bims-mikwok 2024-06-16 papers

bims-mikwok

Biomed News

on Mitochondrial quality control

Issue of 2024‒06‒16
27 papers selected by
Gavin McStay, Liverpool John Moores University

MTFP1 controls mitochondrial fusion to regulate inner membrane quality control and maintain mtDNA levels.
Mitochondrial quality control dysfunction in osteoarthritis: Mechanisms, therapeutic strategies & future prospects.
Pyruvate kinase M2 sustains cardiac mitochondrial quality surveillance in septic cardiomyopathy by regulating prohibitin 2 abundance via S91 phosphorylation.
Reproductive regulation of the mitochondrial stress response in Caenorhabditis elegans.
ARHGAP26/GRAF1 orchestrates actin remodeling and membrane dynamics to drive mitochondrial clearance and promote fuel flexibility.
The interplay between mitophagy and mitochondrial ROS in acute lung injury.
Zishenhuoxue decoction-induced myocardial protection against ischemic injury through TMBIM6-VDAC1-mediated regulation of calcium homeostasis and mitochondrial quality surveillance.
The Ubiquitin Ligase RBX2/SAG Regulates Mitochondrial Ubiquitination and Mitophagy.
Activation of BK channels prevents diabetes-induced osteopenia by regulating mitochondrial Ca2+ and SLC25A5/ANT2-PINK1-PRKN-mediated mitophagy.
SS-31 treatment ameliorates cardiac mitochondrial morphology and defective mitophagy in a murine model of Barth syndrome.
Role of Yme1 in mitochondrial protein homeostasis: from regulation of protein import, OXPHOS function to lipid synthesis and mitochondrial dynamics.
AKAP1 alleviates VSMC phenotypic modulation and neointima formation by inhibiting Drp1-dependent mitochondrial fission.
Signal-sustained imaging of mitophagy with an Enzyme-Activatable Metabolic Lipid-Labeling Probe.
Drp1 and neuroinflammation: Deciphering the interplay between mitochondrial dynamics imbalance and inflammation in neurodegenerative diseases.
Mammalian target of differentiation-inducing factor-1 is mitochondrial malate dehydrogenase for activation of AMP-activated protein kinase and induction of mitochondrial fission.
SIRT3-mediated OPA1 deacetylation protects against sepsis-induced acute lung injury by inhibiting alveolar macrophage pro-inflammatory polarization.
Mitochondrial membrane synthesis, remodelling and cellular trafficking.
Regulation of mitochondrial network architecture and function in mesenchymal stem cells by micropatterned surfaces.
Targeting complement C3a receptor resolves mitochondrial hyperfusion and subretinal microglial activation in progranulin-deficient frontotemporal dementia.
Transcutaneous Auricular Vagus Nerve Stimulation Ameliorates Preeclampsia-Induced Apoptosis of Placental Trophoblastic Cells Via Inhibiting the Mitochondrial Unfolded Protein Response.
Resveratrol impinges on retrograde communication without inducing mitochondrial biogenesis in aged rat soleus muscle.
The miR-30-5p/TIA-1 axis directs cellular senescence by regulating mitochondrial dynamics.
3-MCPD Induces Renal Cell Pyroptosis and Inflammation by Inhibiting ESCRT-III-Mediated Cell Repair and Mitophagy.
Mitoregulin supports mitochondrial membrane integrity and protects against cardiac ischemia-reperfusion injury.
Deoxynivalenol Induces Drp-1-Mediated Mitochondrial Dysfunction via Elevating Oxidative Stress.
The Role and Mechanism of Ambra1-Mediated Mitophagy in TDCPP-Exposed Mouse Hippocampal Neurons.
Diverse Functions of Parkin in Midbrain Dopaminergic Neurons.

Cell. 2024 Jun 05. pii: S0092-8674(24)00526-9. [Epub ahead of print]

MTFP1 controls mitochondrial fusion to regulate inner membrane quality control and maintain mtDNA levels.

Luis Carlos Tábara, Stephen P Burr, Michele Frison, Suvagata R Chowdhury, Vincent Paupe, Yu Nie, Mark Johnson, Jara Villar-Azpillaga, Filipa Viegas, Mayuko Segawa, Hanish Anand, Kasparas Petkevicius, Patrick F Chinnery, Julien Prudent.

  Mitochondrial dynamics play a critical role in cell fate decisions and in controlling mtDNA levels and distribution. However, the molecular mechanisms linking mitochondrial membrane remodeling and quality control to mtDNA copy number (CN) regulation remain elusive. Here, we demonstrate that the inner mitochondrial membrane (IMM) protein mitochondrial fission process 1 (MTFP1) negatively regulates IMM fusion. Moreover, manipulation of mitochondrial fusion through the regulation of MTFP1 levels results in mtDNA CN modulation. Mechanistically, we found that MTFP1 inhibits mitochondrial fusion to isolate and exclude damaged IMM subdomains from the rest of the network. Subsequently, peripheral fission ensures their segregation into small MTFP1-enriched mitochondria (SMEM) that are targeted for degradation in an autophagic-dependent manner. Remarkably, MTFP1-dependent IMM quality control is essential for basal nucleoid recycling and therefore to maintain adequate mtDNA levels within the cell.

Keywords:  IMM quality control; IMM remodeling; MTFP1; autophagy; fission and fusion; mitochondria; mitochondrial dynamics; mitophagy; mtDNA

DOI:  https://doi.org/10.1016/j.cell.2024.05.017
Arch Gerontol Geriatr. 2024 Jun 04. pii: S0167-4943(24)00198-5. [Epub ahead of print]125 105522

Mitochondrial quality control dysfunction in osteoarthritis: Mechanisms, therapeutic strategies & future prospects.

Chiyuen Cheung, Shaoqin Tu, Yi Feng, Chuiming Wan, Hong Ai, Zheng Chen.

  Osteoarthritis (OA) is a prevalent chronic joint disease characterized by articular cartilage degeneration, pain, and disability. Emerging evidence indicates that mitochondrial quality control dysfunction contributes to OA pathogenesis. Mitochondria are essential organelles to generate cellular energy via oxidative phosphorylation and regulate vital processes. Impaired mitochondria can negatively impact cellular metabolism and result in the generation of harmful reactive oxygen species (ROS). Dysfunction in mitochondrial quality control mechanisms has been increasingly linked to OA onset and progression. This review summarizes current knowledge on the role of mitochondrial quality control disruption in OA, highlighting disturbed mitochondrial dynamics, impaired mitochondrial biogenesis, antioxidant defenses and mitophagy. The review also discusses potential therapeutic strategies targeting mitochondrial Quality Control in OA, offering future perspectives on advancing OA therapeutic strategies.

Keywords:  Mitochondrial dysfunction; Mitochondrial quality control; Mitophagy; Osteoarthritis; Oxidative stress

DOI:  https://doi.org/10.1016/j.archger.2024.105522
Cell Mol Life Sci. 2024 Jun 10. 81(1): 254

Pyruvate kinase M2 sustains cardiac mitochondrial quality surveillance in septic cardiomyopathy by regulating prohibitin 2 abundance via S91 phosphorylation.

Yingzhen Du, Jialei Li, Zhe Dai, Yuxin Chen, Yao Zhao, Xiaoman Liu, Tian Xia, Pingjun Zhu, Yijin Wang.

  The endogenous mitochondrial quality control (MQC) system serves to protect mitochondria against cellular stressors. Although mitochondrial dysfunction contributes to cardiac damage during many pathological conditions, the regulatory signals influencing MQC disruption during septic cardiomyopathy (SC) remain unclear. This study aimed to investigate the involvement of pyruvate kinase M2 (PKM2) and prohibitin 2 (PHB2) interaction followed by MQC impairment in the pathogenesis of SC. We utilized LPS-induced SC models in PKM2 transgenic (PKM2TG) mice, PHB2S91D-knockin mice, and PKM2-overexpressing HL-1 cardiomyocytes. After LPS-induced SC, cardiac PKM2 expression was significantly downregulated in wild-type mice, whereas PKM2 overexpression in vivo sustained heart function, suppressed myocardial inflammation, and attenuated cardiomyocyte death. PKM2 overexpression relieved sepsis-related mitochondrial damage via MQC normalization, evidenced by balanced mitochondrial fission/fusion, activated mitophagy, restored mitochondrial biogenesis, and inhibited mitochondrial unfolded protein response. Docking simulations, co-IP, and domain deletion mutant protein transfection experiments showed that PKM2 phosphorylates PHB2 at Ser91, preventing LPS-mediated PHB2 degradation. Additionally, the A domain of PKM2 and the PHB domain of PHB2 are required for PKM2-PHB2 binding and PHB2 phosphorylation. After LPS exposure, expression of a phosphorylation-defective PHB2S91A mutant negated the protective effects of PKM2 overexpression. Moreover, knockin mice expressing a phosphorylation-mimetic PHB2S91D mutant showed improved heart function, reduced inflammation, and preserved mitochondrial function following sepsis induction. Abundant PKM2 expression is a prerequisite to sustain PKM2-PHB2 interaction which is a key element for preservation of PHB2 phosphorylation and MQC, presenting novel interventive targets for the treatment of septic cardiomyopathy.

Keywords:  MQC; Mitochondria; PHB2; PKM2; Septic cardiomyopathy

DOI:  https://doi.org/10.1007/s00018-024-05253-9
Cell Rep. 2024 Jun 07. pii: S2211-1247(24)00664-8. [Epub ahead of print]43(6): 114336

Reproductive regulation of the mitochondrial stress response in Caenorhabditis elegans.

Nikolaos Charmpilas, Aggeliki Sotiriou, Konstantinos Axarlis, Nektarios Tavernarakis, Thorsten Hoppe.

  Proteome integrity is fundamental for cellular and organismal homeostasis. The mitochondrial unfolded protein response (UPRmt), a key component of the proteostasis network, is activated in a non-cell-autonomous manner in response to mitochondrial stress in distal tissues. However, the importance of inter-tissue communication for UPRmt inducibility under physiological conditions remains elusive. Here, we show that an intact germline is essential for robust UPRmt induction in the Caenorhabditis elegans somatic tissues. A series of nematode mutants with germline defects are unable to respond to genetic or chemical UPRmt inducers. Our genetic analysis suggests that reproductive signals, rather than germline stem cells, are responsible for somatic UPRmt induction. Consistent with this observation, we show that UPRmt is sexually dimorphic, as male nematodes are inherently unresponsive to mitochondrial stress. Our findings highlight a paradigm of germline-somatic communication and suggest that reproductive cessation is a primary cause of age-related UPRmt decline.

Keywords:  C. elegans; CP: Developmental biology; CP: Molecular biology; aging; germline; mitochondria; proteostasis; unfolded protein response

DOI:  https://doi.org/10.1016/j.celrep.2024.114336
Autophagy. 2024 Jun 10. 1-3

ARHGAP26/GRAF1 orchestrates actin remodeling and membrane dynamics to drive mitochondrial clearance and promote fuel flexibility.

Qiang Zhu, Joan M Taylor.

  The serine/threonine kinase, PINK1, and the E3 ubiquitin ligase, PRKN/Parkin facilitate LC3-dependent autophagosomal encasement and lysosomal clearance of dysfunctional mitochondria, and defects in this pathway contribute to the pathogenesis of numerous cardiometabolic and neurological diseases. Although dynamic actin remodeling has recently been shown to play an important role in governing spatiotemporal control of mitophagy, the mechanisms remain unclear. We recently found that the RhoGAP, ARHGAP26/GRAF1 is a PRKN-binding protein that is rapidly recruited to damaged mitochondria where upon phosphorylation by PINK1 it serves to coordinate phagophore capture by regulating mitochondrial-associated actin remodeling and by facilitating PRKN-LC3 interactions. Because ARHGAP26 phosphorylation on PINK1-dependent sites is dysregulated in human heart failure and ARHGAP26 depletion in mouse hearts blunts mitochondrial clearance and attenuates compensatory metabolic adaptations to stress, this enzyme may be a tractable target to treat the many diseases associated with mitochondrial dysfunction.

Keywords:  Actin dynamics; GRAF1; PINK1; Parkin; mitophagy

DOI:  https://doi.org/10.1080/15548627.2024.2361576
Mitochondrion. 2024 Jun 12. pii: S1567-7249(24)00078-3. [Epub ahead of print] 101920

The interplay between mitophagy and mitochondrial ROS in acute lung injury.

Yizhi Zhong, Siwei Xia, Gaojian Wang, Qinxue Liu, Fengjie Ma, Yijin Yu, Yaping Zhang, Lu Qian, Li Hu, Junran Xie.

  Mitochondria orchestrate the production of new mitochondria and the removal of damaged ones to dynamically maintain mitochondrial homeostasis through constant biogenesis and clearance mechanisms. Mitochondrial quality control particularly relies on mitophagy, defined as selective autophagy with mitochondria-targeting specificity. Most ROS are derived from mitochondria, and the physiological concentration of mitochondrial ROS (mtROS) is no longer considered a useless by-product, as it has been proven to participate in immune and autophagy pathway regulation. However, excessive mtROS appears to be a pathogenic factor in several diseases, including acute lung injury (ALI). The interplay between mitophagy and mtROS is complex and closely related to ALI. Here, we review the pathways of mitophagy, the intricate relationship between mitophagy and mtROS, the role of mtROS in the pathogenesis of ALI, and their effects and related progression in ALI induced by different conditions.

Keywords:  Acute lung injury; Mechanism; Mitochondrial reactive oxygen species; Mitophagy; Oxidative stress

DOI:  https://doi.org/10.1016/j.mito.2024.101920
Phytomedicine. 2023 Dec 30. pii: S0944-7113(23)00689-X. [Epub ahead of print]132 155331

Zishenhuoxue decoction-induced myocardial protection against ischemic injury through TMBIM6-VDAC1-mediated regulation of calcium homeostasis and mitochondrial quality surveillance.

Xing Chang, Siyuan Zhou, Jinfeng Liu, Yanli Wang, Xuanke Guan, Qiaomin Wu, Zhiming Liu, Ruxiu Liu.

  BACKGROUND: Zishenhuoxue decoction (ZSHX), a Chinese herbal medicine, exhibits myocardial and vascular endothelial protective properties. The intricate regulatory mechanisms underlying myocardial ischemic injury and its association with dysfunctional mitochondrial quality surveillance (MQS) remain elusive.HYPOTHESIS/PURPOSE: To study the protective effect of ZSHX on ischemic myocardial injury in mice using a TMBIM6 gene-modified animal model and mitochondrial quality control-related experiments.
STUDY DESIGN: Using model animals and myocardial infarction surgery-induced ischemic myocardial injury TMBIM6 gene-modified mouse models, the pharmacological activity of ZSHX in inhibiting ischemic myocardial injury and mitochondrial homeostasis disorder in vivo was tested.
METHODS: Our focal point entailed scrutinizing the impact of ZSHX on ischemic myocardial impairment through the prism of TMBIM6. This endeavor was undertaken utilizing mice characterized by heart-specific TMBIM6 knockout (TMBIM6CKO) and their counterparts, the TMBIM6 transgenic (TMBIM6TG) and VDAC1 transgenic (VDAC1TG) mice.
RESULTS: ZSHX demonstrated dose-dependent effectiveness in mitigating ischemic myocardial injury and enhancing mitochondrial integrity. TMBIM6CKO hindered ZSHX's cardio-therapeutic and mitochondrial protective effects, while ZSHX's benefits persisted in TMBIM6TG mice. TMBIM6CKO also blocked ZSHX's regulation of mitochondrial function in HR-treated cardiomyocytes. Hypoxia disrupted the MQS in cardiomyocytes, including calcium overload, excessive fission, mitophagy issues, and disrupted biosynthesis. ZSHX counteracted these effects, thereby normalizing MQS and inhibiting calcium overload and cardiomyocyte necroptosis. Our results also showed that hypoxia-induced TMBIM6 blockade resulted in the over-activation of VDAC1, a major mitochondrial calcium uptake pathway, while ZSHX could increase the expression of TMBIM6 and inhibit VDAC1-mediated calcium overload and MQS abnormalities.
CONCLUSIONS: Our findings suggest that ZSHX regulates mitochondrial calcium homeostasis and MQS abnormalities through a TMBIM6-VDAC1 interaction mechanism, which helps to treat ischemic myocardial injury and provides myocardial protection. This study also offers insights for the clinical translation and application of mitochondrial-targeted drugs in cardiomyocytess.

Keywords:  Calcium overload; Ischemic cardiomyopathy; Mitochondrial quality surveillance; TMBIM6; VDAC1; ZSHX

DOI:  https://doi.org/10.1016/j.phymed.2023.155331
Circ Res. 2024 Jun 14.

The Ubiquitin Ligase RBX2/SAG Regulates Mitochondrial Ubiquitination and Mitophagy.

Wenjuan Wang, Ermin Li, Jianqiu Zou, Chen Qu, Juan Ayala, Yuan Wen, Md Sadikul Islam, Neal L Weintraub, David J Fulton, Qiangrong Liang, Jiliang Zhou, Jinbao Liu, Jie Li, Yi Sun, Huabo Su.

  BACKGROUND: Clearance of damaged mitochondria via mitophagy is crucial for cellular homeostasis. Apart from Parkin, little is known about additional Ub (ubiquitin) ligases that mediate mitochondrial ubiquitination and turnover, particularly in highly metabolically active organs such as the heart.METHODS: In this study, we have combined in silico analysis and biochemical assay to identify CRL (cullin-RING ligase) 5 as a mitochondrial Ub ligase. We generated cardiomyocytes and mice lacking RBX2 (RING-box protein 2; also known as SAG [sensitive to apoptosis gene]), a catalytic subunit of CRL5, to understand the effects of RBX2 depletion on mitochondrial ubiquitination, mitophagy, and cardiac function. We also performed proteomics analysis and RNA-sequencing analysis to define the impact of loss of RBX2 on the proteome and transcriptome.
RESULTS: RBX2 and CUL (cullin) 5, 2 core components of CRL5, localize to mitochondria. Depletion of RBX2 inhibited mitochondrial ubiquitination and turnover, impaired mitochondrial membrane potential and respiration, increased cardiomyocyte cell death, and has a global impact on the mitochondrial proteome. In vivo, deletion of the Rbx2 gene in adult mouse hearts suppressed mitophagic activity, provoked accumulation of damaged mitochondria in the myocardium, and disrupted myocardial metabolism, leading to the rapid development of dilated cardiomyopathy and heart failure. Similarly, ablation of RBX2 in the developing heart resulted in dilated cardiomyopathy and heart failure. The action of RBX2 in mitochondria is not dependent on Parkin, and Parkin gene deletion had no impact on the onset and progression of cardiomyopathy in RBX2-deficient hearts. Furthermore, RBX2 controls the stability of PINK1 in mitochondria.
CONCLUSIONS: These findings identify RBX2-CRL5 as a mitochondrial Ub ligase that regulates mitophagy and cardiac homeostasis in a Parkin-independent, PINK1-dependent manner.

Keywords:  heart failure; mitochondria; mitophagy; protein kinases; ubiquitination

DOI:  https://doi.org/10.1161/CIRCRESAHA.124.324285
Autophagy. 2024 Jun 14.

Activation of BK channels prevents diabetes-induced osteopenia by regulating mitochondrial Ca2+ and SLC25A5/ANT2-PINK1-PRKN-mediated mitophagy.

Lan Jiang, Haidong He, Yuyan Tang, Jiawei Li, Svetlana Reilly, Hong Xin, Zhiping Li, Hui Cai, Xuemei Zhang.

  Osteopenia and osteoporosis are among the most common metabolic bone diseases and represent major public health problems, with sufferers having an increased fracture risk. Diabetes is one of the most common diseases contributing to osteopenia and osteoporosis. However, the mechanisms underlying diabetes-induced osteopenia and osteoporosis remain unclear. Bone reconstruction, including bone formation and absorption, is a dynamic process. Large-conductance Ca2+-activated K+ channels (BK channels) regulate the function of bone marrow-derived mesenchymal stem cells, osteoblasts, and osteoclasts. Our previous studies revealed the relationship between BK channels and the function of osteoblasts via various pathways under physiological conditions. In this study, we reported a decrease in the expression of BK channels in mice with diabetes-induced osteopenia. BK deficiency enhanced mitochondrial Ca2+ and activated classical PINK1 (PTEN induced putative kinase 1)-PRKN/Parkin (parkin RBR E3 ubiquitin protein ligase)-dependent mitophagy, whereas the upregulation of BK channels inhibited mitophagy in osteoblasts. Moreover, SLC25A5/ANT2 (solute carrier family 25 (mitochondrial carrier, adenine nucleotide translocator), member 5), a critical inner mitochondrial membrane protein participating in PINK1-PRKN-dependent mitophagy, was also regulated by BK channels. Overall, these data identified a novel role of BK channels in regulating mitophagy in osteoblasts, which might be a potential target for diabetes-induced bone diseases.

Keywords:  Adenine nucleotide translocator; BK channel; PINK1-PRKN pathway; mitochondrial calcium; mitophagy

DOI:  https://doi.org/10.1080/15548627.2024.2367184
Sci Rep. 2024 06 13. 14(1): 13655

SS-31 treatment ameliorates cardiac mitochondrial morphology and defective mitophagy in a murine model of Barth syndrome.

Silvia Russo, Domenico De Rasmo, Roberta Rossi, Anna Signorile, Simona Lobasso.

Barth syndrome (BTHS) is a lethal rare genetic disorder, which results in cardiac dysfunction, severe skeletal muscle weakness, immune issues and growth delay. Mutations in the TAFAZZIN gene, which is responsible for the remodeling of the phospholipid cardiolipin (CL), lead to abnormalities in mitochondrial membrane, including alteration of mature CL acyl composition and the presence of monolysocardiolipin (MLCL). The dramatic increase in the MLCL/CL ratio is the hallmark of patients with BTHS, which is associated with mitochondrial bioenergetics dysfunction and altered membrane ultrastructure. There are currently no specific therapies for BTHS. Here, we showed that cardiac mitochondria isolated from TAFAZZIN knockdown (TazKD) mice presented abnormal ultrastructural membrane morphology, accumulation of vacuoles, pro-fission conditions and defective mitophagy. Interestingly, we found that in vivo treatment of TazKD mice with a CL-targeted small peptide (named SS-31) was able to restore mitochondrial morphology in tafazzin-deficient heart by affecting specific proteins involved in dynamic process and mitophagy. This agrees with our previous data showing an improvement in mitochondrial respiratory efficiency associated with increased supercomplex organization in TazKD mice under the same pharmacological treatment. Taken together our findings confirm the beneficial effect of SS-31 in the amelioration of tafazzin-deficient dysfunctional mitochondria in a BTHS animal model.

DOI: https://doi.org/10.1038/s41598-024-64368-y
Biochem Soc Trans. 2024 Jun 12. pii: BST20240450. [Epub ahead of print]

Role of Yme1 in mitochondrial protein homeostasis: from regulation of protein import, OXPHOS function to lipid synthesis and mitochondrial dynamics.

Kwan Ting Kan, Joel Wilcock, Hui Lu.

  Mitochondria are essential organelles of eukaryotic cells and thus mitochondrial proteome is under constant quality control and remodelling. Yme1 is a multi-functional protein and subunit of the homo-hexametric complex i-AAA proteinase. Yme1 plays vital roles in the regulation of mitochondrial protein homeostasis and mitochondrial plasticity, ranging from substrate degradation to the regulation of protein functions involved in mitochondrial protein biosynthesis, energy production, mitochondrial dynamics, and lipid biosynthesis and signalling. In this mini review, we focus on discussing the current understanding of the roles of Yme1 in mitochondrial protein import via TIM22 and TIM23 pathways, oxidative phosphorylation complex function, as well as mitochondrial lipid biosynthesis and signalling, as well as a brief discussion of the role of Yme1 in modulating mitochondrial dynamics.

Keywords:  i-AAA proteinase; mitochondrial protein homeostasis; mitochondrial protein import; oxidative phosphorylation complex; protein function

DOI:  https://doi.org/10.1042/BST20240450
Biomed Pharmacother. 2024 Jun 07. pii: S0753-3322(24)00742-X. [Epub ahead of print]176 116858

AKAP1 alleviates VSMC phenotypic modulation and neointima formation by inhibiting Drp1-dependent mitochondrial fission.

Jingwen Sun, Yuting Shao, Lele Pei, Qingyu Zhu, Xiaoqiang Yu, Wenjuan Yao.

  The roles and mechanisms of A-kinase anchoring protein 1 (AKAP1) in vascular smooth muscle cell (VSMC) phenotypic modulation and neointima formation are currently unknown. AKAP1 is a mitochondrial PKA-anchored protein and maintains mitochondrial homeostasis. This study aimed to investigate how AKAP1/PKA signaling plays a protective role in inhibiting VSMC phenotypic transformation and neointima formation by regulating mitochondrial fission. The results showed that both PDGF-BB treatment and balloon injury reduced the transcription, expression, and mitochondrial anchoring of AKAP1. In vitro, the overexpression of AKAP1 significantly inhibited PDGF-BB mediated VSMC proliferation and migration, whereas AKAP1 knockdown further aggravated VSMC phenotypic transformation. Additionally, in the balloon injury model in vivo, AKAP1 overexpression reduced neointima formation, the muscle fiber area ratio, and rat VSMC proliferation and migration. Furthermore, PDGF-BB and balloon injury inhibited Drp1 phosphorylation at Ser637 and promoted Drp1 activity and mitochondrial midzone fission; AKAP1 overexpression reversed these effects. AKAP1 overexpression also inhibited the distribution of mitochondria at the plasma membrane and the reduction of PKARIIβ expression induced by PDGF-BB, as evidenced by an increase in mitochondria-plasma membrane distance as well as PKARIIβ protein levels. Moreover, the PKA agonist promoted Drp1 phosphorylation (Ser637) and inhibited PDGF-BB-mediated mitochondrial fission, cell proliferation, and migration. The PKA antagonist reversed the increase in Drp1 phosphorylation (Ser637) and the decline in mitochondrial midzone fission and VSMC phenotypic transformation caused by AKAP1 overexpression. The results of this study reveal that AKAP1 protects VSMCs against phenotypic modulation by improving Drp1 phosphorylation at Ser637 through PKA and inhibiting mitochondrial fission, thereby preventing neointima formation.

Keywords:  AKAP1; Mitochondrial fission; Neointima formation; PKA; VSMC phenotypic modulation

DOI:  https://doi.org/10.1016/j.biopha.2024.116858
Autophagy. 2024 Jun 14.

Signal-sustained imaging of mitophagy with an Enzyme-Activatable Metabolic Lipid-Labeling Probe.

Xiaoxue Zou, Shixiong Wen, Lichun Xu, Lei Gao, Xunxiang Wang, Xiao Hu, Jiahuai Han, Shoufa Han.

  Imaging of mitophagy is of significance as aberrant mitophagy is engaged in multiple diseases. Mitophagy has been imaged with synthetic or biotic pH sensors by reporting pH acidification en route delivery into lysosomes. To circumvent uncertainty of acidity-dependent signals, we herein report an enzyme-activatable probe covalently attached on mitochondrial inner membrane (ECAM) for signal-persist mitophagy imaging. ECAM is operated via ΔΨm-driven accumulation of Mito-proGreen in mitochondria and covalent linking of the trapped probe with azidophospholipids metabolically incorporated into the mitochondrial inner membrane. Upon mitophagy, ECAM is delivered into lysosomes and hydrolyzed by LNPEP/leucyl aminopeptidase, yielding turn-on green fluorescence that is immune to lysosomal acidity changes and stably retained in fixed cells. With ECAM, phorbol-12-myristate-13-acetate (PMA) was identified as a highly potent inducer of mitophagy. Overcoming signal susceptibility of pH probes and liability of ΔΨm probes to dissipation from stressed mitochondria, ECAM offers an attractive tool to study mitophagy and mitophagy-inducing therapeutic agents.

Keywords:  Enzyme activation; fluorescence-on; metabolic lipid labeling; mitophagy imaging; ph-independent fluorescence

DOI:  https://doi.org/10.1080/15548627.2024.2367192
Neurobiol Dis. 2024 Jun 08. pii: S0969-9961(24)00160-8. [Epub ahead of print]198 106561

Drp1 and neuroinflammation: Deciphering the interplay between mitochondrial dynamics imbalance and inflammation in neurodegenerative diseases.

Peiyang Cai, Wuhao Li, Ye Xu, Hui Wang.

  Neuroinflammation and mitochondrial dysfunction are closely intertwined with the pathophysiology of neurological disorders. Recent studies have elucidated profound alterations in mitochondrial dynamics across a spectrum of neurological disorders. Dynamin-related protein 1 (DRP1) emerges as a pivotal regulator of mitochondrial fission, with its dysregulation disrupting mitochondrial homeostasis and fueling neuroinflammation, thereby exacerbating disease severity. In addition to its role in mitochondrial dynamics, DRP1 plays a crucial role in modulating inflammation-related pathways. This review synthesizes important functions of DRP1 in the central nervous system (CNS) and the impact of epigenetic modification on the progression of neurodegenerative diseases. The intricate interplay between neuroinflammation and DRP1 in microglia and astrocytes, central contributors to neuroinflammation, is expounded upon. Furthermore, the use of DRP1 inhibitors to influence the activation of microglia and astrocytes, as well as their involvement in processes such as mitophagy, mitochondrial oxidative stress, and calcium ion transport in CNS-mediated neuroinflammation, is scrutinized. The modulation of microglia to astrocyte crosstalk by DRP1 and its role in inflammatory neurodegeneration is also highlighted. Overall, targeting DRP1 presents a promising avenue for ameliorating neuroinflammation and enhancing the therapeutic management of neurological disorders.

Keywords:  DRP1; Mitochondrial fission; Neuroinflammation; Reactive microglia and astrocytes

DOI:  https://doi.org/10.1016/j.nbd.2024.106561
Life Sci. 2024 Jun 07. pii: S0024-3205(24)00397-7. [Epub ahead of print]351 122807

Mammalian target of differentiation-inducing factor-1 is mitochondrial malate dehydrogenase for activation of AMP-activated protein kinase and induction of mitochondrial fission.

Masaki Arioka, Koichi Miura, Ruzhe Han, Kazunobu Igawa, Fumi Takahashi-Yanaga, Toshiyuki Sasaguri.

  AIMS: Differentiation-inducing factor-1 (DIF-1) is a polyketide produced by Dictyostelium discoideum that inhibits growth and migration, while promoting the differentiation of Dictyostelium stalk cells through unknown mechanisms. DIF-1 localizes in stalk mitochondria. In addition to its effect on Dictyostelium, DIF-1 also inhibits growth and migration, and induces mitochondrial fission followed by mitophagy in mammalian cells, at least in part by activating AMP-activated protein kinase (AMPK). In a previous study, we found that DIF-1 binds to mitochondrial malate dehydrogenase (MDH2) and inhibits its activity in HeLa cells. In the present study, we investigated whether MDH2 serves as a pharmacological target of DIF-1 in mammalian cells.MAIN METHODS: To examine the enzymatic activity of MDH, mitochondrial morphology, and molecular mechanisms of DIF-1 action, we conducted an MDH reverse reaction assay, immunofluorescence staining, western blotting, and RNA interference using mammalian cells such as human umbilical vein endothelial cells, human cervical cancer cells, mouse endothelial cells, and mouse breast cancer cells.
KEY FINDINGS: DIF-1 inhibited mitochondrial but not cytoplasmic MDH activity. Similar to DIF-1, LW6, an authentic MDH2 inhibitor, induced phosphorylation of AMPK, resulting in the phosphorylation of acetyl-CoA carboxylase (ACC) and the dephosphorylation of p70 S6 kinase with approximately the same potency. DIF-1 and LW6 induced mitochondrial fission. Furthermore, MDH2 knockdown using siRNA reproduced the DIF-1 action on the AMPK signaling and mitochondrial morphology. Conversely, an AMPK inhibitor prevented DIF-1-induced mitochondrial fission.
SIGNIFICANCE: We propose that MDH2 is a mammalian target of DIF-1 for the activation of AMPK and induction of mitochondrial fission.

Keywords:  AMP-activated protein kinase; Differentiation-inducing factor-1; Mitochondrial fission; Mitochondrial malate dehydrogenase

DOI:  https://doi.org/10.1016/j.lfs.2024.122807
Antioxid Redox Signal. 2024 Jun 14.

SIRT3-mediated OPA1 deacetylation protects against sepsis-induced acute lung injury by inhibiting alveolar macrophage pro-inflammatory polarization.

Maomao Sun, Yuying Li, Gege Xu, Junrui Zhu, Ruimin Lu, Sheng An, Zhenhua Zeng, Zhiya Deng, Ran Cheng, Qin Zhang, Yi Yao, Junjie Wu, Yuan Zhang, Hongbin Hu, Zhonqing Chen, Qiaobing Huang, Jie Wu.

AIMS: Mitochondrial dynamics in alveolar macrophages (AMs) are associated with sepsis-induced acute lung injury (ALI). In this study, we aimed to investigate whether changes in mitochondrial dynamics could alter the polarization of AMs in sepsis-induced ALI and to explore the regulatory mechanism of mitochondrial dynamics by focusing on SIRT3-induced optic atrophy protein 1 (OPA1) deacetylation.RESULTS: The AMs of sepsis-induced ALI showed imbalanced mitochondrial dynamics and polarization to the M1 macrophage phenotype. In sepsis, SIRT3 overexpression promotes mitochondrial dynamic equilibrium in AMs. However, 3TYP-specific inhibition of SIRT3 increased the mitochondrial dynamic imbalance and pro-inflammatory polarization of AMs and further aggravated sepsis-induced ALI. OPA1 is directly bound to and deacetylated by SIRT3 in AMs. In AMs of sepsis-induced ALI, SIRT3 protein expression was decreased and OPA1 acetylation was increased. OPA1 acetylation at the lysine 792 amino acid residue (OPA1-K792) promotes self-cleavage and is associated with an imbalance in mitochondrial dynamics. However, decreased acetylation of OPA1-K792 reversed the pro-inflammatory polarization of AMs and protected the barrier function of alveolar epithelial cells in sepsis-induced ALI.
INNOVATION: Our study revealed for the first time the regulation of mitochondrial dynamics and AMs polarization by SIRT3-mediated deacetylation of OPA1 in sepsis-induced ALI, which may serve as an intervention target for precision therapy of the disease.
CONCLUSIONS: Our data suggest that imbalanced mitochondrial dynamics promote pro-inflammatory polarization of AMs in sepsis-induced ALI, and that deacetylation of OPA1 mediated by SIRT3 improves mitochondrial dynamic equilibrium, thereby ameliorating lung injury.

DOI: https://doi.org/10.1089/ars.2023.0322
J Inherit Metab Dis. 2024 Jun 14.

Mitochondrial membrane synthesis, remodelling and cellular trafficking.

Martina Messina, Frédéric M Vaz, Shamima Rahman.

  Mitochondria are dynamic cellular organelles with complex roles in metabolism and signalling. Primary mitochondrial disorders are a group of approximately 400 monogenic disorders arising from pathogenic genetic variants impacting mitochondrial structure, ultrastructure and/or function. Amongst these disorders, defects of complex lipid biosynthesis, especially of the unique mitochondrial membrane lipid cardiolipin, and membrane biology are an emerging group characterised by clinical heterogeneity, but with recurrent features including cardiomyopathy, encephalopathy, neurodegeneration, neuropathy and 3-methylglutaconic aciduria. This review discusses lipid synthesis in the mitochondrial membrane, the mitochondrial contact site and cristae organising system (MICOS), mitochondrial dynamics and trafficking, and the disorders associated with defects of each of these processes. We highlight overlapping functions of proteins involved in lipid biosynthesis and protein import into the mitochondria, pointing to an overarching coordination and synchronisation of mitochondrial functions. This review also focuses on membrane interactions between mitochondria and other organelles, namely the endoplasmic reticulum, peroxisomes, lysosomes and lipid droplets. We signpost disorders of these membrane interactions that may explain the observation of secondary mitochondrial dysfunction in heterogeneous pathological processes. Disruption of these organellar interactions ultimately impairs cellular homeostasis and organismal health, highlighting the central role of mitochondria in human health and disease.

Keywords:  MAM; MERC; MICOS; cardiolipin; cell trafficking; mitochondrial lipid biosynthesis; organellar crosstalk; primary mitochondrial disease

DOI:  https://doi.org/10.1002/jimd.12766
Regen Biomater. 2024 ;11 rbae052

Regulation of mitochondrial network architecture and function in mesenchymal stem cells by micropatterned surfaces.

Zixuan Dong, Weiju Han, Panyu Jiang, Lijing Hao, Xiaoling Fu.

  Mitochondrial network architecture, which is closely related to mitochondrial function, is mechanically sensitive and regulated by multiple stimuli. However, the effects of microtopographic cues on mitochondria remain poorly defined. Herein, polycaprolactone (PCL) surfaces were used as models to investigate how micropatterns regulate mitochondrial network architecture and function in rat adipose-derived stem cells (rASCs). It was found that large pit (LP)-induced rASCs to form larger and more complex mitochondrial networks. Consistently, the expression of key genes related to mitochondrial dynamics revealed that mitochondrial fusion (MFN1 and MFN2) and midzone fission (DRP1 and MFF) were increased in rASCs on LP. In contrast, the middle pit (MP)-enhanced mitochondrial biogenesis, as evidenced by the larger mitochondrial area and higher expression of PGC-1. Both LP and MP promoted ATP production in rASCs. It is likely that LP increased ATP levels through modulating mitochondrial network architecture while MP stimulated mitochondria biogenesis to do so. Our study clarified the regulation of micropatterned surfaces on mitochondria, highlighting the potential of LP and MP as a simple platform to stimulate mitochondria and the subsequent cellular function of MSCs.

Keywords:  mesenchymal stem cells; micropatterned surface; mitochondrial function; mitochondrial network architecture; regulation of mitochondria

DOI:  https://doi.org/10.1093/rb/rbae052
bioRxiv. 2024 Jun 01. pii: 2024.05.29.595206. [Epub ahead of print]

Targeting complement C3a receptor resolves mitochondrial hyperfusion and subretinal microglial activation in progranulin-deficient frontotemporal dementia.

Li Xuan Tan, Frederike Cosima Oertel, An Cheng, Yann Cobigo, Azeen Keihani, Daniel J Bennett, Ahmed Abdelhak, Shivany Condor Montes, Makenna Chapman, Robert Y Chen, Christian Cordano, Michael E Ward, Kaitlin Casaletto, Joel H Kramer, Howard J Rosen, Adam Boxer, Bruce L Miller, Ari J Green, Fanny M Elahi, Aparna Lakkaraju.

Mutations in progranulin ( GRN ) cause frontotemporal dementia ( GRN -FTD) due to deficiency of the pleiotropic protein progranulin. GRN -FTD exhibits diverse pathologies including lysosome dysfunction, lipofuscinosis, microgliosis, and neuroinflammation. Yet, how progranulin loss causes disease remains unresolved. Here, we report that non-invasive retinal imaging of GRN -FTD patients revealed deficits in photoreceptors and the retinal pigment epithelium (RPE) that correlate with cognitive decline. Likewise, Grn -/- mice exhibit early RPE dysfunction, microglial activation, and subsequent photoreceptor loss. Super-resolution live imaging and transcriptomic analyses identified RPE mitochondria as an early driver of retinal dysfunction. Loss of mitochondrial fission protein 1 (MTFP1) in Grn -/- RPE causes mitochondrial hyperfusion and bioenergetic defects, leading to NF-kB-mediated activation of complement C3a-C3a receptor signaling, which drives further mitochondrial hyperfusion and retinal inflammation. C3aR antagonism restores RPE mitochondrial integrity and limits subretinal microglial activation. Our study identifies a previously unrecognized mechanism by which progranulin modulates mitochondrial integrity and complement-mediated neuroinflammation.

DOI: https://doi.org/10.1101/2024.05.29.595206
Neurosci Bull. 2024 Jun 14.

Transcutaneous Auricular Vagus Nerve Stimulation Ameliorates Preeclampsia-Induced Apoptosis of Placental Trophoblastic Cells Via Inhibiting the Mitochondrial Unfolded Protein Response.

Jing Zhao, Yanan Yang, Jiayi Qin, Siyu Tao, Chunmei Jiang, Huixuan Huang, Qiunan Wan, Yuqi Chen, Shouzhu Xu, Haifa Qiao.

  Preeclampsia is a serious obstetric complication. Currently, there is a lack of effective preventive approaches for this disease. Recent studies have identified transcutaneous auricular vagus nerve stimulation (taVNS) as a potential novel non-pharmaceutical therapeutic modality for preeclampsia. In this study, we investigated whether taVNS inhibits apoptosis of placental trophoblastic cells through ROS-induced UPRmt. Our results showed that taVNS promoted the release of acetylcholine (ACh). ACh decreased the expression of UPRmt by inhibiting the formation of mitochondrial ROS (mtROS), presumably through M3AChR. This reduced the release of pro-apoptotic proteins (cleaved caspase-3, NF-κB-p65, and cytochrome C) and helped preserve the morphological and functional integrity of mitochondria, thus reducing the apoptosis of placental trophoblasts, improving placental function, and relieving preeclampsia. Our study unravels the potential pathophysiological mechanism of preeclampsia. In-depth characterization of the UPRmt is essential for developing more effective therapeutic strategies for preeclampsia targeting mitochondrial function.

Keywords:  Acetylcholine; Mitochondrial unfolded protein response; Placental trophoblastic cells; Preeclampsia; Reactive oxygen species; Transcutaneous auricular vagus nerve stimulation

DOI:  https://doi.org/10.1007/s12264-024-01244-9
Exp Gerontol. 2024 Jun 12. pii: S0531-5565(24)00127-X. [Epub ahead of print] 112485

Resveratrol impinges on retrograde communication without inducing mitochondrial biogenesis in aged rat soleus muscle.

Rosa Di Lorenzo, Guglielmina Chimienti, Anna Picca, Lucia Trisolini, Tiziana Latronico, Grazia Maria Liuzzi, Vito Pesce, Christiaan Leuweenburgh, Angela Maria Serena Lezza.

  The natural polyphenol resveratrol (RSV) might counteract the skeletal muscle age-related loss of muscle mass and strength/function partly acting on mitochondria. This work analysed the effects of a six-week administration of RSV (50 mg/kg/day) in the oxidative Soleus (Sol) skeletal muscle of old rats (27 months old). RSV effects on key mitochondrial biogenesis proteins led to un unchanged amount of SIRT1 protein and a marked decrease (60 %) in PGC-1α protein. In addition, Peroxyredoxin 3 (PRXIII) protein decreased by 50 %, which on overall suggested the absence of induction of mitochondrial biogenesis by RSV in old Sol. A novel direct correlation between PGC-1α and PRXIII proteins was demonstrated by correlation analysis in RSV and ad-libitum (AL) rats, supporting the reciprocally coordinated expression of the proteins. RSV supplementation led to an unexpected 50 % increase in the frequency of the oxidized base OH8dG in mtDNA. Furthermore, RSV supplementation induced a 50 % increase in the DRP1 protein of mitochondrial dynamics. In both rat groups an inverse correlation between PGC-1α and the frequency of OH8dG as well as an inverse correlation between PRXIII and the frequency of OH8dG were also found, suggestive of a relationship between oxidative damage to mtDNA and mitochondrial biogenesis activity. Such results may indicate that the antioxidant activity of RSV in aged Sol impinged on the oxidative fiber-specific, ROS-mediated, retrograde communication, thereby affecting the expression of SIRT1, PGC-1α and PRXIII, reducing the compensatory responses to the age-related mitochondrial oxidative stress and decline.

Keywords:  Mitochondrial biogenesis; Rat soleus skeletal muscle; Resveratrol

DOI:  https://doi.org/10.1016/j.exger.2024.112485
Cell Death Dis. 2024 Jun 10. 15(6): 404

The miR-30-5p/TIA-1 axis directs cellular senescence by regulating mitochondrial dynamics.

Hyosun Tak, Seongho Cha, Youlim Hong, Myeongwoo Jung, Seungyeon Ryu, Sukyoung Han, Seung Min Jeong, Wook Kim, Eun Kyung Lee.

Senescent cells exhibit a diverse spectrum of changes in their morphology, proliferative capacity, senescence-associated secretory phenotype (SASP) production, and mitochondrial homeostasis. These cells often manifest with elongated mitochondria, a hallmark of cellular senescence. However, the precise regulatory mechanisms orchestrating this phenomenon remain predominantly unexplored. In this study, we provide compelling evidence for decreases in TIA-1, a pivotal regulator of mitochondrial dynamics, in models of both replicative senescence and ionizing radiation (IR)-induced senescence. The downregulation of TIA-1 was determined to trigger mitochondrial elongation and enhance the expression of senescence-associated β-galactosidase, a marker of cellular senescence, in human foreskin fibroblast HS27 cells and human keratinocyte HaCaT cells. Conversely, the overexpression of TIA-1 mitigated IR-induced cellular senescence. Notably, we identified the miR-30-5p family as a novel factor regulating TIA-1 expression. Augmented expression of the miR-30-5p family was responsible for driving mitochondrial elongation and promoting cellular senescence in response to IR. Taken together, our findings underscore the significance of the miR-30-5p/TIA-1 axis in governing mitochondrial dynamics and cellular senescence.

DOI: https://doi.org/10.1038/s41419-024-06797-1
J Agric Food Chem. 2024 Jun 10.

3-MCPD Induces Renal Cell Pyroptosis and Inflammation by Inhibiting ESCRT-III-Mediated Cell Repair and Mitophagy.

Ranran Zhang, Shuang Guan, Zhuoqun Meng, Xuming Deng, Jing Lu.

  3-Monochloropropane-1,2-diol (3-MCPD) is a chloropropyl alcohol contaminant mainly from the thermal processing of food and could affect kidneys. Pyroptosis is programmed cell death mediated by inflammasomes and gasdermins, and excessive cellular pyroptosis and inflammation can lead to tissue injury. In the present study, we found that 3-MCPD increased lactate dehydrogenase (LDH) levels in vitro and in vivo, increased the protein expression of NOD-like receptor family pyrin domain containing 3 (NLRP3), N-terminal domain of GSDMD (GSDMD-N), and cleaved caspase-1 and promoted the release of interleukin-1β (IL-1β) and interleukin-18 (IL-18), which induced renal cell pyroptosis and inflammation. Mechanistic studies indicated that the addition of N-acetylcysteine (NAC), a ROS scavenger, inhibited NLRP3 activation and attenuated pyroptosis. Furthermore, we revealed that 3-MCPD induced ROS accumulation by inhibiting ESCRT-III-mediated mitophagy. These results were further validated by the overexpression of charged multivesicular body protein 4B (CHMP4B), a key subunit of ESCRT-III, and the addition of the mitophagy activator carbonyl cyanide m-chlorophenylhydrazone (CCCP) and rapamycin (Rapa). Thus, our results showed that 3-MCPD could induce mitochondrial damage and produce ROS. 3-MCPD suppressed mitophagy, leading to the accumulation of damaged mitochondria and ROS, thereby activating NLRP3 and pyroptosis. Meanwhile, 3-MCPD-mediated suppression of ESCRT-III hindered the repair of GSDMD-induced cell membrane rupture, which further caused the occurrence of pyroptosis. Our findings provide new perspectives for studying the mechanisms underlying 3-MCPD-induced renal injury.

Keywords:  3-monochloropropane-1,2-diol; ESCRT-III; kidney injury; mitophagy; pyroptosis

DOI:  https://doi.org/10.1021/acs.jafc.4c01994
bioRxiv. 2024 Jun 01. pii: 2024.05.31.596875. [Epub ahead of print]

Mitoregulin supports mitochondrial membrane integrity and protects against cardiac ischemia-reperfusion injury.

Colleen S Stein, Xiaoming Zhang, Nathan H Witmer, Edward Ross Pennington, Saame Raza Shaikh, Ryan L Boudreau.

We and others discovered a highly-conserved mitochondrial transmembrane microprotein, named Mitoregulin (Mtln), that supports lipid metabolism. We reported that Mtln strongly binds cardiolipin (CL), increases mitochondrial respiration and Ca 2+ retention capacities, and reduces reactive oxygen species (ROS). Here we extend our observation of Mtln-CL binding and examine Mtln influence on cristae structure and mitochondrial membrane integrity during stress. We demonstrate that mitochondria from constitutive- and inducible Mtln-knockout (KO) mice are susceptible to membrane freeze-damage and that this can be rescued by acute Mtln re-expression. In mitochondrial-simulated lipid monolayers, we show that synthetic Mtln decreases lipid packing and monolayer elasticity. Lipidomics revealed that Mtln-KO heart tissues show broad decreases in 22:6-containing lipids and increased cardiolipin damage/remodeling. Lastly, we demonstrate that Mtln-KO mice suffer worse myocardial ischemia-reperfusion injury, hinting at a translationally-relevant role for Mtln in cardioprotection. Our work supports a model in which Mtln binds cardiolipin and stabilizes mitochondrial membranes to broadly influence diverse mitochondrial functions, including lipid metabolism, while also protecting against stress.

DOI: https://doi.org/10.1101/2024.05.31.596875
Chem Res Toxicol. 2024 Jun 14.

Deoxynivalenol Induces Drp-1-Mediated Mitochondrial Dysfunction via Elevating Oxidative Stress.

Sakshi Mishra, Radhika Kapoor, Sushma, Sonam Kanchan, Gaurav Jha, Divyansh Sharma, Bhawna Tomar, Srikanta Kumar Rath.

Mitochondrial dysfunction is often linked to neurotoxicity and neurological diseases and stems from oxidative stress, yet effective therapies are lacking. Deoxynivalenol (DON or vomitoxin) is one of the most common and hazardous type-B trichothecene mycotoxins, which contaminates crops used for food and animal feed. Despite the abundance of preliminary reports, comprehensive investigations are scarce to explore the relationship between these fungal metabolites and neurodegenerative disorders. The present study aimed to elucidate the precise role of DON in mitochondrial dynamics and cell death in neuronal cells. Excessive mitochondrial fission is associated with the pathology of several neurodegenerative diseases. Human SH-SY5Y cells were treated with different concentrations of DON (250-1000 ng/mL). Post 24 and 48 h DON treatment, the indexes were measured as follows: generation of reactive oxygen species (ROS), ATP levels, mitochondrial membrane potential, calcium levels, and cytotoxicity in SH-SY5Y cells. The results showed that cytotoxicity, intracellular calcium levels, and ROS in the DON-treated group increased, while the ATP levels and mitochondrial membrane potential decreased in a dose-dependent manner. With increasing DON concentrations, the expression levels of P-Drp-1, mitochondrial fission proteins Mff, and Fis-1 were elevated with reduced activities of MFN1, MFN2, and OPA1, further resulting in an increased expression of autophagic marker LC3 and beclin-1. The reciprocal relationship between mitochondrial damage and ROS generation is evident as ROS can instigate structural and functional deficiencies within the mitochondria. Consequently, the impaired mitochondria facilitate the release of ROS, thereby intensifying the cycle of damage and exacerbating the overall process. Using specific hydroxyl, superoxide inhibitors, and calcium chelators, our study confirmed that ROS and Ca2+-mediated signaling pathways played essential roles in DON-induced Drp1 phosphorylation. Therefore, ROS and mitochondrial fission inhibitors could provide critical research tools for drug development in mycotoxin-induced neurodegenerative diseases.

DOI: https://doi.org/10.1021/acs.chemrestox.4c00066
Neurochem Res. 2024 Jun 08.

The Role and Mechanism of Ambra1-Mediated Mitophagy in TDCPP-Exposed Mouse Hippocampal Neurons.

Xiaowei Zhang, Chuzhi Lin, Hengfang Hu, Wei Zhao, Guanlin Li, Yun Xia, Nengzhou Chen.

  Tri(1,3-dichloro-2-propyl)phosphate (TDCPP) is one of the most widely used organophosphorus flame retardants in consumer products. TDCPP has been confirmed to be neurotoxic, but its mechanism has not been clarified and may be related to mitophagy. AMBRA1 can promote neurological autophagy, but whether AMBRA1 is involved in the mechanism of TDCPP-induced neurotoxicity has not been elucidated. In this study, the optimal neuronal damage model was established by exposing mice hippocampal neurons to TDCPP. Furthermore, on the basis of this model, siRNA was used to knock down AMBRA1. Combined with qRT-PCR and Western blot techniques, we identified AMBRA1-mediated mitophagy-induced neuronal damage in vitro mechanism. The experimental results indicated that TDCPP treatment for 24 h led to a decrease in the cell viability of mouse hippocampal neurons, causing neuronal damage. Meanwhile, TDCPP exposure increased autophagy marker proteins p62 and LC3B, and down-regulated mitochondrial DNA ND1 damage and TOMM20 protein, suggesting that TDCPP exposure promoted mitophagy. In addition, TDCPP exposure led to changes in the expression of AMBRA1 and the key factors of mitophagy, FUNDC1, PINK1, and PARKIN, whereas mitophagy was inhibited after knockdown of AMBRA1. The research results indicated that exposure to TDCPP induced neuronal damage and promoted mitophagy. The mechanism may be that AMBRA1 promoted mitophagy in neuronal cells through the PARKIN-dependent/non-dependent pathway. This study revealed the toxic effects of TDCPP on the nervous system and its potential molecular mechanisms, which provided important clues for further understanding the mechanism of action of AMBAR1-mediated mitophagy.

Keywords:  AMBRA1; Mitophagy; Neuronal damage; TDCPP

DOI:  https://doi.org/10.1007/s11064-024-04160-6
Mov Disord. 2024 Jun 10.

Diverse Functions of Parkin in Midbrain Dopaminergic Neurons.

Pingping Song, Dimitri Krainc.

  Parkinson's disease (PD) is characterized by preferential degeneration of midbrain dopaminergic neurons that contributes to its typical clinical manifestation. Mutations in the parkin gene (PARK2) represent a relatively common genetic cause of early onset PD. Parkin has been implicated in PINK1-dependent mitochondrial quantity control by targeting dysfunctional mitochondria to lysosomes via mitophagy. Recent evidence suggests that parkin can be activated in PINK1-independent manner to regulate synaptic function in human dopaminergic neurons. Neuronal activity triggers CaMKII-mediated activation of parkin and its recruitment to synaptic vesicles where parkin promotes binding of synaptojanin-1 to endophilin A1 and facilitates vesicle endocytosis. In PD patient neurons, disruption of this pathway on loss of parkin leads to defective recycling of synaptic vesicles and accumulation of toxic oxidized dopamine that at least in part explains preferential vulnerability of midbrain dopaminergic neurons. These findings suggest a convergent mechanism for PD-linked mutations in parkin, synaptojanin-1, and endophilin A1 and highlight synaptic dysfunction as an early pathogenic event in PD. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Keywords:  Parkin functions; Parkinson's disease; dopaminergic neurons; synaptic terminal

DOI:  https://doi.org/10.1002/mds.29890