyladenine (3-MA) on epilepsy behavior through observation in PTZ-kindled models.
RESULTS: The methylated derivative of adenine, known as 3-MA, has been extensively utilized in the field of autophagy research. The transferrin protein is internalized from the extracellular environment into the intracellular space via the CME pathway. Tf-A488 uses a fluorescent marker to track CME. Western blot showed that the expression of Parkin was significantly increased in the PTZ-kindled model (p < 0.05), while 3-MA could reduce the expression (p < 0.05). The fluorescence uptake of MitoTracker and LysoTracker was increased in the primary cultured neurons induced by magnesium-free extracellular fluid (p < 0.05); the fluorescence uptake of Tf-A488 was significantly decreased in the 3-MA group compared with the control group (p < 0.05). Following hippocampal injection of Tf-A488, both the epilepsy group and the 3-MA group exhibited decreased fluorescence uptake, with a more pronounced effect observed in the 3-MA group. Inhibition of mitophagy by 3-MA from day 3 to day 9 progressively exacerbated seizure severity and shortened latency.
SIGNIFICANCE: It is speculated that the aggravation of seizures by 3-MA may be related to the failure to remove damaged mitochondria in time and effectively after inhibiting mitochondrial autophagy, affecting the vesicle endocytosis function of CME and increasing the susceptibility to epilepsy.
SUMMARY: Abnormal mitophagy was observed in a chronic pentylenetetrazol-induced seizure model and a Mg2+-free-induced spontaneous recurrent epileptiform discharge model. A fluorescent transferrin marker was utilized to track clathrin-mediated endocytosis. Using an autophagy inhibitor (3-methyladenine) on primary cultured neurons, we discovered that inhibition of autophagy led to a reduction in fluorescent transferrin uptake, while impairing clathrin-mediated endocytosis function mediated by mitophagy. Finally, we examined the effects of 3-methyladenine in an animal model of seizures showing that it exacerbated seizure severity. Ultimately, this study provides insights into potential mechanisms through which mitophagy regulates clathrin-mediated endocytosis in epilepsy.

Keywords:  3‐methyladenine; Clathrin‐mediated‐endocytosis; epilepsy; mitochondrial autophagy

DOI:  https://doi.org/10.1002/epi4.12945
Methods Mol Biol. 2024 ;2803 75-86

Quantitative Assessment of Mitochondrial Morphology and Electrophysiological Function in the Diabetic Heart.

Marine Cacheux, Michael Rudokas, Andrew Tieu, Joanna Abi Rizk, Madelyn E Hummel, Fadi G Akar.

  Mitochondria within a cardiomyocyte form a highly dynamic network that undergoes fusion and fission events in response to acute and chronic stressors, such as hyperglycemia and diabetes mellitus. Changes in mitochondrial architecture and morphology not only reflect their capacity for oxidative phosphorylation and ATP synthesis but also impact their subcellular localization and interaction with other organelles. The role of these ultrastructural abnormalities in modulating electrophysiological properties and excitation-contraction coupling remains largely unknown and warrants direct investigation considering the growing appreciation of the functional and structural coupling between the mitochondrial network, the calcium cycling machinery, and sarcolemmal ion channels in the cardiac myocyte. In this Methods in Molecular Biology chapter, we provide a protocol that allows for a quantitative assessment of mitochondrial shape and morphology in control and diabetic hearts that had undergone detailed electrophysiological measurements using high resolution optical action potential (AP) mapping.

Keywords:  Diabetes Mellitus; Electron Microscopy; Mitochondria; Myocardium; Optical Mapping

DOI:  https://doi.org/10.1007/978-1-0716-3846-0_6
Cancer Lett. 2024 Apr 30. pii: S0304-3835(24)00320-3. [Epub ahead of print] 216927

Small-molecule Molephantin induces apoptosis and mitophagy flux blockage through ROS production in glioblastoma.

Zhipeng Ling, Junping Pan, Zhongfei Zhang, Guisi Chen, Jiayuan Geng, Qiang Lin, Tao Zhang, Shuqin Cao, Cheng Chen, Jinrong Lin, Hongyao Yuan, Weilong Ding, Fei Xiao, Xinke Xu, Fangcheng Li, Guocai Wang, Yubo Zhang, Junliang Li.

  Glioblastoma (GBM), one of the most malignant brain tumors in the world, has limited treatment options and a dismal survival rate. Effective and safe disease-modifying drugs for glioblastoma are urgently needed. Here, we identified a small molecule, Molephantin (EM-5), effectively penetrated the blood-brain barrier (BBB) and demonstrated notable antitumor effects against GBM with good safety profiles both in vitro and in vivo. Mechanistically, EM-5 not only inhibits the proliferation and invasion of GBM cells but also induces cell apoptosis through the reactive oxygen species (ROS)-mediated PI3K/Akt/mTOR pathway. Furthermore, EM-5 causes mitochondrial dysfunction and blocks mitophagy flux by impeding the fusion of mitophagosomes with lysosomes. It is noteworthy that EM-5 does not interfere with the initiation of autophagosome formation or lysosomal function. Additionally, the mitophagy flux blockage caused by EM-5 was driven by the accumulation of intracellular ROS. In vivo, EM-5 exhibited significant efficacy in suppressing tumor growth in a xenograft model. Collectively, our findings not only identified EM-5 as a promising, effective, and safe lead compound for treating GBM but also uncovered its underlying mechanisms from the perspective of apoptosis and mitophagy.

Keywords:  EM-5; Glioblastoma; ROS; apoptosis; mitophagy flux

DOI:  https://doi.org/10.1016/j.canlet.2024.216927
Phytomedicine. 2024 Apr 27. pii: S0944-7113(24)00328-3. [Epub ahead of print]129 155669

Pharmacological mechanism of natural antidepressants: The role of mitochondrial quality control.

Shimeng Lv, Guangheng Zhang, Yitong Lu, Xia Zhong, Yufei Huang, Yuexiang Ma, Wei Yan, Jing Teng, Sheng Wei.

  BACKGROUND: Depression is a mental illness characterized by persistent sadness and a reduced capacity for pleasure. In clinical practice, SSRIs and other medications are commonly used for therapy, despite their various side effects. Natural products present distinct advantages, including synergistic interactions among multiple components and targeting multiple pathways, suggesting their tremendous potential in depression treatment. Imbalance in mitochondrial quality control (MQC) plays a significant role in the pathology of depression, emphasizing the importance of regulating MQC as a potential intervention strategy in addressing the onset and progression of depression. However, the role and mechanism through which natural products regulate MQC in depression treatments still need to be comprehensively elucidated, particularly in clinical and preclinical settings.PURPOSE: This review was aimed to summarize the findings of recent studies and outline the pharmacological mechanisms by which natural products modulate MQC to exert antidepressant effects. Additionally, it evaluated current research limitations and proposed new strategies for future preclinical and clinical applications in the depression domain.
METHODS: To study the main pharmacological mechanisms underlying the regulation of MQC by natural products in the treatment of depression, we conducted a thorough search across databases such as PubMed, Web of Science, and ScienceDirect databases to classify and summarize the relationship between MQC and depression, as well as the regulatory mechanisms of natural products.
RESULTS: Numerous studies have shown that irregularities in the MQC system play an important role in the pathology of depression, and the regulation of the MQC system is involved in antidepressant treatments. Natural products mainly regulate the MQC system to induce antidepressant effects by alleviating oxidative stress, balancing ATP levels, promoting mitophagy, maintaining calcium homeostasis, optimizing mitochondrial dynamics, regulating mitochondrial membrane potential, and enhancing mitochondrial biogenesis.
CONCLUSIONS: We comprehensively summarized the regulation of natural products on the MQC system in antidepressants, providing a unique perspective for the application of natural products within antidepressant therapy. However, extensive efforts are imperative in clinical and preclinical investigations to delve deeper into the mechanisms underlying how antidepressant medications impact MQC, which is crucial for the development of effective antidepressant treatments.

Keywords:  Antidepressant; Depression; Mitochondrial quality control; Molecular biological functions; Natural product; Pharmacological mechanisms

DOI:  https://doi.org/10.1016/j.phymed.2024.155669
Exp Gerontol. 2024 Apr 29. pii: S0531-5565(24)00083-4. [Epub ahead of print]191 112441

TROP2 promotes PINK1-mediated mitophagy and apoptosis to accelerate the progression of senile chronic obstructive pulmonary disease by up-regulating DRP1 expression.

Yipu Zhao, Zhengjie Wu.

  Chronic obstructive pulmonary disease (COPD) is a chronic airway inflammatory disease characterised by irreversible airflow limitation. The elderly are a vulnerable population for developing COPD. With the growth of age, physiological degenerative changes occur in the thorax, bronchus, lung and vascular wall, which can lead to age-related physiological attenuation of lung function in the elderly, so the prevalence of COPD increases with age. Its pathogenesis has not yet been truly clarified. Mitophagy plays an important role in maintaining the stability of mitochondrial function and intracellular environment by scavenging damaged mitochondria. Currently, studies have shown that trophoblast antigen 2 (TROP2) expression is up-regulated in airway basal cells of patients with COPD, suggesting that TROP2 is involved in the progression of COPD. However, whether it is involved in disease progression by regulating mitochondrial function remains unclear. In this study, compared with non-smoking non-COPD patients, the expression of TROP2 in lung tissues of smoking non-COPD patients and patients with COPD increased, and TROP2 expression in patients with COPD was higher than that in smoking non-COPD patients. To further explore the role of TROP2, we stimulated BEAS-2B with cigarette smoke to construct an in vitro model. We found that TROP2 expression increased, whereas TROP2 silencing reversed the cigarette smoke extract-induced decrease in mitochondrial membrane potential, increased reactive oxygen species content, decreased adenosine triphosphate (ATP) production, increased inflammatory factor secretion and increased apoptosis. In addition, we searched online bioinformatics and screened the gene dynamin-related protein 1 (DRP1) related to mitophagy as the research object. Co-IP assay verified the binding relationship between DRP1 and TROP2. Further study found that TROP2 promoted mitophagy and apoptosis of BEAS-2B cells by up-regulating the expression of DRP1. In addition, PTEN-induced putative kinase 1 (PINK1) is a potential binding protein of DRP1, and DRP1 accelerated mitophagy and apoptosis of BEAS-2B cells by promoting the expression of PINK1. We established a COPD SD rat model by cigarette smoke exposure and LPS instillation and treated it by intraperitoneal injection of si-TROP2. The results showed that TROP2 silencing restored lung function and reduced the secretion of inflammatory factors in bronchoalveolar lavage fluid. In conclusion, TROP2 can be used as a new reference for COPD treatment.

Keywords:  Chronic obstructive pulmonary disease; DRP1; Mitophagy; PINK1; TROP2

DOI:  https://doi.org/10.1016/j.exger.2024.112441
Apoptosis. 2024 Apr 27.

SIRT1 regulates mitochondrial fission to alleviate high altitude hypoxia inducedcardiac dysfunction in rats via the PGC-1α-DRP1/FIS1/MFF pathway.

Hongbao Xu, Xiaona Song, Xiaoru Zhang, Guangrui Wang, Xiaoling Cheng, Ling Zhang, Zirou Wang, Ran Li, Chongyi Ai, Xinxing Wang, Lingling Pu, Zhaoli Chen, Weili Liu.

  High-altitude exposure has been linked to cardiac dysfunction. Silent information regulator factor 2-related enzyme 1 (sirtuin 1, SIRT1), a nicotinamide adenine dinucleotide-dependent deacetylase, plays a crucial role in regulating numerous cardiovascular diseases. However, the relationship between SIRT1 and cardiac dysfunction induced by hypobaric hypoxia (HH) remains unexplored. This study aims to assess the impact of SIRT1 on HH-induced cardiac dysfunction and delve into the underlying mechanisms, both in vivo and in vitro. In this study, we have demonstrated that exposure to HH results in cardiomyocyte injury, along with the downregulation of SIRT1 and mitochondrial dysfunction. Upregulating SIRT1 significantly inhibits mitochondrial fission, improves mitochondrial function, reduces cardiomyocyte injury, and consequently enhances cardiac function in HH-exposed rats. Additionally, HH exposure triggers aberrant expression of mitochondrial fission-regulated proteins, with a decrease in PPARγ coactivator 1 alpha (PGC-1α) and mitochondrial fission factor (MFF) and an increase in mitochondrial fission 1 (FIS1) and dynamin-related protein 1 (DRP1), all of which are mitigated by SIRT1 upregulation. Furthermore, inhibiting PGC-1α diminishes the positive effects of SIRT1 regulation on the expression of DRP1, MFF, and FIS1, as well as mitochondrial fission. These findings demonstrate that SIRT1 alleviates HHinduced cardiac dysfunction by preventing mitochondrial fission through the PGC-1α-DRP1/FIS1/MFF pathway.

Keywords:  Cardiac dysfunction; High altitude; Hypobaric hypoxia; Mitochondrial dysfunction; Mitochondrial fission; SIRT1

DOI:  https://doi.org/10.1007/s10495-024-01954-5
Int Immunopharmacol. 2024 Apr 27. pii: S1567-5769(24)00629-5. [Epub ahead of print]133 112111

BMAL1 alleviates myocardial damage in sepsis by activating SIRT1 signaling and promoting mitochondrial autophagy.

Wen Tang, Rennan Guo, Congyu Hu, Yang Yang, Danping Yang, Xiaxia Chen, Yan Liu.

  BACKGROUND: Brain and muscle arnt-like protein-1 (BMAL1) deficiency is associated with myocardial dysfunction and suppressed sirtuin 1 (SIRT1). However, whether BMAL1 promotes mitophagy via SIRT1 to alleviate myocardial injury in sepsis remains unknown.METHODS: An in vitro myocardial injury model was established using lipopolysaccharide (LPS)-treated H9C2 cells. Knockdown or overexpression of genes was performed using plasmid transfection. Gene and protein expression was assessed by qRT-PCR and Western blot, respectively. Cell proliferation was evaluated using cell counting kit-8, and cellular apoptosis and reactive oxygen species (ROS) levels were analyzed using flow cytometry. An in vivo myocardial injury model of sepsis was established by cecal ligation and puncture in rats. Myocardial function was characterized by analyzing the damage-associated proteins, inflammatory factors, ejection fraction, and fraction shortening.
RESULTS: sgBMAL1 significantly decreased BMAL1 levels and remarkably increased the sensitivity of H9C2 cells to LPS stimulation, consequently enhancing LPS-induced apoptosis, inflammation, and ROS levels. These effects were further attenuated by BMAL1 overexpression. BMAL1 knockdown inhibited the expression of SIRT1 and mitophagy-associated proteins. SIRT1 overexpression reversed the enhancement of shBMAL1 on cell proliferation and inflammation. In the rat model of sepsis, BMAL1 overexpression decreased the myocardial injury-associated proteins to recover the myocardial function and suppressed inflammatory activities by promoting mitophagy via SIRT1.
CONCLUSION: BMAL1 enhances mitophagy dependent on SIRT1, thereby alleviating myocardial injury in sepsis.

Keywords:  BMAL1; Mitophagy; Myocardial injury; SIRT1; Sepsis

DOI:  https://doi.org/10.1016/j.intimp.2024.112111
Ecotoxicol Environ Saf. 2024 Apr 27. pii: S0147-6513(24)00436-6. [Epub ahead of print]278 116360

Molecular crosstalk and putative mechanisms underlying mitochondrial quality control: The hidden link with methylmercury-induced cognitive impairment.

Yi Hu, Li Zhang, Changsong Tian, Fang Chen, Ping Li, Aihua Zhang, Wenjuan Wang.

  Methylmercury (MeHg) is a neurotoxin associated with foetal neurodevelopmental and adult cognitive deficits. Neurons are highly dependent on the tricarboxylic acid cycle and oxidative phosphorylation to produce ATP and meet their high energy demands. Therefore, mitochondrial quality control (MQC) is critical for neuronal homeostasis. While existing studies have generated a wealth of data on the toxicity of MeHg, the complex cascades and molecular pathways governing the mitochondrial network remain to be elucidated. Here, 0.6, 1.2 and 2.4 mg/kg body weight of MeHg were administered intragastrically to pregnant Sprague Dawley rats to model maternal MeHg exposure. The results of the in vivo study revealed that MeHg-treated rats tended to perform more directionless repetitive strategies in the Morris Water Maze and fewer target-orientation strategies than control offspring. Moreover, pathological injury and synaptic toxicity were observed in the hippocampus. Transmission electron microscopy (TEM) demonstrated that the autophagosomes encapsulated damaged mitochondria, while showing a typical mitochondrial fission phenotype, which was supported by the activation of PINK1-dependent key regulators of mitophagy. Moreover, there was upregulation of DRP1 and FIS1. Additionally, MeHg compensation promoted mitochondrial biogenesis, as evidenced by the activation of the mitochondrial PGC1-α-NRF1-TFAM signalling pathway. Notably, SIRT3/AMPK was activated by MeHg, and the expression and activity of p-AMPK, p-LKB1 and SIRT3 were consistently coordinated. Collectively, these findings provide new insights into the potential molecular mechanisms regulating MeHg-induced cognitive deficits through SIRT3/AMPK MQC network coordination.

Keywords:  Heavy metal; Methylmercury; Mitochondria; Neurodevelopment

DOI:  https://doi.org/10.1016/j.ecoenv.2024.116360
Avian Dis. 2024 Mar;68(1): 25-32

Asiatic Acid Alleviates Lipopolysaccharide-Induced Acute Myocardial Injury by Promoting Mitophagy and Regulating Mitochondrial Dynamics in Broilers.

Xiaoyue Pang, Wenyue Qiu, Xinting Zhang, Jianjia Huang, Shuilian Zhou, Rongmei Wang, Zhaoxin Tang, Rongsheng Su.

  Acute myocardial injury (AMI) induced by lipopolysaccharide (LPS) can cause cardiovascular dysfunction and lead to death in poultry. Traditional antibiotic therapy has been found to have many limitations and negative effects. Asiatic acid (AA) is a naturally occurring pentacyclic triterpenoid that is extracted from Centella asiatica and has anti-inflammatory, antioxidant, and anticancer pharmacological properties. Previously, we studied the effect of AA on LPS-induced liver and kidney injury; however, the impact of AA on LPS-induced AMI remained unclear. Sixty 1-day-old broilers were randomly divided into control group, LPS group, LPS + AA 15 mg/kg group, LPS + AA 30 mg/kg group, LPS + AA 60 mg/kg group, and control + AA 60 mg/kg group. The histopathology of cardiac tissues was detected by hematoxylin and eosin (H&E) staining. The mRNA and protein expressions related to mitochondrial dynamics and mitophagy were detected by quantitative real-time PCR, western blot, immunofluorescence, and immunohistochemistry. Disorganized myocardial cells and fractured myocardial fibers were found in the LPS group, and obvious red-blood-cell filling can be seen in the gaps between the myocardial fibers in the low-dose AA group. Nevertheless, the medium and high dose of AA obviously attenuated these changes. Our results showed that AA significantly restored the mRNA and protein expressions related to mitochondrial dynamic through further promoting mitophagy. This study revealed the effect of AA on LPS-induced AMI in broilers. Mechanically, AA regulated mitochondrial dynamic homeostasis and further promoted mitophagy. These novel findings indicate that AA may be a potential drug for LPS-induced AMI in broilers.

Keywords:  Asiatic acid; acute myocardial injury; lipopolysaccharide; mitochondrial dynamics; mitophagy

DOI:  https://doi.org/10.1637/aviandiseases-D-23-00036
Free Radic Biol Med. 2024 Apr 30. pii: S0891-5849(24)00428-3. [Epub ahead of print]

A Role of ROS-dependent Defects in Mitochondrial Dynamic and Autophagy in Carbon Black Nanoparticle-mediated Myocardial Cell Damage.

Zehua Xu, Jing Li, Bowen Su, Hongying Gao, Miaomiao Ren, Yi Lin, Heqing Shen.

  Carbon black nanoparticles (CBNPs) are widely distributed in the environment and are increasingly recognized as a contributor in the development of cardiovascular disease. A variety of cardiac injuries and diseases result from structural and functional damage to cardiomyocytes. This study explored the mechanisms of CBNPs-mediated myocardial toxicity. CBNPs were given to mice through intra-tracheal instillation and it was demonstrated that the particles can be taken up into the cardiac tissue. Exposure to CBNPs induced cardiomyocyte inflammation and apoptosis. In combination with in vitro experiments, we showed that CBNPs increased the ROS and induced mitochondria fragmentation. Functionally, CBNPs-exposed cardiomyocyte exhibited depolarization of the mitochondrial membrane potential, release of cytochrome c, and activation of pro-apoptotic BAX, thereby initiating programmed cell death. On the other hand, CBNPs impaired autophagy, leading to the inadequate removal of dysfunctional mitochondria. The excess accumulation of damaged mitochondria further stimulated NF-κB activation and triggered the NLRP3 inflammasome pathway. Both the antioxidant N-acetylcysteine and the autophagy activator rapamycin were effective to attenuate the damage of CBNPs on cardiomyocytes. Taken together, this study elucidated the potential mechanism underlying CBNPs-induced myocardial injury and provided a scientific reference for the evaluation and prevention of the CBNPs-related heart risk.

Keywords:  CBNPs; NF-κB/NLRP3; apoptosis; cardiomyocyte; mitochondrial quality control

DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.04.241