bims-mikwok 2024-06-30 papers

bims-mikwok

Biomed News

on Mitochondrial quality control

Issue of 2024‒06‒30
29 papers selected by
Gavin McStay, Liverpool John Moores University

Control of mitophagy initiation and progression by the TBK1 adaptors NAP1 and SINTBAD.
Zearalenone modulates the function of goat endometrial cells via the mitochondrial quality control system.
Harnessing Mitochondrial Stress for Health and Disease: Opportunities and Challenges.
Gypenosides exert cardioprotective effects by promoting mitophagy and activating PI3K/Akt/GSK-3β/Mcl-1 signaling.
PGAM5 interacts with and maintains BNIP3 to license cancer-associated muscle wasting.
Mitochondrial DNA Instability Supersedes Parkin Mutations in Driving Mitochondrial Proteomic Alterations and Functional Deficits in Polg Mutator Mice.
Targeting DRP1 with Mdivi-1 to correct mitochondrial abnormalities in ADOA plus syndrome.
Moderate-Intensity Exercise Enhances Mitochondrial Biogenesis Markers in the Skeletal Muscle of a Mouse Model Affected by Diet-Induced Obesity.
ATF5-Mediated Mitochondrial Unfolded Protein Response (UPRmt) Protects Neurons Against Oxygen-Glucose Deprivation and Cerebral Ischemia.
The extracellular matrix integrates mitochondrial homeostasis.
ADT-OH exhibits anti-metastatic activity on triple-negative breast cancer by combinatorial targeting of autophagy and mitochondrial fission.
Cardiovascular disease: Mitochondrial dynamics and mitophagy crosstalk mechanisms with novel programmed cell death and macrophage polarisation.
Knockout Mouse Studies Show That Mitochondrial CLPP Peptidase and CLPX Unfoldase Act in Matrix Condensates near IMM, as Fast Stress Response in Protein Assemblies for Transcript Processing, Translation, and Heme Production.
Pharmacologic Activation of Integrated Stress Response Kinases Inhibits Pathologic Mitochondrial Fragmentation.
Mitochondrial Protease Oct1p Regulates Mitochondrial Homeostasis and Influences Pathogenicity through Affecting Hyphal Growth and Biofilm Formation Activities in Candida albicans.
FoxG1/BNIP3 axis promotes mitophagy and blunts cisplatin resistance in osteosarcoma.
The catalytic activity of methyltransferase METTL15 is dispensable for its role in mitochondrial ribosome biogenesis.
Simple prerequisite of presequence for mitochondrial protein import in the unicellular red alga Cyanidioschyzon merolae.
LPS-related muscle loss is associated with the alteration of Bacteroidetes abundance, systemic inflammation, and mitochondrial morphology in a weaned piglet model.
A positive FOXP3/lncRNA SNHG1 feedback axis ameliorates cardiomyocytes hypertrophy by negatively regulating Parkin-mediated mitophagy.
Age-related changes in the mitochondrial, synthesis of steroids, and cellular homeostasis of the chicken ovary.
Uremic Toxin Receptor AhR Facilitates Renal Senescence and Fibrosis via Suppressing Mitochondrial Biogenesis.
Electron Microscopic Mapping of Mitochondrial Morphology in the Cochlear Nerve Fibers.
A quinolinyl resveratrol derivative alleviates acute ischemic stroke injury by promoting mitophagy for neuroprotection via targeting CK2α'.
ATAD3 is a limiting factor in mitochondrial biogenesis and adipogenesis of white adipocyte-like 3T3-L1 cells.
[Retracted] Sirt1 inhibits HG‑induced endothelial injury: Role of Mff‑based mitochondrial fission and F‑actin homeostasis‑mediated cellular migration.
The fnr-like mutants confer isoxaben tolerance by initiating mitochondrial retrograde signalling.
Mitochondrial homeostasis in odontoblast: Physiology, pathogenesis and targeting strategies.
Role of mitochondrial homeostasis in D-galactose-induced cardiovascular ageing from bench to bedside.

Nat Struct Mol Biol. 2024 Jun 25.

Control of mitophagy initiation and progression by the TBK1 adaptors NAP1 and SINTBAD.

Elias Adriaenssens, Thanh Ngoc Nguyen, Justyna Sawa-Makarska, Grace Khuu, Martina Schuschnig, Stephen Shoebridge, Marvin Skulsuppaisarn, Emily Maria Watts, Kitti Dora Csalyi, Benjamin Scott Padman, Michael Lazarou, Sascha Martens.

Mitophagy preserves overall mitochondrial fitness by selectively targeting damaged mitochondria for degradation. The regulatory mechanisms that prevent PTEN-induced putative kinase 1 (PINK1) and E3 ubiquitin ligase Parkin (PINK1/Parkin)-dependent mitophagy and other selective autophagy pathways from overreacting while ensuring swift progression once initiated are largely elusive. Here, we demonstrate how the TBK1 (TANK-binding kinase 1) adaptors NAP1 (NAK-associated protein 1) and SINTBAD (similar to NAP1 TBK1 adaptor) restrict the initiation of OPTN (optineurin)-driven mitophagy by competing with OPTN for TBK1. Conversely, they promote the progression of nuclear dot protein 52 (NDP52)-driven mitophagy by recruiting TBK1 to NDP52 and stabilizing its interaction with FIP200. Notably, OPTN emerges as the primary recruiter of TBK1 during mitophagy initiation, which in return boosts NDP52-mediated mitophagy. Our results thus define NAP1 and SINTBAD as cargo receptor rheostats, elevating the threshold for mitophagy initiation by OPTN while promoting the progression of the pathway once set in motion by supporting NDP52. These findings shed light on the cellular strategy to prevent pathway hyperactivity while still ensuring efficient progression.

DOI: https://doi.org/10.1038/s41594-024-01338-y
FASEB J. 2024 Jul 15. 38(13): e23701

Zearalenone modulates the function of goat endometrial cells via the mitochondrial quality control system.

Guomin Zhang, Cheng Zeng, Xuan Sun, Qi Zhang, Yifei Wang, Rongxin Xia, Qingyang Mai, Gang Xue, Han Huang, Feng Wang.

  Zearalenone (ZEN) is a mycotoxin known for its estrogen-like effects, which can disrupt the normal physiological function of endometrial cells and potentially lead to abortion in female animals. However, the precise mechanism by which ZEN regulates endometrial function remains unclear. In this study, we found that the binding receptor estrogen receptors for ZEN is extensively expressed across various segments of the uterus and within endometrial cells, and a certain concentration of ZEN treatment reduced the proliferation capacity of goat endometrial epithelial cells (EECs) and endometrial stromal cells (ESCs). Meanwhile, cell cycle analysis revealed that ZEN treatment leaded to cell cycle arrest in goat EECs and ESCs. To explore the underlying mechanism, we investigated the mitochondrial quality control systems and observed that ZEN triggered excessive mitochondrial fission and disturbed the balance of mitochondrial fusion-fission dynamics, impaired mitochondrial biogenesis, increased mitochondrial unfolded protein response and mitophagy in goat EECs and ESCs. Additionally, ZEN treatment reduced the activities of mitochondrial respiratory chain complexes, heightened the production of hydrogen peroxide and reactive oxygen species, and caused cellular oxidative stress and mitochondrial dysfunction. These results suggest that ZEN has adverse effects on goat endometrium cells by disrupting the mitochondrial quality control system and affecting cell cycle and proliferation. Understanding the underlying molecular pathways involved in ZEN-induced mitochondrial dysfunction and its consequences on cell function will provide critical insights into the reproductive toxicity of ZEN and contribute to safeguarding the health and wellbeing of animals and humans exposed to this mycotoxin.

Keywords:  cell proliferation; endometrial cells; goat; mitochondrial quality control system; zearalenone

DOI:  https://doi.org/10.1096/fj.202302198RR
Biology (Basel). 2024 May 29. pii: 394. [Epub ahead of print]13(6):

Harnessing Mitochondrial Stress for Health and Disease: Opportunities and Challenges.

Yujia Sun, Linlu Jin, Yixue Qin, Zhi Ouyang, Jian Zhong, Ye Zeng.

  Mitochondria, essential organelles orchestrating cellular metabolism, have emerged as central players in various disease pathologies. Recent research has shed light on mitohormesis, a concept proposing an adaptive response of mitochondria to minor disturbances in homeostasis, offering novel therapeutic avenues for mitochondria-related diseases. This comprehensive review explores the concept of mitohormesis, elucidating its induction mechanisms and occurrence. Intracellular molecules like reactive oxygen species (ROS), calcium, mitochondrial unfolded proteins (UPRmt), and integrated stress response (ISR), along with external factors such as hydrogen sulfide (H2S), physical stimuli, and exercise, play pivotal roles in regulating mitohormesis. Based on the available evidence, we elucidate how mitohormesis maintains mitochondrial homeostasis through mechanisms like mitochondrial quality control and mitophagy. Furthermore, the regulatory role of mitohormesis in mitochondria-related diseases is discussed. By envisioning future applications, this review underscores the significance of mitohormesis as a potential therapeutic target, paving the way for innovative interventions in disease management.

Keywords:  cellular metabolism; mitochondrial dysfunction; mitohormesis; reactive oxygen species

DOI:  https://doi.org/10.3390/biology13060394
PeerJ. 2024 ;12 e17538

Gypenosides exert cardioprotective effects by promoting mitophagy and activating PI3K/Akt/GSK-3β/Mcl-1 signaling.

Yizhe Zheng, Wei Wei, Yukun Wang, Tingting Li, Yundong Wei, Si Gao.

  Background: Gynostemma pentaphyllum (Thunb.) Makino, a well-known edible and medicinal plant, has anti-aging properties and is used to treataging-associated conditions such as diabetes, metabolic syndrome, and cardiovascular diseases. Gypenosides (GYPs) are the primary constituents of G. pentaphyllum. Increasing evidence indicates that GYPs are effective at preserving mitochondrial homeostasis and preventing heart failure (HF). This study aimed to uncover the cardioprotective mechanisms of GYPs related to mitochondrial regulation.Methods: The bioactive components in GYPs and the potential targets in treating HF were obtained and screened using the network pharmacology approach, followed by drug-disease target prediction and enrichment analyses. The pharmacological effects of GYPs in cardioprotection, mitochondrial function, mitochondrial quality control, and underlying mechanisms were further investigated in Doxorubicin (Dox)-stimulated H9c2 cardiomyocytes.
Results: A total of 88 bioactive compounds of GYPs and their respective 71 drug-disease targets were identified. The hub targets covered MAPK, EGFR, PI3KCA, and Mcl-1. Enrichment analysis revealed that the pathways primarily contained PI3K/Akt, MAPK, and FoxO signalings, as well as calcium regulation, protein phosphorylation, apoptosis, and mitophagy process. In Dox-stimulated H9c2 rat cardiomyocytes, pretreatment with GYPs increased cell viability, enhanced cellular ATP content, restored basal oxygen consumption rate (OCR), and improved mitochondrial membrane potential (MMP). Furthermore, GYPs improved PINK1/parkin-mediated mitophagy without influencing mitochondrial fission/fusion proteins and the autophagic LC3 levels. Mechanistically, the phosphorylation of PI3K, Akt, GSK-3β, and the protein level of Mcl-1 was upregulated by GYP treatment.
Conclusion: Our findings reveal that GYPs exert cardioprotective effects by rescuing the defective mitophagy, and PI3K/Akt/GSK-3β/Mcl-1 signaling is potentially involved in this process.

Keywords:  GSK-3β; Gypenosides; Heart failure; Mcl-1; Mitochondria; Mitophagy; PI3K/Akt pathway

DOI:  https://doi.org/10.7717/peerj.17538
Autophagy. 2024 Jun 26. 1-16

PGAM5 interacts with and maintains BNIP3 to license cancer-associated muscle wasting.

Qingyuan Zhang, Chunhui Chen, Ye Ma, Xinyi Yan, Nianhong Lai, Hao Wang, Baogui Gao, Anna Meilin Gu, Qinrui Han, Qingling Zhang, Lei La, Xuegang Sun.

  Regressing the accelerated degradation of skeletal muscle protein is a significant goal for cancer cachexia management. Here, we show that genetic deletion of Pgam5 ameliorates skeletal muscle atrophy in various tumor-bearing mice. pgam5 ablation represses excessive myoblast mitophagy and effectively suppresses mitochondria meltdown and muscle wastage. Next, we define BNIP3 as a mitophagy receptor constitutively associating with PGAM5. bnip3 deletion restricts body weight loss and enhances the gastrocnemius mass index in the age- and tumor size-matched experiments. The NH2-terminal region of PGAM5 binds to the PEST motif-containing region of BNIP3 to dampen the ubiquitination and degradation of BNIP3 to maintain continuous mitophagy. Finally, we identify S100A9 as a pro-cachectic chemokine via activating AGER/RAGE. AGER deficiency or S100A9 inhibition restrains skeletal muscle loss by weakening the interaction between PGAM5 and BNIP3. In conclusion, the AGER-PGAM5-BNIP3 axis is a novel but common pathway in cancer-associated muscle wasting that can be targetable. Abbreviation: AGER/RAGE: advanced glycation end-product specific receptor; BA1: bafilomycin A1; BNIP3: BCL2 interacting protein 3; BNIP3L: BCL2 interacting protein 3 like; Ckm-Cre: creatinine kinase, muscle-specific Cre; CM: conditioned medium; CON/CTRL: control; CRC: colorectal cancer; FUNDC1: FUN14 domain containing 1; MAP1LC3A/LC3A: microtubule associated protein 1 light chain 3 alpha; PGAM5: PGAM family member 5, mitochondrial serine/threonine protein phosphatase; S100A9: S100 calcium binding protein A9; SQSTM1/p62: sequestosome 1; TOMM20: translocase of outer mitochondrial membrane 20; TIMM23: translocase of inner mitochondrial membrane 23; TSKO: tissue-specific knockout; VDAC1: voltage dependent anion channel 1.

Keywords:  AGER; S100A9; cachexia; cancer; mitophagy; muscle atrophy

DOI:  https://doi.org/10.1080/15548627.2024.2360340
Int J Mol Sci. 2024 Jun 11. pii: 6441. [Epub ahead of print]25(12):

Mitochondrial DNA Instability Supersedes Parkin Mutations in Driving Mitochondrial Proteomic Alterations and Functional Deficits in Polg Mutator Mice.

Andrew J Trease, Steven Totusek, Eliezer Z Lichter, Kelly L Stauch, Howard S Fox.

  Mitochondrial quality control is essential in mitochondrial function. To examine the importance of Parkin-dependent mechanisms in mitochondrial quality control, we assessed the impact of modulating Parkin on proteome flux and mitochondrial function in a context of reduced mtDNA fidelity. To accomplish this, we crossed either the Parkin knockout mouse or ParkinW402A knock-in mouse lines to the Polg mitochondrial mutator line to generate homozygous double mutants. In vivo longitudinal isotopic metabolic labeling was followed by isolation of liver mitochondria and synaptic terminals from the brain, which are rich in mitochondria. Mass spectrometry and bioenergetics analysis were assessed. We demonstrate that slower mitochondrial protein turnover is associated with loss of mtDNA fidelity in liver mitochondria but not synaptic terminals, and bioenergetic function in both tissues is impaired. Pathway analysis revealed loss of mtDNA fidelity is associated with disturbances of key metabolic pathways, consistent with its association with metabolic disorders and neurodegeneration. Furthermore, we find that loss of Parkin leads to exacerbation of Polg-driven proteomic consequences, though it may be bioenergetically protective in tissues exhibiting rapid mitochondrial turnover. Finally, we provide evidence that, surprisingly, dis-autoinhibition of Parkin (ParkinW402A) functionally resembles Parkin knockout and fails to rescue deleterious Polg-driven effects. Our study accomplishes three main outcomes: (1) it supports recent studies suggesting that Parkin dependence is low in response to an increased mtDNA mutational load, (2) it provides evidence of a potential protective role of Parkin insufficiency, and (3) it draws into question the therapeutic attractiveness of enhancing Parkin function.

Keywords:  Parkin; Parkinson’s disease; aging; metabolism; mitochondria; mitophagy

DOI:  https://doi.org/10.3390/ijms25126441
JCI Insight. 2024 Jun 25. pii: e180582. [Epub ahead of print]

Targeting DRP1 with Mdivi-1 to correct mitochondrial abnormalities in ADOA plus syndrome.

Yan Lin, Dongdong Wang, Busu Li, Jiayin Wang, Ling Xu, Xiaohan Sun, Kunqian Ji, Chuanzhu Yan, Fuchen Liu, Yuying Zhao.

  Autosomal dominant optic atrophy plus (ADOA+) is characterized by primary optic nerve atrophy accompanied by a spectrum of degenerative neurological symptoms. Despite ongoing research, no effective treatments are currently available for this condition. Our study provided evidence for the pathogenicity of an unreported c.1780T>C variant in the OPA1 gene through patient-derived skin fibroblasts and an engineered HEK293T cell line with OPA1 downregulation. We demonstrated that OPA1 insufficiency promoted mitochondrial fragmentation and increased DRP1 expression, disrupting mitochondrial dynamics. Consequently, this disruption enhanced mitophagy and caused mitochondrial dysfunction, contributing to the ADOA+ phenotype. Notably, the Drp1 inhibitor, mitochondrial division inhibitor-1 (Mdivi-1), effectively mitigated the adverse effects of OPA1 impairment. These effects included reduced Drp1 phosphorylation, decreased mitochondrial fragmentation, and balanced mitophagy. Thus, we propose that intervening in DRP1 with Mdivi-1 could correct mitochondrial abnormalities, offering a promising therapeutic approach for managing ADOA+.

Keywords:  Autophagy; Drug therapy; Mitochondria; Neuroscience; Ophthalmology

DOI:  https://doi.org/10.1172/jci.insight.180582
Nutrients. 2024 Jun 12. pii: 1836. [Epub ahead of print]16(12):

Moderate-Intensity Exercise Enhances Mitochondrial Biogenesis Markers in the Skeletal Muscle of a Mouse Model Affected by Diet-Induced Obesity.

Lauren Jun, Emily Knight, Tom L Broderick, Layla Al-Nakkash, Brielle Tobin, Thangiah Geetha, Jeganathan Ramesh Babu.

  Skeletal muscle is composed of bundles of muscle fibers with distinctive characteristics. Oxidative muscle fiber types contain higher mitochondrial content, relying primarily on oxidative phosphorylation for ATP generation. Notably, as a result of obesity, or following prolonged exposure to a high-fat diet, skeletal muscle undergoes a shift in fiber type toward a glycolytic type. Mitochondria are highly dynamic organelles, constantly undergoing mitochondrial biogenesis and dynamic processes. Our study aims to explore the impact of obesity on skeletal muscle mitochondrial biogenesis and dynamics and also ascertain whether the skeletal muscle fiber type shift occurs from the aberrant mitochondrial machinery. Furthermore, we investigated the impact of exercise in preserving the oxidative muscle fiber types despite obesity. Mice were subjected to a normal standard chow and water or high-fat diet with sugar water (HFS) with or without exercise training. After 12 weeks of treatment, the HFS diet resulted in a noteworthy reduction in the markers of mitochondrial content, which was recovered by exercise training. Furthermore, higher mitochondrial biogenesis markers were observed in the exercised group with a subsequent increase in the mitochondrial fission marker. In conclusion, these findings imply a beneficial impact of moderate-intensity exercise on the preservation of oxidative capacity in the muscle of obese mouse models.

Keywords:  exercise; high-fat diet; mitochondria; obesity; skeletal muscle

DOI:  https://doi.org/10.3390/nu16121836
Stroke. 2024 Jul;55(7): 1904-1913

ATF5-Mediated Mitochondrial Unfolded Protein Response (UPRmt) Protects Neurons Against Oxygen-Glucose Deprivation and Cerebral Ischemia.

Hong An, Bing Zhou, Kazuhide Hayakawa, Violeta Durán Laforet, Ji-Hyun Park, Yoshihiko Nakamura, Emiri T Mandeville, Ning Liu, Shuzhen Guo, Zhanyang Yu, Jingfei Shi, Di Wu, Wenlu Li, Eng H Lo, Xunming Ji.

  BACKGROUND: The mitochondrial unfolded protein response (UPRmt) is an evolutionarily conserved mitochondrial response that is critical for maintaining mitochondrial and energetic homeostasis under cellular stress after tissue injury and disease. Here, we ask whether UPRmt may be a potential therapeutic target for ischemic stroke.METHODS: We performed the middle cerebral artery occlusion and oxygen-glucose deprivation models to mimic ischemic stroke in vivo and in vitro, respectively. Oligomycin and meclizine were used to trigger the UPRmt. We used 2,3,5-triphenyltetrazolium chloride staining, behavioral tests, and Nissl staining to evaluate cerebral injury in vivo. The Cell Counting Kit-8 assay and the Calcein AM Assay Kit were conducted to test cerebral injury in vitro.
RESULTS: Inducing UPRmt with oligomycin protected neuronal cultures against oxygen-glucose deprivation. UPRmt could also be triggered with meclizine, and this Food and Drug Administration-approved drug also protected neurons against oxygen-glucose deprivation. Blocking UPRmt with siRNA against activating transcription factor 5 eliminated the neuroprotective effects of meclizine. In a mouse model of focal cerebral ischemia, pretreatment with meclizine was able to induce UPRmt in vivo, which reduced infarction and improved neurological outcomes.
CONCLUSIONS: These findings suggest that the UPRmt is important in maintaining the survival of neurons facing ischemic/hypoxic stress. The UPRmt mechanism may provide a new therapeutic avenue for ischemic stroke.

Keywords:  homeostasis; ischemic stroke; meclizine; oligomycins; unfolded protein response

DOI:  https://doi.org/10.1161/STROKEAHA.123.045550
Cell. 2024 Jun 24. pii: S0092-8674(24)00638-X. [Epub ahead of print]

The extracellular matrix integrates mitochondrial homeostasis.

Hanlin Zhang, C Kimberly Tsui, Gilberto Garcia, Larry K Joe, Haolun Wu, Ayane Maruichi, Wudi Fan, Sentibel Pandovski, Peter H Yoon, Brant M Webster, Jenni Durieux, Phillip A Frankino, Ryo Higuchi-Sanabria, Andrew Dillin.

  Cellular homeostasis is intricately influenced by stimuli from the microenvironment, including signaling molecules, metabolites, and pathogens. Functioning as a signaling hub within the cell, mitochondria integrate information from various intracellular compartments to regulate cellular signaling and metabolism. Multiple studies have shown that mitochondria may respond to various extracellular signaling events. However, it is less clear how changes in the extracellular matrix (ECM) can impact mitochondrial homeostasis to regulate animal physiology. We find that ECM remodeling alters mitochondrial homeostasis in an evolutionarily conserved manner. Mechanistically, ECM remodeling triggers a TGF-β response to induce mitochondrial fission and the unfolded protein response of the mitochondria (UPRMT). At the organismal level, ECM remodeling promotes defense of animals against pathogens through enhanced mitochondrial stress responses. We postulate that this ECM-mitochondria crosstalk represents an ancient immune pathway, which detects infection- or mechanical-stress-induced ECM damage, thereby initiating adaptive mitochondria-based immune and metabolic responses.

Keywords:  TGF-β; TMEM2; extracellular matrix; hyaluronan; immunity; mitochondria

DOI:  https://doi.org/10.1016/j.cell.2024.05.057
Cell Death Dis. 2024 Jun 28. 15(6): 463

ADT-OH exhibits anti-metastatic activity on triple-negative breast cancer by combinatorial targeting of autophagy and mitochondrial fission.

Shihui Yu, Zhiting Cao, Fangfang Cai, Yingying Yao, Xiaoyao Chang, Xiaoyang Wang, Hongqin Zhuang, Zi-Chun Hua.

High basal autophagy and enhanced mitochondrial fission in triple-negative breast cancer (TNBC) cells support cell migration and promote plasticity of cancer cell metabolism. Here, we suggest a novel combination therapy approach for the treatment of TNBC that targets Drp1-mediated mitochondrial fission and autophagy pathways. Hydrogen sulfide (H2S) mediates a myriad of biological processes, including autophagy and mitochondrial function. In this study, we demonstrated that 5-(4-hydroxyphenyl)-3H-1,2-dithiole-3-thione (ADT-OH), one of the most widely utilized sustained-release H2S donors, effectively suppresses metastasis of TNBC cells in the absence of proliferation inhibition in vitro and in vivo. ADT-OH treatment ameliorated autophagy flux by suppressing autophagosome formation and induced mitochondrial elongation through decreasing expression of dynamin-related protein 1 (Drp1) and increasing expression of mitochondrial fusion protein (Mfn2). At the same time, ADT-OH downregulated mitophagy flux and inhibited mitochondrial function, eventually leading to the inhibition of migration and invasion in TNBC cells. In vivo, intraperitoneal administration of ADT-OH revealed a potent anti-metastatic activity in three different animal models, the MDA-MB-231 orthotopic xenograft model, the 4T1-Luci orthotopic model and the 4T1-Luci tail vein metastasis model. However, ADT-OH has an extremely low water solubility, which is a significant barrier to its effectiveness. Thus, we demonstrated that the solubility of ADT-OH in water can be improved significantly by absorption with hydroxypropyl-β-cyclodextrin (CD). Remarkably, the obtained CD-ADT-OH demonstrated superior anti-cancer effect to ADT-OH in vivo. Altogether, this study describes a novel regulator of mammalian mitochondrial fission and autophagy, with potential utility as an experimental therapeutic agent for metastatic TNBC.

DOI: https://doi.org/10.1038/s41419-024-06829-w
Pharmacol Res. 2024 Jun 21. pii: S1043-6618(24)00203-2. [Epub ahead of print]206 107258

Cardiovascular disease: Mitochondrial dynamics and mitophagy crosstalk mechanisms with novel programmed cell death and macrophage polarisation.

Dandan Liu, Hewei Qin, Yang Gao, Mengyan Sun, Mengnan Wang.

  Several cardiovascular illnesses are associated with aberrant activation of cellular pyroptosis, ferroptosis, necroptosis, cuproptosis, disulfidptosis, and macrophage polarisation as hallmarks contributing to vascular damage and abnormal cardiac function. Meanwhile, these three novel forms of cellular dysfunction are closely related to mitochondrial homeostasis. Mitochondria are the main organelles that supply energy and maintain cellular homeostasis. Mitochondrial stability is maintained through a series of regulatory pathways, such as mitochondrial fission, mitochondrial fusion and mitophagy. Studies have shown that mitochondrial dysfunction (e.g., impaired mitochondrial dynamics and mitophagy) promotes ROS production, leading to oxidative stress, which induces cellular pyroptosis, ferroptosis, necroptosis, cuproptosis, disulfidptosis and macrophage M1 phenotypic polarisation. Therefore, an in-depth knowledge of the dynamic regulation of mitochondria during cellular pyroptosis, ferroptosis, necroptosis, cuproptosis, disulfidptosis and macrophage polarisation is necessary to understand cardiovascular disease development. This paper systematically summarises the impact of changes in mitochondrial dynamics and mitophagy on regulating novel cellular dysfunctions and macrophage polarisation to promote an in-depth understanding of the pathogenesis of cardiovascular diseases and provide corresponding theoretical references for treating cardiovascular diseases.

Keywords:  Cuproptosis; Disulfidptosis; Ferroptosis; Macrophage polarization; Mitochondrial dynamics; Mitophagy

DOI:  https://doi.org/10.1016/j.phrs.2024.107258
Genes (Basel). 2024 May 27. pii: 694. [Epub ahead of print]15(6):

Knockout Mouse Studies Show That Mitochondrial CLPP Peptidase and CLPX Unfoldase Act in Matrix Condensates near IMM, as Fast Stress Response in Protein Assemblies for Transcript Processing, Translation, and Heme Production.

Jana Key, Suzana Gispert, Georg Auburger.

  LONP1 is the principal AAA+ unfoldase and bulk protease in the mitochondrial matrix, so its deletion causes embryonic lethality. The AAA+ unfoldase CLPX and the peptidase CLPP also act in the matrix, especially during stress periods, but their substrates are poorly defined. Mammalian CLPP deletion triggers infertility, deafness, growth retardation, and cGAS-STING-activated cytosolic innate immunity. CLPX mutations impair heme biosynthesis and heavy metal homeostasis. CLPP and CLPX are conserved from bacteria to humans, despite their secondary role in proteolysis. Based on recent proteomic-metabolomic evidence from knockout mice and patient cells, we propose that CLPP acts on phase-separated ribonucleoprotein granules and CLPX on multi-enzyme condensates as first-aid systems near the inner mitochondrial membrane. Trimming within assemblies, CLPP rescues stalled processes in mitoribosomes, mitochondrial RNA granules and nucleoids, and the D-foci-mediated degradation of toxic double-stranded mtRNA/mtDNA. Unfolding multi-enzyme condensates, CLPX maximizes PLP-dependent delta-transamination and rescues malformed nascent peptides. Overall, their actions occur in granules with multivalent or hydrophobic interactions, separated from the aqueous phase. Thus, the role of CLPXP in the matrix is compartment-selective, as other mitochondrial peptidases: MPPs at precursor import pores, m-AAA and i-AAA at either IMM face, PARL within the IMM, and OMA1/HTRA2 in the intermembrane space.

Keywords:  ALAS; GFM1; ISC; OAT; PNPT1; Perrault syndrome type 3 (PRLTS3); RNA-G4; VWA8; iron toxicity; pyridoxal-5′-phosphate

DOI:  https://doi.org/10.3390/genes15060694
bioRxiv. 2024 Jun 10. pii: 2024.06.10.598126. [Epub ahead of print]

Pharmacologic Activation of Integrated Stress Response Kinases Inhibits Pathologic Mitochondrial Fragmentation.

Kelsey R Baron, Samantha Oviedo, Sophia Krasny, Mashiat Zaman, Rama Aldakhlallah, Prakhyat Mathur, Gerald Pfeffer, Michael J Bollong, Timothy Shutt, Danielle A Grotjahn, R Luke Wiseman.

Excessive mitochondrial fragmentation is associated with the pathologic mitochondrial dysfunction implicated in the pathogenesis of etiologically-diverse diseases, including many neurodegenerative disorders. The integrated stress response (ISR) - comprising the four eIF2α kinases PERK, GCN2, PKR, and HRI - is a prominent stress-responsive signaling pathway that regulates mitochondrial morphology and function in response to diverse types of pathologic insult. This suggests that pharmacologic, stress-independent activation of the ISR represents a potential strategy to mitigate pathologic mitochondrial fragmentation associated with human disease. Here, we show that pharmacologic, stress-independent activation of the ISR kinases HRI or GCN2 promotes adaptive mitochondrial elongation and prevents mitochondrial fragmentation induced by the calcium ionophore ionomycin. Further, we show that stress-independent activation of these ISR kinases reduces mitochondrial fragmentation and restores basal mitochondrial morphology in patient fibroblasts expressing the pathogenic D414V variant of the pro-fusion mitochondrial GTPase MFN2 associated with neurological dysfunctions including ataxia, optic atrophy, and sensorineural hearing loss. These results identify pharmacologic, stress-independent activation of ISR kinases as a potential strategy to prevent pathologic mitochondrial fragmentation induced by disease-relevant chemical and genetic insults, further motivating the pursuit of highly selective ISR kinase-activating compounds as a therapeutic strategy to mitigate mitochondrial dysfunction implicated in diverse human diseases.

DOI: https://doi.org/10.1101/2024.06.10.598126
J Fungi (Basel). 2024 May 30. pii: 391. [Epub ahead of print]10(6):

Mitochondrial Protease Oct1p Regulates Mitochondrial Homeostasis and Influences Pathogenicity through Affecting Hyphal Growth and Biofilm Formation Activities in Candida albicans.

Xiaoxiao Zhu, Feng Jin, Guangyuan Yang, Tian Zhuang, Cangcang Zhang, Hanjing Zhou, Xiaojia Niu, Hongchen Wang, Daqiang Wu.

  Mitochondria, as the core metabolic organelles, play a crucial role in aerobic respiration/biosynthesis in fungi. Numerous studies have demonstrated a close relationship between mitochondria and Candida albicans virulence and drug resistance. Here, we report an octapeptide-aminopeptidase located in the mitochondrial matrix named Oct1p. Its homolog in the model fungus Saccharomyces cerevisiae is one of the key proteins in maintaining mitochondrial respiration and protein stability. In this study, we utilized evolutionary tree analysis, gene knockout experiments, mitochondrial function detection, and other methods to demonstrate the impact of Oct1p on the mitochondrial function of C. albicans. Furthermore, through transcriptome analysis, real-time quantitative PCR, and morphological observation, we discovered that the absence of Oct1p results in functional abnormalities in C. albicans, affecting hyphal growth, cell adhesion, and biofilm formation. Finally, the in vivo results of the infection of Galleria mellonella larvae and vulvovaginal candidiasis in mice indicate that the loss of Oct1p led to the decreased virulence of C. albicans. In conclusion, this study provides a solid theoretical foundation for treating Candida diseases, developing new targeted drugs, and serves as a valuable reference for investigating the connection between mitochondria and virulence in other pathogenic fungi.

Keywords:  Candida albicans; Oct1p; hypha formation; mitochondria; virulence

DOI:  https://doi.org/10.3390/jof10060391
Cancer Sci. 2024 Jun 26.

FoxG1/BNIP3 axis promotes mitophagy and blunts cisplatin resistance in osteosarcoma.

Baolong Pan, Yan Li, Huiyun Han, Lu Zhang, Xuemei Hu, Yanyu Pan, Zhuohui Peng.

  Cisplatin (CDDP) is a commonly used chemotherapeutic for osteosarcoma (OS) patients, and drug resistance remains as a major hurdle to undermine the treatment outcome. Here, we investigated the potential involvement of FoxG1 and BNIP3 in CDDP resistance of OS cells. FoxG1 and BNIP3 expression levels were detected in the CDDP-sensitive and CDDP-resistant OS tumors and cell lines. Mitophagy was observed through transmission electron microscope analysis. The sensitivity to CDDP in OS cells upon FoxG1 overexpression was examined in cell and animal models. We found that FoxG1 and BNIP3 showed significant downregulation in the CDDP-resistant OS tumor samples and cell lines. CDDP-resistant OS tumor specimens and cells displayed impaired mitophagy. FoxG1 overexpression promoted BNIP3 expression, enhanced mitophagy in CDDP-resistant OS cells, and resensitized the resistant cells to CDDP treatment in vitro and in vivo. Our data highlighted the role of the FoxG1/BNIP3 axis in regulating mitophagy and dictating CDDP resistance in OS cells, suggesting targeting FoxG1/BNIP3-dependent mitophagy as a potential strategy to overcome CDDP resistance in OS.

Keywords:  BNIP3; FoxG1; cisplatin (CDDP); drug resistance; mitophgy; osteosarcoma (OS)

DOI:  https://doi.org/10.1111/cas.16242
RNA Biol. 2024 Jan;21(1): 23-30

The catalytic activity of methyltransferase METTL15 is dispensable for its role in mitochondrial ribosome biogenesis.

Christian D Mutti, Lindsey Van Haute, Michal Minczuk.

  Ribosomes are large macromolecular complexes composed of both proteins and RNA, that require a plethora of factors and post-transcriptional modifications for their biogenesis. In human mitochondria, the ribosomal RNA is post-transcriptionally modified at ten sites. The N4-methylcytidine (m4C) methyltransferase, METTL15, modifies the 12S rRNA of the small subunit at position C1486. The enzyme is essential for mitochondrial protein synthesis and assembly of the mitoribosome small subunit, as shown here and by previous studies. Here, we demonstrate that the m4C modification is not required for small subunit biogenesis, indicating that the chaperone-like activity of the METTL15 protein itself is an essential component for mitoribosome biogenesis.

Keywords:  Mitochondrial ribosome; chaperone; epitranscriptomics; methyltransferase; mitochondria; ribosomal RNA

DOI:  https://doi.org/10.1080/15476286.2024.2369374
J Cell Sci. 2024 Jun 28. pii: jcs.262042. [Epub ahead of print]

Simple prerequisite of presequence for mitochondrial protein import in the unicellular red alga Cyanidioschyzon merolae.

Riko Hirata, Yuko Mogi, Kohei Takahashi, Hisayoshi Nozaki, Tetsuya Higashiyama, Yamato Yoshida.

  Mitochondrial biogenesis relies on hundreds of proteins that are derived from genes encoded in the nucleus. According to characteristic properties of N-terminal targeting peptides (TP) and multi-step authentication by the protein translocase called the TOM complex, nascent polypeptides satisfying the requirements are imported into mitochondria. However, it is unknown whether eukaryotic cells with a single mitochondrion per cell have a similar complexity of presequence requirements for mitochondrial protein import compared to other eukaryotes with multiple mitochondria. Based on putative mitochondrial TP sequences in the unicellular red alga Cyanidioschyzon merolae, we designed synthetic TPs (synTPs) and showed that functional TPs must have at least one basic residue and a specific amino acid composition, although their physicochemical properties are not strictly determined. Combined with the simple composition of the TOM complex in C. merolae, our results suggest that a regional positive charge in TP is verified solely by TOM22 for mitochondrial protein import in C. merolae. The simple authentication mechanism indicates that the monomitochondrial C. merolae does not need to increase the cryptographic complexity of the lock-and-key mechanism for mitochondrial protein import.

Keywords:  Mitochondrial presequence; Mitochondrial protein import; Monomitochondrial eukaryote; Unicellular red alga

DOI:  https://doi.org/10.1242/jcs.262042
Sci China Life Sci. 2024 Jun 21.

LPS-related muscle loss is associated with the alteration of Bacteroidetes abundance, systemic inflammation, and mitochondrial morphology in a weaned piglet model.

Jiayi Yu, Changbing Zheng, Qiuping Guo, Yulong Yin, Yehui Duan, Fengna Li.

  We previously demonstrated that lipopolysaccharide (LPS) injection-induced immune stress could impair muscle growth in weaned piglets, but the precise mechanisms behind this remain elusive. Here, we found that chronic immune stress induced by LPS resulted in a significant reduction of 36.86% in the total muscle mass of piglets at 5 d post-treatment compared with the control group. At 1 d, prior to muscle mass loss, multiple alterations were noted in response to LPS treatment. These included a reduction in the abundance of Bacteroidetes, an increase in serum concentrations of pro-inflammatory cytokines, compromised mitochondrial morphology, and an upregulation in the expression of dynamin-related protein 1 (Drp1), a critical protein involved in mitochondrial fission. We highlight a strong negative correlation between Bacteroidetes abundance and the levels of serum pro-inflammatory cytokines, corroborated by in vivo intervention strategies in the musculature of both pig and mouse models. Mechanistically, the effects of Bacteroidetes on inflammation and muscle mass loss may involve the signaling pathway of the tauro-β-muricholic acid-fibroblast growth factor 15. Furthermore, the induction of overexpression of inflammatory cytokines, achieved without LPS treatment through oral administration of recombinant human IL-6 (rhIL-6), led to increased levels of circulating cytokines, subsequently causing a decrease in muscle mass. Notably, pre-treatment with Mdivi-1, an inhibitor of Drp-1, markedly attenuated the LPS-induced elevation in reactive oxygen species levels and rescued the associated decline in muscle mass. Collectively, these data indicate that LPS-induced muscle mass loss was linked to the reduction of Bacteroidetes abundance, increased inflammation, and the disruption of mitochondrial morphology. These insights offer promising avenues for the identification of potential therapeutic targets aimed at mitigating muscle mass loss.

Keywords:  Bacteroidetes; inflammation; mitochondrial morphology; muscle mass loss; piglets

DOI:  https://doi.org/10.1007/s11427-023-2552-7
Int Immunopharmacol. 2024 Jun 21. pii: S1567-5769(24)01047-6. [Epub ahead of print]137 112526

A positive FOXP3/lncRNA SNHG1 feedback axis ameliorates cardiomyocytes hypertrophy by negatively regulating Parkin-mediated mitophagy.

Jingyi Zhang, Xuemei Luo, Xian Yang, Baoyan Wang, Lufeng Zheng, Simin Yan.

  In this study, we identified FOXP3 as a transcription factor for lncRNA SNHG1, which exerts a significant protective role against cardiomyocyte hypertrophy. Through DNA-pull down experiments and ChIP analysis, we confirmed that FOXP3 could bind to the promoter of SNHG1. Luciferase reporter and RT-qPCR experiments validated that FOXP3 overexpression promoted SNHG1 expression in cardiomyocytes. Furthermore, in a model of cardiomyocyte hypertrophy, FOXP3 expression was upregulated, particularly in cardiomyocytes. Functional assays demonstrated that FOXP3 overexpression inhibited cardiomyocyte hypertrophy, while FOXP3 knockdown held the opposite effect. Additionally, we revealed that lncRNA SNHG1 acted as a sponge for miR-182, miR-326, and miR-3918, thereby stabilizing FOXP3 mRNA in cardiomyocytes. The protective role of SNHG1 against cardiomyocyte hypertrophy was found to depend on the presence of FOXP3, forming a positive FOXP3/SNHG1 feedback axis. Moreover, we unveiled this positive FOXP3/SNHG1 feedback axis suppressed cardiomyocyte hypertrophy by negatively regulating Parkin-mediated mitophagy. These findings provide novel insights into the molecular mechanisms underlying cardiomyocyte hypertrophy and offer potential therapeutic targets for related interventions.

Keywords:  Cardiomyocytes hypertrophy; FOXP3; Mitophagy; Parkin; SNHG1

DOI:  https://doi.org/10.1016/j.intimp.2024.112526
Anim Reprod Sci. 2024 Jun 21. pii: S0378-4320(24)00131-3. [Epub ahead of print]267 107540

Age-related changes in the mitochondrial, synthesis of steroids, and cellular homeostasis of the chicken ovary.

Xiao-Zhi Zhan, Pei Luo, Chen Zhang, Liu-Jun Zhang, Xu Shen, Dan-Li Jiang, Wen-Jun Liu.

  In poultry reproduction, the decline of ovarian function due to aging is related to dysfunction of mitochondria exacerbated by a reduction in antioxidant capacity, ultimately leading to follicle atresia and decreased egg production. However, the mechanisms of mitochondrial dysfunction in the chicken ovary in aging have remained to be understood. Hence, this study aims to investigate the effects of aging on mitochondrial function and cellular homeostasis. We collect ovarian tissue, small white follicles (SWF), large white follicles (LWF), and small yellow follicles (SYF) from three different laying periods of hens. The transmission electron microscopy (TEM) results showed that mitochondrial damage occurred in ovarian tissue during the late laying period (LP), characterized by structural swelling, scattered mitochondrial cristae, and an increase in the vacuoles. At the same time, with age, the synthesis of steroid hormones in the ovaries and follicular tissues is reduced. The levels of autophagy and cell apoptosis in ovarian tissues were both increased in the LP. In addition, aging adversely impacts mitochondrial function, leading to a decrease in mitochondrial unfolded protein response (UPRmt) functions. This study will expand the knowledge about regressing ovarian aging in hens and increasing egg production in older layers for poultry production.

Keywords:  Aging; Apoptosis; Autophagy; Mitochondrial function; Steroidogenesis; UPR(mt)

DOI:  https://doi.org/10.1016/j.anireprosci.2024.107540
Adv Sci (Weinh). 2024 Jun 28. e2402066

Uremic Toxin Receptor AhR Facilitates Renal Senescence and Fibrosis via Suppressing Mitochondrial Biogenesis.

Hongyan Xie, Ninghao Yang, Li Lu, Xi'ang Sun, Jingyao Li, Xin Wang, Hengjiang Guo, Li Zhou, Jun Liu, Huijuan Wu, Chen Yu, Wei Zhang, Limin Lu.

  Retention of metabolic end-products in the bodily fluids of patients with chronic kidney disease (CKD) may lead to uremia. The uremic toxin indoxyl sulfate (IS), a tryptophan metabolite, is an endogenous ligand of aryl hydrocarbon receptor (AhR). It is clarified that the upregulation and activation of AhR by IS in tubular epithelial cells (TECs) promote renal senescence and fibrosis. Renal TEC-specific knockout of AhR attenuates renal senescence and fibrosis, as well as the suppression of PGC1α-mediated mitochondrial biogenesis in ischemia reperfusion (IR)- or IS-treated CKD mice kidneys. Overexpression of peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC1α) attenuates IS-induced cell senescence and extracellular matrix production in cultured TECs. Mechanistically, AhR is able to interact with PGC1α and promotes the ubiquitin degradation of PGC1α via its E3 ubiquitin ligase activity. In summary, the elevation and activation of AhR by the accumulated uremic toxins in the progression of CKD accelerate renal senescence and fibrosis by suppressing mitochondrial biogenesis via promoting ubiquitination and proteasomal degradation of PGC1α.

Keywords:  PGC1α; aryl hydrocarbon receptor; cell senescence; mitochondrial biogenesis; renal fibrosis

DOI:  https://doi.org/10.1002/advs.202402066
J Assoc Res Otolaryngol. 2024 Jun 27.

Electron Microscopic Mapping of Mitochondrial Morphology in the Cochlear Nerve Fibers.

Yan Lu, Yi Jiang, Fangfang Wang, Hao Wu, Yunfeng Hua.

  To enable nervous system function, neurons are powered in a use-dependent manner by mitochondria undergoing morphological-functional adaptation. In a well-studied model system-the mammalian cochlea, auditory nerve fibers (ANFs) display distinct electrophysiological properties, which is essential for collectively sampling acoustic information of a large dynamic range. How exactly the associated mitochondrial networks are deployed in functionally differentiated ANFs remains scarcely interrogated. Here, we leverage volume electron microscopy and machine-learning-assisted image analysis to phenotype mitochondrial morphology and distribution along ANFs of full-length in the mouse cochlea inner spiral bundle. This reveals greater variance in mitochondrial size with increased ANF habenula to terminal path length. Particularly, we analyzed the ANF terminal-residing mitochondria, which are critical for local calcium uptake during sustained afferent activities. Our results suggest that terminal-specific enrichment of mitochondria, in addition to terminal size and overall mitochondrial abundance of the ANF, correlates with heterogenous mitochondrial contents of the terminal.

Keywords:  Auditory nerve fiber; Mitochondrion; Mouse cochlea; Volume electron microscopy

DOI:  https://doi.org/10.1007/s10162-024-00957-y
Int Immunopharmacol. 2024 Jun 21. pii: S1567-5769(24)01045-2. [Epub ahead of print]137 112524

A quinolinyl resveratrol derivative alleviates acute ischemic stroke injury by promoting mitophagy for neuroprotection via targeting CK2α'.

Libin Xu, Yan Mi, Qingqi Meng, Yeshu Liu, Yongping Wang, Ying Zhang, Yuxin Yang, Guoliang Chen, Yueyang Liu, Yue Hou.

  Ischemic stroke (IS) is a serious threat to human health. The naturally derived small molecule (E)-5-(2-(quinolin-4-yl) ethenyl) benzene-1,3-diol (RV01) is a quinolinyl analog of resveratrol with great potential in the treatment of IS. The aim of this study was to investigate the potential mechanisms and targets for the protective effect of the RV01 on IS. The mouse middle cerebral artery occlusion and reperfusion (MCAO/R) and oxygen-glucose deprivation and reperfusion (OGD/R) models were employed to evaluate the effects of RV01 on ischemic injury and neuroprotection. RV01 was found to significantly increase the survival of SH-SY5Y cells and prevent OGD/R-induced apoptosis in SH-SY5Y cells. Furthermore, RV01 reduced oxidative stress and mitochondrial damage by promoting mitophagy in OGD/R-exposed SH-SY5Y cells. Knockdown of CK2α' abolished the RV01-mediated promotion on mitophagy and alleviation on mitochondrial damage as well as neuronal injury after OGD/R. These results were further confirmed by molecular docking, drug affinity responsive target stability and cellular thermal shift assay analysis. Importantly, in vivo study showed that treatment with the CK2α' inhibitor CX-4945 abolished the RV01-mediated alleviation of cerebral infarct volume, brain edema, cerebral blood flow and neurological deficit in MCAO/R mice. These data suggest that RV01 effectively reduces damage caused by acute ischemic stroke by promoting mitophagy through its interaction with CK2α'. These findings offer valuable insights into the underlying mechanisms through which RV01 exerts its therapeutic effects on IS.

Keywords:  (E)-5-(2-(quinolin-4-yl) vinyl) benzene-1, 3-diol; CK2α’; Ischemic stroke; Mitophagy; Neurons

DOI:  https://doi.org/10.1016/j.intimp.2024.112524
Cell Biol Int. 2024 Jun 23.

ATAD3 is a limiting factor in mitochondrial biogenesis and adipogenesis of white adipocyte-like 3T3-L1 cells.

Shuijie Li, Rui Xu, Yao Yao, Denis Rousseau.

  ATAD3 is a vital ATPase of the inner mitochondrial membrane of pluri-cellular eukaryotes, with largely unknown functions but early required for organism development as necessary for mitochondrial biogenesis. ATAD3 knock-down in C. elegans inhibits at first the development of adipocyte-like intestinal tissue so we used mouse adipocyte model 3T3-L1 cells to analyze ATAD3 functions during adipogenesis and lipogenesis in a mammalian model. ATAD3 function was studied by stable and transient modulation of ATAD3 expression in adipogenesis- induced 3T3-L1 cells using Knock-Down and overexpression strategies, exploring different steps of adipocyte differentiation and lipogenesis. We show that (i) an increase in ATAD3 is preceding differentiation-induced mitochondrial biogenesis; (ii) downregulation of ATAD3 inhibits adipogenesis, lipogenesis, and impedes overexpression of many mitochondrial proteins; (iii) ATAD3 re-expression rescues the phenotype of ATAD3 KD, and (iv) differentiation and lipogenesis are accelerated by ATAD3 overexpression, but inhibited by expression of a dominant-negative mutant. We further show that the ATAD3 KD phenotype is not due to altered insulin signal but involves a limitation of mitochondrial biogenesis linked to Drp1. These results demonstrate that ATAD3 is limiting for in vitro mitochondrial biogenesis and adipogenesis/lipogenesis and therefore that ATAD3 mutation/over- or under-expression could be involved in adipogenic and lipogenic pathologies.

Keywords:  3T3‐L1 cells; ACC; AMPK; ATAD3; Drp1; adipocyte

DOI:  https://doi.org/10.1002/cbin.12206
Int J Mol Med. 2024 Aug;pii: 66. [Epub ahead of print]54(2):

[Retracted] Sirt1 inhibits HG‑induced endothelial injury: Role of Mff‑based mitochondrial fission and F‑actin homeostasis‑mediated cellular migration.

Ruijie Qin, Lina Zhang, Dong Lin, Fei Xiao, Lixin Guo.

  Following the publication of this paper, it was drawn to the Editor's attention by a concerned reader that certain of the immunochemistry data shown in Figs. 4K and 7G were strikingly similar to data appearing in different form in other research articles written by different authors at different research institutes that had either already been published, or were submitted for publication at around the same time. Owing to the fact that contentious data in the above article had already been published elsewhere prior to its submission to International Journal of Molecular Medicine, the Editor has decided that this paper should be retracted from the Journal. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive a satisfactory reply. The Editor apologizes to the readership for any inconvenience caused. [International Journal of Molecular Medicine 44: 89‑102, 2019; DOI: 10.3892/ijmm.2019.4185].

Keywords:  c-Jun N-terminal kinase; dynamin-1-like protein; high glucose injury; human umbilical vein endothelial cells; mitochondrial fission factor; sirtuin 1

DOI:  https://doi.org/10.3892/ijmm.2024.5390
Plant Biotechnol J. 2024 Jun 27.

The fnr-like mutants confer isoxaben tolerance by initiating mitochondrial retrograde signalling.

Ronan C Broad, Michael Ogden, Arka Dutta, Peter M Dracatos, James Whelan, Staffan Persson, Ghazanfar Abbas Khan.

  Isoxaben is a pre-emergent herbicide used to control broadleaf weeds. While the phytotoxic mechanism is not completely understood, isoxaben interferes with cellulose synthesis. Certain mutations in cellulose synthase complex proteins can confer isoxaben tolerance; however, these mutations can cause compromised cellulose synthesis and perturbed plant growth, rendering them unsuitable as herbicide tolerance traits. We conducted a genetic screen to identify new genes associated with isoxaben tolerance by screening a selection of Arabidopsis thaliana T-DNA mutants. We found that mutations in a FERREDOXIN-NADP(+) OXIDOREDUCTASE-LIKE (FNRL) gene enhanced tolerance to isoxaben, exhibited as a reduction in primary root stunting, reactive oxygen species accumulation and ectopic lignification. The fnrl mutant did not exhibit a reduction in cellulose levels following exposure to isoxaben, indicating that FNRL operates upstream of isoxaben-induced cellulose inhibition. In line with these results, transcriptomic analysis revealed a highly reduced response to isoxaben treatment in fnrl mutant roots. The fnrl mutants displayed constitutively induced mitochondrial retrograde signalling, and the observed isoxaben tolerance is partially dependent on the transcription factor ANAC017, a key regulator of mitochondrial retrograde signalling. Moreover, FNRL is highly conserved across all plant lineages, implying conservation of its function. Notably, fnrl mutants did not show a growth penalty in shoots, making FNRL a promising target for biotechnological applications in breeding isoxaben tolerance in crops.

Keywords:  cellulose; isoxaben; mitochondria; plastid

DOI:  https://doi.org/10.1111/pbi.14421
Life Sci. 2024 Jun 23. pii: S0024-3205(24)00387-4. [Epub ahead of print] 122797

Mitochondrial homeostasis in odontoblast: Physiology, pathogenesis and targeting strategies.

Xiang Meng, Hanqing Mao, Minting Wan, Linxin Lu, Zhi Chen, Lu Zhang.

  Caries and pulpitis remain a major global disease burden and affect the quality of life of patients. Odontoblasts are key players in the progression of caries and pulpitis, not only secreting and mineralizing to form dentin, but also acting as a wall of defense to initiate immune defenses. Mitochondrion is an information processor for numerous cellular activities, and dysregulation of mitochondrion homeostasis not only affects cellular metabolism but also triggers a wide range of diseases. Elucidating mitochondrial homeostasis in odontoblasts can help deepen scholars' understanding of odontoblast-associated diseases. Articles on mitochondrial homeostasis in odontoblasts were evaluated for information pertinent to include in this narrative review. This narrative review focused on understanding the complex interplay between mitochondrial homeostasis in odontoblasts under physiological and pathological conditions. Furthermore, mitochondria-centered therapeutic strategies (including mitochondrial base editing, targeting platforms, and mitochondrial transplantation) were emphasized by resolving key genes that regulate mitochondrial function. Mitochondria are involved in odontoblast differentiation and function, and act as mitochondrial danger-associated molecular patterns (mtDAMPs) to mediate odontoblast pathological progression. Novel mitochondria-centered therapeutic strategies are particularly attractive as emerging therapeutic approaches for the maintenance of mitochondrial homeostasis. It is expected to probe key events of odontoblast differentiation and advance the clinical resolution of dentin formation and mineralization disorders and odontoblast-related diseases.

Keywords:  Mitochondrial danger-associated molecular patterns; Mitochondrial homeostasis; Mitochondrial transplantation; Odontoblasts; Therapeutic strategies

DOI:  https://doi.org/10.1016/j.lfs.2024.122797
Mitochondrion. 2024 Jun 24. pii: S1567-7249(24)00081-3. [Epub ahead of print] 101923

Role of mitochondrial homeostasis in D-galactose-induced cardiovascular ageing from bench to bedside.

Yogita Sahu, Pratiksha Jamadade, Krushna Ch Maharana, Sanjiv Singh.

  Ageing is an inevitable phenomenon which affects the cellular to the organism level in the progression of the time. Oxidative stress and inflammation are now widely regarded as the key processes involved in the aging process, which may then cause significant harm to mitochondrial DNA, leading to apoptosis. Normal circulatory function is a significant predictor of disease-free life expectancy. Indeed, disorders affecting the cardiovascular system, which are becoming more common, are the primary cause of worldwide morbidity, disability, and mortality. Cardiovascular aging may precede or possibly underpin overall, age-related health decline. Numerous studies have foundmitochondrial mechanistc approachplays a vital role in the in the onset and development of aging. The D-galactose (D-gal)-induced aging model is well recognized and commonly used in the aging study. In this review we redeposit the association of the previous and current studies on mitochondrial homeostasis and its underlying mechanisms in D-galactose cardiovascular ageing. Further we focus the novel and the treatment strategies to combat the major complication leading to the cardiovascular ageing.

Keywords:  Cardiovascular ageing; D-galactose; Mitochondrial Dynamics; Mitochondrial Homeostasis; Mitophagy

DOI:  https://doi.org/10.1016/j.mito.2024.101923