bims-mikwok 2024-07-14 papers

bims-mikwok

Biomed News

on Mitochondrial quality control

Issue of 2024‒07‒14
29 papers selected by
Gavin McStay, Liverpool John Moores University

PPTC7 antagonizes mitophagy by promoting BNIP3 and NIX degradation via SCFFBXL4.
Dual-localized PPTC7 limits mitophagy through proximal and dynamic interactions with BNIP3 and NIX.
Mitochondrial Quality Control in Ovarian Function: From Mechanisms to Therapeutic Strategies.
Role of mitophagy in pulmonary hypertension: Targeting the mechanism and pharmacological intervention.
Slc25a3-dependent copper transport controls flickering-induced Opa1 processing for mitochondrial safeguard.
Dietary salt promotes cognitive impairment through repression of SIRT3/PINK1-mediated mitophagy and fission.
BL-918 activates PINK1/Parkin signaling pathway to ameliorate the progression of Parkinson's disease.
Publisher Correction: ISGylation of DRP1 closely balances other post-translational modifications to mediate mitochondrial fission.
Differential distribution of PINK1 and Parkin in the primate brain implies distinct roles.
Hexokinase 1 forms rings that regulate mitochondrial fission during energy stress.
Protein aggregation in plant mitochondria lacking Lon1 inhibits translation and induces unfolded protein responses.
Differentiation activates mitochondrial OPA1 processing in myoblast cell lines.
Canagliflozin Mitigates Diabetic Cardiomyopathy through Enhanced PINK1-Parkin Mitophagy.
Inhibition of dynamin-related protein 1-filamin interaction improves systemic glucose metabolism.
Recovery from cold-induced mitochondrial fission in endothelial cells requires reconditioning temperatures of ≥ 25◦C.
Hypoxia-Preconditioned BMSC-Derived Exosomes Induce Mitophagy via the BNIP3-ANAX2 Axis to Alleviate Intervertebral Disc Degeneration.
Activation of Nemo-like Kinase in Diamond Blackfan Anemia suppresses early erythropoiesis by preventing mitochondrial biogenesis.
Resveratrol ameliorates mitochondrial biogenesis and reproductive outcomes in women with polycystic ovary syndrome undergoing assisted reproduction: a randomized, triple-blind, placebo-controlled clinical trial.
Oxidative stress induces ferroptosis in tendon stem cells by regulating mitophagy through cGAS-STING pathway.
The iAAA-mitochondrial protease YME1L1 regulates the degradation of the short-lived mitochondrial transporter SLC25A38.
Mitochondrial dynamics in pulmonary disease: Implications for the potential therapeutics.
Mitophagy and clear cell renal cell carcinoma: insights from single-cell and spatial transcriptomics analysis.
Response to comment on: BGP-15 alleviates LPS-induced depression-like behavior by promoting mitophagy.
Maintaining mitochondrial NAD+ homeostasis is key for heat-induced skeletal muscle injury prevention despite presence of intracellular cation alterations.
Structural and mechanistic studies on human LONP1 redefine the hand-over-hand translocation mechanism.
Melatonin regulates microglial M1/M2 polarization via AMPKα2-mediated mitophagy in attenuating sepsis-associated encephalopathy.
Inhibition of NLRP3 inflammasome ameliorates LPS-induced neuroinflammatory injury in mice via PINK1/Parkin pathway.
Mitochondrial Quality Control Processes at the Crossroads of Cell Death and Survival: Mechanisms and Signaling Pathways.
Fumarate-1 Mediates the Regulation of Mitochondrial Homeostasis by PGC-1α to Promote Cell Pyroptosis and Inhibit the Progression of Thyroid Cancer.

EMBO Rep. 2024 Jul 11.

PPTC7 antagonizes mitophagy by promoting BNIP3 and NIX degradation via SCFFBXL4.

Giang Thanh Nguyen-Dien, Brendan Townsend, Prajakta Gosavi Kulkarni, Keri-Lyn Kozul, Soo Siang Ooi, Denaye N Eldershaw, Saroja Weeratunga, Meihan Liu, Mathew Jk Jones, S Sean Millard, Dominic Ch Ng, Michele Pagano, Alexis Bonfim-Melo, Tobias Schneider, David Komander, Michael Lazarou, Brett M Collins, Julia K Pagan.

  Mitophagy must be carefully regulated to ensure that cells maintain appropriate numbers of functional mitochondria. The SCFFBXL4 ubiquitin ligase complex suppresses mitophagy by controlling the degradation of BNIP3 and NIX mitophagy receptors, and FBXL4 mutations result in mitochondrial disease as a consequence of elevated mitophagy. Here, we reveal that the mitochondrial phosphatase PPTC7 is an essential cofactor for SCFFBXL4-mediated destruction of BNIP3 and NIX, suppressing both steady-state and induced mitophagy. Disruption of the phosphatase activity of PPTC7 does not influence BNIP3 and NIX turnover. Rather, a pool of PPTC7 on the mitochondrial outer membrane acts as an adaptor linking BNIP3 and NIX to FBXL4, facilitating the turnover of these mitophagy receptors. PPTC7 accumulates on the outer mitochondrial membrane in response to mitophagy induction or the absence of FBXL4, suggesting a homoeostatic feedback mechanism that attenuates high levels of mitophagy. We mapped critical residues required for PPTC7-BNIP3/NIX and PPTC7-FBXL4 interactions and their disruption interferes with both BNIP3/NIX degradation and mitophagy suppression. Collectively, these findings delineate a complex regulatory mechanism that restricts BNIP3/NIX-induced mitophagy.

Keywords:  BNIP3; FBXL4; Mitophagy; NIX; PPTC7

DOI:  https://doi.org/10.1038/s44319-024-00181-y
Life Sci Alliance. 2024 Sep;pii: e202402765. [Epub ahead of print]7(9):

Dual-localized PPTC7 limits mitophagy through proximal and dynamic interactions with BNIP3 and NIX.

Lianjie Wei, Mehmet Oguz Gok, Jordyn D Svoboda, Keri-Lyn Kozul, Merima Forny, Jonathan R Friedman, Natalie M Niemi.

PPTC7 is a mitochondrial-localized phosphatase that suppresses BNIP3- and NIX-mediated mitophagy, but the mechanisms underlying this regulation remain ill-defined. Here, we demonstrate that loss of PPTC7 upregulates BNIP3 and NIX post-transcriptionally and independent of HIF-1α stabilization. Loss of PPTC7 prolongs the half-life of BNIP3 and NIX while blunting their accumulation in response to proteasomal inhibition, suggesting that PPTC7 promotes the ubiquitin-mediated turnover of BNIP3 and NIX. Consistently, overexpression of PPTC7 limits the accumulation of BNIP3 and NIX protein levels, which requires an intact catalytic motif but is surprisingly independent of its targeting to mitochondria. Consistently, we find that PPTC7 is dual-localized to the outer mitochondrial membrane and the matrix. Importantly, anchoring PPTC7 to the outer mitochondrial membrane is sufficient to blunt BNIP3 and NIX accumulation, and proximity labeling and fluorescence co-localization experiments demonstrate that PPTC7 dynamically associates with BNIP3 and NIX within the native cellular environment. Collectively, these data reveal that a fraction of PPTC7 localizes to the outer mitochondrial membrane to promote the proteasomal turnover of BNIP3 and NIX, limiting basal mitophagy.

DOI: https://doi.org/10.26508/lsa.202402765
Reprod Sci. 2024 Jul 09.

Mitochondrial Quality Control in Ovarian Function: From Mechanisms to Therapeutic Strategies.

Xiaomei Wang, Yuxin Liu, Jinzheng Wang, Xueyi Lu, Zhipeng Guo, Shenmin Lv, Zhenyu Sun, Tan Gao, Fei Gao, Jinxiang Yuan.

  Mitochondrial quality control plays a critical role in cytogenetic development by regulating various cell-death pathways and modulating the release of reactive oxygen species (ROS). Dysregulated mitochondrial quality control can lead to a broad spectrum of diseases, including reproductive disorders, particularly female infertility. Ovarian insufficiency is a significant contributor to female infertility, given its high prevalence, complex pathogenesis, and profound impact on women's health. Understanding the pathogenesis of ovarian insufficiency and devising treatment strategies based on this understanding are crucial. Oocytes and granulosa cells (GCs) are the primary ovarian cell types, with GCs regulated by oocytes, fulfilling their specific energy requirements prior to ovulation. Dysregulation of mitochondrial quality control through gene knockout or external stimuli can precipitate apoptosis, inflammatory responses, or ferroptosis in both oocytes and GCs, exacerbating ovarian insufficiency. This review aimed to delineate the regulatory mechanisms of mitochondrial quality control in GCs and oocytes during ovarian development. This study highlights the adverse consequences of dysregulated mitochondrial quality control on GCs and oocyte development and proposes therapeutic interventions for ovarian insufficiency based on mitochondrial quality control. These insights provide a foundation for future clinical approaches for treating ovarian insufficiency.

Keywords:  Apoptosis; Granulosa cells; Mitochondrial dynamics; Mitophagy; Oocyte; Ovarian insufficiency

DOI:  https://doi.org/10.1007/s43032-024-01634-4
Mitochondrion. 2024 Jul 09. pii: S1567-7249(24)00086-2. [Epub ahead of print]78 101928

Role of mitophagy in pulmonary hypertension: Targeting the mechanism and pharmacological intervention.

Jia-Jing Wan, Jian Yi, Fei-Ying Wang, Xia Li, Chao Zhang, Lan Song, Ai-Guo Dai.

  Mitophagy, a crucial pathway in eukaryotic cells, selectively eliminates dysfunctional mitochondria, thereby maintaining cellular homeostasis via mitochondrial quality control. Pulmonary hypertension (PH) refers to a pathological condition where pulmonary arterial pressure is abnormally elevated due to various reasons, and the underlying pathogenesis remains elusive. This article examines the molecular mechanisms underlying mitophagy, emphasizing its role in PH and the progress in elucidating related molecular signaling pathways. Additionally, it highlights current drug regulatory pathways, aiming to provide novel insights into the prevention and treatment of pulmonary hypertension.

Keywords:  Mechanism; Mitophagy; Pulmonary hypertension

DOI:  https://doi.org/10.1016/j.mito.2024.101928
Dev Cell. 2024 Jul 03. pii: S1534-5807(24)00386-1. [Epub ahead of print]

Slc25a3-dependent copper transport controls flickering-induced Opa1 processing for mitochondrial safeguard.

Daisuke Murata, Shubhrajit Roy, Svetlana Lutsenko, Miho Iijima, Hiromi Sesaki.

  Following the Goldilocks principle, mitochondria size must be "just right." Mitochondria balance division and fusion to avoid becoming too big or too small. Defects in this balance produce dysfunctional mitochondria in human diseases. Mitochondrial safeguard (MitoSafe) is a defense mechanism that protects mitochondria against extreme enlarging by suppressing fusion in mammalian cells. In MitoSafe, hyperfused mitochondria elicit flickering-short pulses of mitochondrial depolarization. Flickering activates an inner membrane protease, Oma1, which in turn proteolytically inactivates a mitochondrial fusion protein, Opa1. The mechanisms underlying flickering are unknown. Using a live-imaging screen, we identified Slc25a3 (a mitochondrial carrier transporting phosphate and copper) as necessary for flickering and Opa1 cleavage. Remarkably, copper, but not phosphate, is critical for flickering. Furthermore, we found that two copper-containing mitochondrial enzymes, superoxide dismutase 1 and cytochrome c oxidase, regulate flickering. Our data identify an unforeseen mechanism linking copper, redox homeostasis, and membrane flickering in mitochondrial defense against deleterious fusion.

Keywords:  division; fusion; mitochondria; stress response; transporter

DOI:  https://doi.org/10.1016/j.devcel.2024.06.008
Mol Cell Biochem. 2024 Jul 13.

Dietary salt promotes cognitive impairment through repression of SIRT3/PINK1-mediated mitophagy and fission.

Haixia Fan, Minghao Yuan, Shenyuan Wang, Xu Yang, Liu Shu, Yinshuang Pu, Qian Zou, Xiaogang Zhang, Chuanling Wang, Zhiyou Cai.

  Dietary salt is increasingly recognized as an independent risk factor for cognitive impairment. However, the exact mechanisms are not yet fully understood. Mitochondria, which play a crucial role in energy metabolism, are implicated in cognitive function through processes such as mitochondrial dynamics and mitophagy. While mitochondrial dysfunction is acknowledged as a significant determinant of cognitive function, the specific relationship between salt-induced cognitive impairment and mitochondrial health has yet to be fully elucidated. Here, we explored the underlying mechanism of cognitive impairment of mice and N2a cells treated with high-salt focusing on the mitochondrial homeostasis with western blotting, immunofluorescence, electron microscopy, RNA sequencing, and more. We further explored the potential role of SIRT3 in salt-induced mitochondrial dysfunction and synaptic alteration through plasmid transfection and siRNA. High salt diet significantly inhibited mitochondrial fission and blocked mitophagy, leading to dysfunctional mitochondria and impaired synaptic plasticity. Our findings demonstrated that SIRT3 not only promote mitochondrial fission by modulating phosphorylated DRP1, but also rescue mitophagy through promoting PINK1/Parkin-dependent pathway. Overall, our data for the first time indicate that mitochondrial homeostasis imbalance is a driver of impaired synaptic plasticity in a cognitive impairment phenotype that is exacerbated by a long-term high-salt diet, and highlight the protective role of SIRT3 in this process.

Keywords:  Cognitive impairment; Dietary salt; Mitochondrial homeostasis; Synaptic plasticity

DOI:  https://doi.org/10.1007/s11010-024-05069-y
J Biol Chem. 2024 Jul 09. pii: S0021-9258(24)02044-1. [Epub ahead of print] 107543

BL-918 activates PINK1/Parkin signaling pathway to ameliorate the progression of Parkinson's disease.

Yi Wang, Siyuan Luo, Huili Su, Zhimeng Wang, Ling Chu, Conggang Zhang.

  The pathogenesis of Parkinson's disease (PD) has been associated with mitochondrial dysfunction. Given that the PINK1/Parkin pathway governs mitochondrial quality control by inducing mitophagy to remove damaged mitochondria, therapeutic approaches to activate PINK1/Parkin-mediated mitophagy have the potential in the treatment of PD. Here, we have identified a new small molecule, BL-918, as an inducer of mitophagy via activating the PINK1/Parkin pathway. BL-918 triggers PINK1 accumulation and Parkin mitochondrial translocation to initiate PINK1/Parkin-mediated mitophagy. We found that mitochondrial membrane potential and mitochondrial permeability transition (mPT) pore were involved in BL-918-induced PINK1/Parkin pathway activation. Moreover, we showed that BL-918 mitigated PD progression in MPTP-induced PD mice in a PINK1-dependent manner. Our results unravel a new activator of the PINK1/Parkin signaling pathway and provide a potential strategy for the treatment of PD and other diseases with dysfunctional mitochondria.

Keywords:  Mitochondrial quality control; Mitophagy; PINK1; Parkin; Parkinson’s disease

DOI:  https://doi.org/10.1016/j.jbc.2024.107543
Cell Death Dis. 2024 Jul 09. 15(7): 488

Publisher Correction: ISGylation of DRP1 closely balances other post-translational modifications to mediate mitochondrial fission.

Palamou Das, Oishee Chakrabarti.

DOI: https://doi.org/10.1038/s41419-024-06857-6
Neural Regen Res. 2025 Apr 01. 20(4): 1124-1134

Differential distribution of PINK1 and Parkin in the primate brain implies distinct roles.

Yanting Liu, Wei Huang, Jiayi Wen, Xin Xiong, Ting Xu, Qi Wang, Xiusheng Chen, Xianxian Zhao, Shihua Li, Xiaojiang Li, Weili Yang.

JOURNAL/nrgr/04.03/01300535-202504000-00028/figure1/v/2024-07-06T104127Z/r/image-tiff The vast majority of in vitro studies have demonstrated that PINK1 phosphorylates Parkin to work together in mitophagy to protect against neuronal degeneration. However, it remains largely unclear how PINK1 and Parkin are expressed in mammalian brains. This has been difficult to address because of the intrinsically low levels of PINK1 and undetectable levels of phosphorylated Parkin in small animals. Understanding this issue is critical for elucidating the in vivo roles of PINK1 and Parkin. Recently, we showed that the PINK1 kinase is selectively expressed as a truncated form (PINK1-55) in the primate brain. In the present study, we used multiple antibodies, including our recently developed monoclonal anti-PINK1, to validate the selective expression of PINK1 in the primate brain. We found that PINK1 was stably expressed in the monkey brain at postnatal and adulthood stages, which is consistent with the findings that depleting PINK1 can cause neuronal loss in developing and adult monkey brains. PINK1 was enriched in the membrane-bound fractionations, whereas Parkin was soluble with a distinguishable distribution. Immunofluorescent double staining experiments showed that PINK1 and Parkin did not colocalize under physiological conditions in cultured monkey astrocytes, though they did colocalize on mitochondria when the cells were exposed to mitochondrial stress. These findings suggest that PINK1 and Parkin may have distinct roles beyond their well-known function in mitophagy during mitochondrial damage.

DOI: https://doi.org/10.4103/NRR.NRR-D-23-01140
Mol Cell. 2024 Jun 28. pii: S1097-2765(24)00512-4. [Epub ahead of print]

Hexokinase 1 forms rings that regulate mitochondrial fission during energy stress.

Johannes Pilic, Benjamin Gottschalk, Benjamin Bourgeois, Hansjörg Habisch, Zhanat Koshenov, Furkan E Oflaz, Yusuf C Erdogan, Seyed M Miri, Esra N Yiğit, Mehmet Ş Aydın, Gürkan Öztürk, Emrah Eroglu, Varda Shoshan-Barmatz, Tobias Madl, Wolfgang F Graier, Roland Malli.

  Metabolic enzymes can adapt during energy stress, but the consequences of these adaptations remain understudied. Here, we discovered that hexokinase 1 (HK1), a key glycolytic enzyme, forms rings around mitochondria during energy stress. These HK1-rings constrict mitochondria at contact sites with the endoplasmic reticulum (ER) and mitochondrial dynamics protein (MiD51). HK1-rings prevent mitochondrial fission by displacing the dynamin-related protein 1 (Drp1) from mitochondrial fission factor (Mff) and mitochondrial fission 1 protein (Fis1). The disassembly of HK1-rings during energy restoration correlated with mitochondrial fission. Mechanistically, we identified that the lack of ATP and glucose-6-phosphate (G6P) promotes the formation of HK1-rings. Mutations that affect the formation of HK1-rings showed that HK1-rings rewire cellular metabolism toward increased TCA cycle activity. Our findings highlight that HK1 is an energy stress sensor that regulates the shape, connectivity, and metabolic activity of mitochondria. Thus, the formation of HK1-rings may affect mitochondrial function in energy-stress-related pathologies.

Keywords:  ER-mitochondria contact sites; energy stress; glucose starvation; glycolysis; hexokinase; live-cell imaging; mitochondrial constriction; mitochondrial fission; non-catalytic functions; protein cluster

DOI:  https://doi.org/10.1016/j.molcel.2024.06.009
Plant Cell Environ. 2024 Jul 11.

Protein aggregation in plant mitochondria lacking Lon1 inhibits translation and induces unfolded protein responses.

Ce Song, Yuanyuan Li, Mengmeng Yang, Tiantian Li, Yuqi Hou, Yinyin Liu, Chang Xu, Jinjian Liu, A Harvey Millar, Ningning Wang, Lei Li.

  Loss of Lon1 led to stunted plant growth and accumulation of nuclear-encoded mitochondrial proteins including Lon1 substrates. However, an in-depth label-free proteomics quantification of mitochondrial proteins in lon1 revealed that the majority of mitochondrial-encoded proteins decreased in abundance. Additionally, we found that lon1 mutants contained protein aggregates in the mitochondrial that were enriched in metabolic enzymes, ribosomal subunits and PPR-containing proteins of the translation apparatus. These mutants exhibited reduced general mitochondrial translation as well as deficiencies in RNA splicing and editing. These findings support the role of Lon1 in maintaining a functional translational apparatus for mitochondrial-encoded gene translation. Transcriptome analysis of lon1 revealed a mitochondrial unfolded protein response reminiscent of the mitochondrial retrograde signalling dependent on the transcription factor ANAC017. Notably, lon1 mutants exhibited transiently elevated ethylene production, and the shortened hypocotyl observed in lon1 mutants during skotomorphogenesis was partially alleviated by ethylene inhibitors. Furthermore, the short root phenotype was partially ameliorated by introducing a mutation in the ethylene receptor ETR1. Interestingly, the upregulation of only a select few target genes was linked to ETR1-mediated ethylene signalling. Together this provides multiple steps in the link between loss of Lon1 and signalling responses to restore mitochondrial protein homoeostasis in plants.

Keywords:  UPR; ethylene; mitochondrion; translation

DOI:  https://doi.org/10.1111/pce.15035
Mitochondrion. 2024 Jul 08. pii: S1567-7249(24)00091-6. [Epub ahead of print]78 101933

Differentiation activates mitochondrial OPA1 processing in myoblast cell lines.

Harpreet Kaur, Omar Carrillo, Iraselia Garcia, Isaiah Ramos, Shaynah St Vallier, Patrick De La Torre, Alma Lopez, Megan Keniry, Daniel Bazan, Jorge Elizondo, K C Grishma, Lee Ann MacMillan-Crow, Robert Gilkerson.

  Mitochondrial optic atrophy-1 (OPA1) plays key roles in adapting mitochondrial structure to bioenergetic function. When transmembrane potential across the inner membrane (Δψm) is intact, long (L-OPA1) isoforms shape the inner membrane through membrane fusion and the formation of cristal junctions. When Δψm is lost, however, OPA1 is cleaved to short, inactive S-OPA1 isoforms by the OMA1 metalloprotease, disrupting mitochondrial structure and priming cellular stress responses such as apoptosis. Previously, we demonstrated that L-OPA1 of H9c2 cardiomyoblasts is insensitive to loss of Δψm via challenge with the protonophore carbonyl cyanide chlorophenyl hydrazone (CCCP), but that CCCP-induced OPA1 processing is activated upon differentiation in media with low serum supplemented with all-trans retinoic acid (ATRA). Here, we show that this developmental induction of OPA1 processing in H9c2 cells is independent of ATRA; moreover, pretreatment of undifferentiated H9c2s with chloramphenicol (CAP), an inhibitor of mitochondrial protein synthesis, recapitulates the Δψm-sensitive OPA1 processing observed in differentiated H9c2s. L6.C11 and C2C12 myoblast lines display the same developmental and CAP-sensitive induction of OPA1 processing, demonstrating a general mechanism of OPA1 regulation in mammalian myoblast cell settings. Restoration of CCCP-induced OPA1 processing correlates with increased apoptotic sensitivity. Moreover, OPA1 knockdown indicates that intact OPA1 is necessary for effective myoblast differentiation. Taken together, our results indicate that a novel developmental mechanism acts to regulate OMA1-mediated OPA1 processing in myoblast cell lines, in which differentiation engages mitochondrial stress sensing.

Keywords:  Differentiation; Mitochondria; OMA1; OPA1; Transmembrane potential

DOI:  https://doi.org/10.1016/j.mito.2024.101933
Int J Mol Sci. 2024 Jun 26. pii: 7008. [Epub ahead of print]25(13):

Canagliflozin Mitigates Diabetic Cardiomyopathy through Enhanced PINK1-Parkin Mitophagy.

Chunru Yang, Cheng Xiao, Zerui Ding, Xiaojun Zhai, Jieying Liu, Miao Yu.

  Diabetic cardiomyopathy (DCM) is a major determinant of mortality in diabetic populations, and the potential strategies are insufficient. Canagliflozin has emerged as a potential cardioprotective agent in diabetes, yet its underlying molecular mechanisms remain unclear. We employed a high-glucose challenge (60 mM for 48 h) in vitro to rat cardiomyocytes (H9C2), with or without canagliflozin treatment (20 µM). In vivo, male C57BL/6J mice were subjected to streptozotocin and a high-fat diet to induce diabetes, followed by canagliflozin administration (10, 30 mg·kg-1·d-1) for 12 weeks. Proteomics and echocardiography were used to assess the heart. Histopathological alterations were assessed by the use of Oil Red O and Masson's trichrome staining. Additionally, mitochondrial morphology and mitophagy were analyzed through biochemical and imaging techniques. A proteomic analysis highlighted alterations in mitochondrial and autophagy-related proteins after the treatment with canagliflozin. Diabetic conditions impaired mitochondrial respiration and ATP production, alongside decreasing the related expression of the PINK1-Parkin pathway. High-glucose conditions also reduced PGC-1α-TFAM signaling, which is responsible for mitochondrial biogenesis. Canagliflozin significantly alleviated cardiac dysfunction and improved mitochondrial function both in vitro and in vivo. Specifically, canagliflozin suppressed mitochondrial oxidative stress, enhancing ATP levels and sustaining mitochondrial respiratory capacity. It activated PINK1-Parkin-dependent mitophagy and improved mitochondrial function via increased phosphorylation of adenosine monophosphate-activated protein kinase (AMPK). Notably, PINK1 knockdown negated the beneficial effects of canagliflozin on mitochondrial integrity, underscoring the critical role of PINK1 in mediating these protective effects. Canagliflozin fosters PINK1-Parkin mitophagy and mitochondrial function, highlighting its potential as an effective treatment for DCM.

Keywords:  diabetic cardiomyopathy; mitochondrial biogenesis; mitochondrial dysfunction; mitophagy; sodium-glucose co-transporter-2 inhibitor

DOI:  https://doi.org/10.3390/ijms25137008
Br J Pharmacol. 2024 Jul 10.

Inhibition of dynamin-related protein 1-filamin interaction improves systemic glucose metabolism.

Yuri Kato, Kohei Ariyoshi, Yasunobu Nohara, Naoya Matsunaga, Tsukasa Shimauchi, Naoya Shindo, Akiyuki Nishimura, Xinya Mi, Sang Geon Kim, Tomomi Ide, Eiji Kawanishi, Akio Ojida, Naoki Nakashima, Yasuo Mori, Motohiro Nishida.

  BACKGROUND AND PURPOSE: Maintaining mitochondrial quality is attracting attention as a new strategy to treat diabetes and diabetic complications. We previously reported that mitochondrial hyperfission by forming a protein complex between dynamin-related protein (Drp) 1 and filamin, mediates chronic heart failure and cilnidipine, initially developed as an L/N-type Ca2+ channel blocker, improves heart failure by inhibiting Drp1-filamin protein complex. We investigated whether cilnidipine improves hyperglycaemia of various diabetic mice models.EXPERIMENTAL APPROACH: Retrospective analysis focusing on haemoglobin A1c (HbA1c) was performed in hypertensive and hyperglycaemic patients taking cilnidipine and amlodipine. After developing diabetic mice by streptozotocin (STZ) treatment, an osmotic pump including drug was implanted intraperitoneally, followed by weekly measurements of blood glucose levels. Mitochondrial morphology was analysed by electron microscopy. A Ca2+ channel-insensitive cilnidipine derivative (1,4-dihydropyridine [DHP]) was synthesized and its pharmacological effect was evaluated using obese (ob/ob) mice fed with high-fat diet (HFD).
KEY RESULTS: In patients, cilnidipine was superior to amlodipine in HbA1c lowering effect. Cilnidipine treatment improved systemic hyperglycaemia and mitochondrial morphological abnormalities in STZ-exposed mice, without lowering blood pressure. Cilnidipine failed to improve hyperglycaemia of ob/ob mice, with suppressing insulin secretion. 1,4-DHP improved hyperglycaemia and mitochondria abnormality in ob/ob mice fed HFD. 1,4-DHP and cilnidipine improved basal oxygen consumption rate of HepG2 cells cultured under 25 mM glucose.
CONCLUSION AND IMPLICATIONS: Inhibition of Drp1-filamin protein complex formation becomes a new strategy for type 2 diabetes treatment.

Keywords:  Drp1; filamin; insulin; mitochondria quality control; type2 diabetes

DOI:  https://doi.org/10.1111/bph.16487
Front Transplant. 2022 ;1 1044551

Recovery from cold-induced mitochondrial fission in endothelial cells requires reconditioning temperatures of ≥ 25◦C.

Leonard Quiring, Luisa Caponi, Dhanusha Schwan, Anja Rech, Ursula Rauen.

  Mitochondrial integrity and function constitute a prerequisite for cellular function and repair processes. We have previously shown that mitochondria of different cell types exhibit pronounced fragmentation under hypothermic conditions. This fission, accompanied by a decline of cellular ATP content, showed reversibility at 37◦C. However, it is unclear whether other temperatures as currently discussed for reconditioning of organs allow this reconstitution of mitochondria. Therefore, we here study in a model of cultured porcine aortic endothelial cells how different rewarming temperatures affect mitochondrial re-fusion and function. After 48 h cold incubation of endothelial cells in Krebs-Henseleit buffer with glucose (5 mM) and deferoxamine (1 mM) at 4◦C pronounced mitochondrial fission was observed. Following 2 h rewarming in cell culture medium, marked fission was still present after rewarming at 10◦ or 15◦C. At 21◦C some re-fusion was visible, which became more marked at 25◦C. Networks of tubular mitochondria similar to control cells only re-appeared at 37◦C. ATP content decreased at 4◦C from 3.6 ± 0.4 to 1.6 ± 0.4 nmol/106 cells and decreased even further when rewarming cells to 10◦ and 15◦C. Values after rewarming at 21◦C were similar to the values before rewarming while ATP gradually increased at higher rewarming temperatures. Metabolic activity dropped to 5 ± 11% of control values during 4◦C incubation and recovered with increasing temperatures to 36 ± 10% at 25◦C and 78 ± 17% at 37◦C. Integrity of monolayers, largely disturbed at 4◦C (large gaps between endothelial cells; cell injury ≤ 1%), showed partial recovery from 15◦C upwards, complete recovery at 37◦C. Endothelial repair processes (scratch assay) at 25◦C were clearly inferior to those at 37◦C. These data suggest that reconditioning temperatures below 21◦C are not optimal with regard to reconstitution of mitochondrial integrity and function. For this goal, temperatures of at least 25◦C appear required, with 30◦C being superior and 37◦C yielding the best results.

Keywords:  endothelium; machine perfusion; mitochondria; mitochondrial dynamics; mitochondrial fragmentation; mitochondrial fusion; transplantation

DOI:  https://doi.org/10.3389/frtra.2022.1044551
Adv Sci (Weinh). 2024 Jul 08. e2404275

Hypoxia-Preconditioned BMSC-Derived Exosomes Induce Mitophagy via the BNIP3-ANAX2 Axis to Alleviate Intervertebral Disc Degeneration.

Yuxin Jin, Ouqiang Wu, Qizhu Chen, Linjie Chen, Zhiguang Zhang, Haijun Tian, Hao Zhou, Kai Zhang, Jianyuan Gao, Xinzhou Wang, Zhenyu Guo, Jing Sun, Kenny Yat Hong Kwan, Morgan Jones, Yan Michael Li, Ehsan Nazarzadeh Zare, Pooyan Makvandi, Xiangyang Wang, Shuying Shen, Aimin Wu.

  Intervertebral disc degeneration (IVDD) is a chronic degenerative disease involving the aging and loss of proliferative capacity of nucleus pulposus cells (NPCs), processes heavily dependent on mitochondrial dynamics and autophagic flux. This study finds that the absence of BCL2/adenovirus E1B 19 kDa interacting protein 3 (BNIP3) is associated with senescence-related NPC degeneration, disrupting mitochondrial quality control. Bone marrow mesenchymal stem cells (BMSCs) have multidirectional differentiation potential and produce extracellular vesicles containing cellular activators. Therefore, in this study, BMSCs are induced under hypoxic stimulation to deliver BNIP3-rich extracellular vesicles to NPCs, thereby alleviating aging-associated mitochondrial autophagic flux, promoting damaged mitochondrial clearance, and restoring mitochondrial quality control. Mechanistically, BNIP3 is shown to interact with the membrane-bound protein annexin A2 (ANXA2), enabling the liberation of the transcription factor EB (TFEB) from the ANXA2-TFEB complex, promoting TFEB nuclear translocation, and regulating autophagy and lysosomal gene activation. Furthermore, a rat model of IVDD is established and verified the in vivo efficacy of the exosomes in repairing disc injuries, delaying NPC aging, and promoting extracellular matrix (ECM) synthesis. In summary, hypoxia-induced BMSC exosomes deliver BNIP3-rich vesicles to alleviate disc degeneration by activating the mitochondrial BNIP3/ANXA2/TFEB axis, providing a new target for IVDD treatment.

Keywords:  Intervertebral disc degeneration; bone marrow mesenchymal stem cells; exosomes; hypoxia‐preconditioned mesenchymal stem cells; matrix reconstruction; mitophagy

DOI:  https://doi.org/10.1002/advs.202404275
J Biol Chem. 2024 Jul 09. pii: S0021-9258(24)02043-X. [Epub ahead of print] 107542

Activation of Nemo-like Kinase in Diamond Blackfan Anemia suppresses early erythropoiesis by preventing mitochondrial biogenesis.

Mark C Wilkes, Aya Shibuya, Y Lucy Liu, Kailen Mark, Jaqueline Mercado, Mallika Saxena, Ryan S Sathianathen, Hye Na Kim, Bertil Glader, Paraic Kenny, Kathleen M Sakamoto.

Diamond Blackfan Anemia (DBA) is a rare macrocytic red blood cell aplasia that usually presents within the first year of life. The vast majority of patients carry a mutation in one of approximately 20 genes that results in ribosomal insufficiency with the most significant clinical manifestations being anemia and a predisposition to cancers. Nemo-like Kinase (NLK) is hyperactivated in the erythroid progenitors of DBA patients and inhibition of this kinase improves erythropoiesis, but how NLK contributes to the pathogenesis of the disease is unknown. Here we report that activated NLK suppresses the critical upregulation of mitochondrial biogenesis required in early erythropoiesis. During normal erythropoiesis, mTORC1 facilitates the translational upregulation of Transcription factor A, mitochondrial (TFAM) and Prohibin 2 (PHB2) to increase mitochondrial biogenesis. In our models of DBA, active NLK phosphorylates the regulatory component of mTORC1, thereby suppressing mTORC1 activity and preventing mTORC1-mediated TFAM and PHB2 upregulation and subsequent mitochondrial biogenesis. Improvement of erythropoiesis that accompanies NLK inhibition is negated when TFAM and PHB2 upregulation is prevented. These data demonstrate that a significant contribution of NLK on the pathogenesis of DBA is through loss of mitochondrial biogenesis.

DOI: https://doi.org/10.1016/j.jbc.2024.107542
J Ovarian Res. 2024 Jul 10. 17(1): 143

Resveratrol ameliorates mitochondrial biogenesis and reproductive outcomes in women with polycystic ovary syndrome undergoing assisted reproduction: a randomized, triple-blind, placebo-controlled clinical trial.

Negar Ajabi Ardehjani, Marzieh Agha-Hosseini, Maryam Shabani Nashtaei, Mahshad Khodarahmian, Maryam Shabani, Masoome Jabarpour, Farzane Fereidouni, Tayebeh Rastegar, Fardin Amidi.

  BACKGROUND: This study was designed to examine the effect of resveratrol on mitochondrial biogenesis, oxidative stress (OS), and assisted reproductive technology (ART) outcomes in individuals with polycystic ovary syndrome (PCOS).METHODS: Fifty-six patients with PCOS were randomly assigned to receive 800 mg/day of resveratrol or placebo for 60 days. The primary outcome was OS in follicular fluid (FF). The secondary outcome involved assessing gene and protein expression related to mitochondrial biogenesis, mitochondrial DNA (mtDNA) copy number, and adenosine triphosphate (ATP) content in granulosa cells (GCs). ART outcomes were evaluated at the end of the trial.
RESULTS: Resveratrol significantly reduced the total oxidant status (TOS) and oxidative stress index (OSI) in FF (P = 0.0142 and P = 0.0039, respectively) while increasing the total antioxidant capacity (TAC) (P < 0.0009). Resveratrol consumption also led to significant increases in the expression of critical genes involved in mitochondrial biogenesis, including peroxisome proliferator-activated receptor gamma coactivator (PGC-1α) and mitochondrial transcription factor A (TFAM) (P = 0.0032 and P = 0.0003, respectively). However, the effect on nuclear respiratory factor 1 (Nrf-1) expression was not statistically significant (P = 0.0611). Resveratrol significantly affected sirtuin1 (SIRT1) and PGC-1α protein levels (P < 0.0001 and P = 0.0036, respectively). Resveratrol treatment improved the mtDNA copy number (P < 0.0001) and ATP content in GCs (P = 0.0014). Clinically, the resveratrol group exhibited higher rates of oocyte maturity (P = 0.0012) and high-quality embryos (P = 0.0013) than did the placebo group. There were no significant differences between the groups in terms of chemical or clinical pregnancy rates (P > 0.05).
CONCLUSIONS: These findings indicate that resveratrol may be a promising therapeutic agent for patients with PCOS undergoing assisted reproduction.
TRIAL REGISTRATION NUMBER: http://www.irct.ir ; IRCT20221106056417N1; 2023 February 09.

Keywords:  Antioxidants; Assisted reproductive technique; Granulosa cells; Mitochondrial biogenesis; Polycystic ovary syndrome; Resveratrol

DOI:  https://doi.org/10.1186/s13048-024-01470-9
Int Immunopharmacol. 2024 Jul 09. pii: S1567-5769(24)01173-1. [Epub ahead of print]138 112652

Oxidative stress induces ferroptosis in tendon stem cells by regulating mitophagy through cGAS-STING pathway.

Yuanyuan Gao, Wenshuang Sun, Junrui Wang, Danli Zhao, Haoyuan Tian, Yangling Qiu, Shufan Ji, Shuqi Wang, Qiuyu Fu, Feng Zhang, Zili Zhang, Feixia Wang, Jiangjuan Shao, Shizhong Zheng, Jia Meng.

  Tendinopathy is one of the most prevalent sports injury diseases in orthopedics. However, there is no effective treatment or medicine. Recently, the discovery of tendon stem cells (TSCs) provides a new perspective to find new therapeutic methods for Tendinopathy. Studies have shown that oxidative stress will inevitably cause TSCs injury during tendinopathy, but the mechanism has not been fully elucidated. Here, we report the oxidative damage of TSCs induced by H2O2 via ferroptosis, as well, treatment with H2O2 raised the proportion of mitochondria engulfed by autophagosomes in TSCs. The suppression of mitophagy by Mdivi-1 significantly attenuates the H2O2-induced ferroptosis in TSCs. Mechanically, H2O2 actives the cGAS-STING pathway, which can regulate the level of mitophagy. Interfering with cGAS could impair mitophagy and the classical ferroptotic events. In the rat model of tendinopathy, interference of cGAS could relieve tendon injury by inhibiting ferroptosis. Overall, these results provided novel implications to reveal the molecular mechanism of tendinopathy, by which pointed to cGAS as a potential therapeutic target for the treatment of tendinopathy.

Keywords:  Ferroptosis; Mitophagy; Oxidative stress; Tendinopathy; Tendon stem cell; cGAS-STING

DOI:  https://doi.org/10.1016/j.intimp.2024.112652
bioRxiv. 2024 Jun 24. pii: 2024.05.12.593764. [Epub ahead of print]

The iAAA-mitochondrial protease YME1L1 regulates the degradation of the short-lived mitochondrial transporter SLC25A38.

Sijie Tan, Alisa Susan Dengler, Rami Zahi Darawsheh, Nora Kory.

Mitochondrial transporters facilitate the exchange of diverse metabolic intermediates across the inner mitochondrial membrane, ensuring an adequate supply of substrates and cofactors to support redox and biosynthetic reactions within the mitochondrial matrix. However, the regulatory mechanisms governing the abundance of these transporters, crucial for maintaining metabolic compartmentalization and mitochondrial functions, remain poorly defined. Through analysis of protein half-life data and mRNA-protein correlations, we identified SLC25A38, a mitochondrial glycine transporter, as a short- lived protein with a half-life of 4 hours under steady-state conditions. Pharmacological inhibition and genetic depletion of various cellular proteolytic systems revealed that SLC25A38 is rapidly degraded by the iAAA-mitochondrial protease YME1L1. Depolarization of the mitochondrial membrane potential induced by the mitochondrial uncoupler carbonyl cyanide m-chlorophenylhydrozone prevented the degradation of SLC25A38. This dual regulation of SLC25A38 abundance by YME1L1 and mitochondrial membrane potential suggests a link between SLC25A38 turnover, the integrity of the inner mitochondrial membrane, and electron transport chain function. These findings open avenues for investigating whether mitochondrial glycine import coordinates with mitochondrial bioenergetics.

DOI: https://doi.org/10.1101/2024.05.12.593764
J Cell Physiol. 2024 Jul 10. e31370

Mitochondrial dynamics in pulmonary disease: Implications for the potential therapeutics.

Hui Li, Xinyan Dai, Junfu Zhou, Yujuan Wang, Shiying Zhang, Jiacheng Guo, Lidu Shen, Hengxiu Yan, Huiling Jiang.

  Mitochondria are dynamic organelles that continuously undergo fusion/fission to maintain normal cell physiological activities and energy metabolism. When mitochondrial dynamics is unbalanced, mitochondrial homeostasis is broken, thus damaging mitochondrial function. Accumulating evidence demonstrates that impairment in mitochondrial dynamics leads to lung tissue injury and pulmonary disease progression in a variety of disease models, including inflammatory responses, apoptosis, and barrier breakdown, and that the role of mitochondrial dynamics varies among pulmonary diseases. These findings suggest that modulation of mitochondrial dynamics may be considered as a valid therapeutic strategy in pulmonary diseases. In this review, we discuss the current evidence on the role of mitochondrial dynamics in pulmonary diseases, with a particular focus on its underlying mechanisms in the development of acute lung injury (ALI)/acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD), asthma, pulmonary fibrosis (PF), pulmonary arterial hypertension (PAH), lung cancer and bronchopulmonary dysplasia (BPD), and outline effective drugs targeting mitochondrial dynamics-related proteins, highlighting the great potential of targeting mitochondrial dynamics in the treatment of pulmonary disease.

Keywords:  mitochondrial dynamics; mitochondrial fission; mitochondrial fusion; pulmonary disease; therapeutic target

DOI:  https://doi.org/10.1002/jcp.31370
Front Immunol. 2024 ;15 1400431

Mitophagy and clear cell renal cell carcinoma: insights from single-cell and spatial transcriptomics analysis.

Lai Jiang, Xing Ren, Jinyan Yang, Haiqing Chen, Shengke Zhang, Xuancheng Zhou, Jinbang Huang, Chenglu Jiang, Yuheng Gu, Jingyi Tang, Guanhu Yang, Hao Chi, Jianhua Qin.

  Background: Clear Cell Renal Cell Carcinoma (ccRCC) is the most common type of kidney cancer, characterized by high heterogeneity and complexity. Recent studies have identified mitochondrial defects and autophagy as key players in the development of ccRCC. This study aims to delve into the changes in mitophagic activity within ccRCC and its impact on the tumor microenvironment, revealing its role in tumor cell metabolism, development, and survival strategies.Methods: Comprehensive analysis of ccRCC tumor tissues using single cell sequencing and spatial transcriptomics to reveal the role of mitophagy in ccRCC. Mitophagy was determined to be altered among renal clear cells by gene set scoring. Key mitophagy cell populations and key prognostic genes were identified using NMF analysis and survival analysis approaches. The role of UBB in ccRCC was also demonstrated by in vitro experiments.
Results: Compared to normal kidney tissue, various cell types within ccRCC tumor tissues exhibited significantly increased levels of mitophagy, especially renal clear cells. Key genes associated with increased mitophagy levels, such as UBC, UBA52, TOMM7, UBB, MAP1LC3B, and CSNK2B, were identified, with their high expression closely linked to poor patient prognosis. Particularly, the ubiquitination process involving the UBB gene was found to be crucial for mitophagy and its quality control.
Conclusion: This study highlights the central role of mitophagy and its regulatory factors in the development of ccRCC, revealing the significance of the UBB gene and its associated ubiquitination process in disease progression.

Keywords:  clear cell renal cell carcinoma; metabolic reprogramming; mitochondrial gene defects; mitophagy; multi-omics analysis; non-negative matrix factorization; prognostic analysis

DOI:  https://doi.org/10.3389/fimmu.2024.1400431
Brain Behav Immun. 2024 Jul 05. pii: S0889-1591(24)00469-0. [Epub ahead of print]120 543-544

Response to comment on: BGP-15 alleviates LPS-induced depression-like behavior by promoting mitophagy.

Qian Liu, Gong-Ping Liu.

DOI: https://doi.org/10.1016/j.bbi.2024.06.029
Appl Physiol Nutr Metab. 2024 Jul 09.

Maintaining mitochondrial NAD+ homeostasis is key for heat-induced skeletal muscle injury prevention despite presence of intracellular cation alterations.

Yifan Chen, Tianzheng Yu, Patricia Deuster.

Mitochondrial dysfunction is implicated in heat-induced skeletal muscle injury and its underlying mechanisms remain unclear. Evidence suggests that cellular ions and molecules, including divalent cations and adenine nucleotides, are involved in the regulation of mitochondrial function. In this study, we examined Ca2+, Mg2+, and NAD+ levels in mouse C2C12 myoblasts and skeletal muscle in response to heat exposure. During heat exposure, mitochondrial Ca2+ levels increased significantly, whereas cytosolic C2+ levels remained unaltered. The mitochondrial Ca2+ levels in the skeletal muscle of heat-exposed mice were 28% higher, compared to control mice. No changes in cytosolic Ca2+ were detected between the two groups. Following heat exposure, cytosolic and mitochondrial Mg2+ levels were reduced by 47% and 23% in C2C12 myoblasts, and by 51% and 44% in mouse skeletal muscles, respectively. In addition, heat exposure decreased mitochondrial NAD+ levels by 32% and 26% in C2C12 myoblasts and mouse skeletal muscles, respectively. Treatment with the NAD+ precursor nicotinamide riboside (NR) partially prevented heat-induced depletion of NAD+. Additionally, NR significantly reduced heat-increased mitochondrial fission, mitochondrial depolarization, and apoptosis in C2C12 myoblasts and mouse skeletal muscles. No effects of NR on heat-induced changes in intracellular Ca2+ and Mg2+ levels were observed. This study provides the in vitro and in vivo evidence that acute heat stress causes alterations in mitochondrial Ca2+, Mg2+, and NAD+ homeostasis. Our results suggest mitochondrial NAD+> homeostasis as a therapeutic target for the prevention of heat-induced skeletal muscle injury.

DOI: https://doi.org/10.1139/apnm-2024-0157
bioRxiv. 2024 Jun 25. pii: 2024.06.24.600538. [Epub ahead of print]

Structural and mechanistic studies on human LONP1 redefine the hand-over-hand translocation mechanism.

Jeffrey T Mindrebo, Gabriel C Lander.

AAA+ enzymes use energy from ATP hydrolysis to remodel diverse cellular targets. Structures of substrate-bound AAA+ complexes suggest that these enzymes employ a conserved hand-over-hand mechanism to thread substrates through their central pore. However, the fundamental aspects of the mechanisms governing motor function and substrate processing within specific AAA+ families remain unresolved. We used cryo-electron microscopy to structurally interrogate reaction intermediates from in vitro biochemical assays to inform the underlying regulatory mechanisms of the human mitochondrial AAA+ protease, LONP1. Our results demonstrate that substrate binding allosterically regulates proteolytic activity, and that LONP1 can adopt a configuration conducive to substrate translocation even when the ATPases are bound to ADP. These results challenge the conventional understanding of the hand-over-hand translocation mechanism, giving rise to an alternative model that aligns more closely with biochemical and biophysical data on related enzymes like ClpX, ClpA, the 26S proteasome, and Lon protease.

DOI: https://doi.org/10.1101/2024.06.24.600538
Biomed Pharmacother. 2024 Jul 07. pii: S0753-3322(24)00976-4. [Epub ahead of print]177 117092

Melatonin regulates microglial M1/M2 polarization via AMPKα2-mediated mitophagy in attenuating sepsis-associated encephalopathy.

Yang Yang, Jinyong Ke, Yang Cao, Yue Gao, Chunshui Lin.

  BACKGROUND: Sepsis-associated encephalopathy (SAE) is a disease characterized by neuroinflammation and cognitive dysfunction caused by systemic infection. Inflammation-induced microglial activation is closely associated with neuroinflammation in SAE. It is widely understood that melatonin has strong anti-inflammatory and immunomodulatory properties beneficial for sepsis-related brain damage. However, the mechanism of melatonin action in SAE has not been fully elucidated.METHODS: The SAE cell model and SAE mouse model were induced by lipopolysaccharide (LPS). Behavioral tests were performed to analyze cognitive function. Microglial markers and M1/M2 markers were measured by immunofluorescence. Mitophagy was assessed by western blot, mt-Keima and transmission electron microscopy experiments. Immunoprecipitation and co-immunoprecipitation assays investigated the interactions between AMP-activated protein kinase α2 (AMPKα2) and PTEN-induced putative kinase 1 (PINK1).
RESULTS: Melatonin suppresses LPS-induced microglia M1 polarization by enhancing mitophagy, thereby attenuating LPS-induced neuroinflammation and behavioral deficits. However, inhibition or knockdown of AMPKα2 can inhibit the enhancement of melatonin on mitophagy, then weaken its promotion of microglia polarization towards M2 phenotype, and eliminate its protective effect on brain function. Furthermore, melatonin enhances mitophagy through activating AMPKα2, promotes PINK1 Ser495 site phosphorylation, and ultimately regulates microglial polarization from M1 to M2.
CONCLUSIONS: Our findings demonstrate that melatonin facilitates microglia polarization towards M2 phenotype to alleviate LPS-induced neuroinflammation, primarily through AMPKα2-mediated enhancement of mitophagy.

Keywords:  AMPKα2; Melatonin; Microglial polarization; Mitophagy; PINK1; Sepsis-associated encephalopathy

DOI:  https://doi.org/10.1016/j.biopha.2024.117092
Neuropharmacology. 2024 Jul 06. pii: S0028-3908(24)00232-6. [Epub ahead of print]257 110063

Inhibition of NLRP3 inflammasome ameliorates LPS-induced neuroinflammatory injury in mice via PINK1/Parkin pathway.

Ao Wang, Guangshang Zhong, Mengjiao Ying, Zhuling Fang, Ying Chen, Haojie Wang, Chunjing Wang, Changqing Liu, Yu Guo.

  Parkinson's disease (PD) is characterized by the severe loss of dopaminergic neurons in the substantia nigra pars compacta, leading to motor dysfunction. The onset of PD is often accompanied by neuroinflammation and α-Synuclein aggregation, and extensive research has focused on the activation of microglial NLRP3 inflammasomes in PD, which promotes the death of dopaminergic neurons. In this study, a model of cerebral inflammatory response was constructed in wild-type and Parkin＋/－ mice through bilateral intraventricular injection of LPS. LPS-induced activation of the NLRP3 inflammasome in wild-type mice promotes the progression of PD. The use of MCC950 in wild mice injected with LPS induces activation of Parkin/PINK and improves autophagy, which in turn improves mitochondrial turnover. It also inhibits LPS-induced inflammatory responses, improves motor function, protects dopaminergic neurons, and inhibits microglia activation. Furthermore, Parkin＋/－ mice exhibited motor dysfunction, loss of dopaminergic neurons, activation of the NLRP3 inflammasome, and α-Synuclein aggregation beginning at an early age. Parkin ± mice exhibited more pronounced microglia activation, greater NLRP3 inflammasome activation, more severe autophagy dysfunction, and more pronounced motor dysfunction after LPS injection compared to wild-type mice. Notably, the use of MCC950 in Parkin ± mice did not ameliorate NLRP3 inflammasome activation, autophagy dysfunction, or α-synuclein aggregation. Thus, MCC950 can only exert its effects in the presence of Parkin/PINK1, and targeting Parkin-mediated NLRP3 inflammasome activation is expected to be a potential therapeutic strategy for Parkinson's disease.

Keywords:  MCC950; NLRP3 inflammasome; Parkin; Parkinson's disease; α-Synuclein

DOI:  https://doi.org/10.1016/j.neuropharm.2024.110063
Int J Mol Sci. 2024 Jul 03. pii: 7305. [Epub ahead of print]25(13):

Mitochondrial Quality Control Processes at the Crossroads of Cell Death and Survival: Mechanisms and Signaling Pathways.

Emanuele Marzetti, Riccardo Calvani, Francesco Landi, Helio José Coelho-Júnior, Anna Picca.

  Biological aging results from an accumulation of damage in the face of reduced resilience. One major driver of aging is cell senescence, a state in which cells remain viable but lose their proliferative capacity, undergo metabolic alterations, and become resistant to apoptosis. This is accompanied by complex cellular changes that enable the development of a senescence-associated secretory phenotype (SASP). Mitochondria, organelles involved in energy provision and activities essential for regulating cell survival and death, are negatively impacted by aging. The age-associated decline in mitochondrial function is also accompanied by the development of chronic low-grade sterile inflammation. The latter shares some features and mediators with the SASP. Indeed, the unloading of damage-associated molecular patterns (DAMPs) at the extracellular level can trigger sterile inflammatory responses and mitochondria can contribute to the generation of DAMPs with pro-inflammatory properties. The extrusion of mitochondrial DNA (mtDNA) via mitochondrial outer membrane permeabilization under an apoptotic stress triggers senescence programs. Additional pathways can contribute to sterile inflammation. For instance, pyroptosis is a caspase-dependent inducer of systemic inflammation, which is also elicited by mtDNA release and contributes to aging. Herein, we overview the molecular mechanisms that may link mitochondrial dyshomeostasis, pyroptosis, sterile inflammation, and senescence and discuss how these contribute to aging and could be exploited as molecular targets for alleviating the cell damage burden and achieving healthy longevity.

Keywords:  DAMPs; SASP; cell death; extracellular vesicles; inflammaging; interleukin; mitochondrial quality control; mitochondrial-derived vesicles; mtDNA; pyroptosis

DOI:  https://doi.org/10.3390/ijms25137305
Recent Pat Anticancer Drug Discov. 2024 Jul 11.

Fumarate-1 Mediates the Regulation of Mitochondrial Homeostasis by PGC-1α to Promote Cell Pyroptosis and Inhibit the Progression of Thyroid Cancer.

Xiaomei Meng, Dong You, Ruizhen Ren.

  BACKGROUND: Thyroid cancer is a rare but increasingly prevalent form of cancer worldwide. The development and progression of thyroid cancer are associated with mitochondrial instability, which refers to alterations in the structure, function, and energy status of mitochondria. These alterations lead to an imbalance in mitochondrial metabolism, causing cellular damage and apoptosis. However, the molecular mechanisms underlying mitochondrial instability and thyroid cancer remain poorly understood.OBJECTIVE: This study aimed to explore the molecular mechanism of delaying the progression of thyroid cancer by regulating mitochondrial homeostasis through fumarate 1-mediated PGC-1α in vitro.
METHODS: Human papillary thyroid carcinoma cell lines (TPC-1 and K-1) and a normal thyroid cell line (Nthy-ori 3-1) were cultured in this study. TPC-1 cells and K-1 cells were separately transfected with oveRNA-FH1 and oveRNA-NC, designated as the oveRNA-FH1 group, oveRNA- NC group, TPC-1 group, and Nthy-ori 3-1 group. Various assays were performed to assess cell viability, proliferation capacity, invasion and migration abilities, as well as mitochondrial morphology changes and the expression of relevant factors. qRT-PCR and Western blot analysis were carried out to analyze the expression changes of PGC-1α, mitochondrial dynamics-related factors, and pyroptosis genes. The goal of these experiments was to evaluate the impact of FH1 on mitochondrial instability and elucidate the specific mechanisms underlying thyroid cancer and mitochondrial instability.
RESULTS: The results of this study demonstrated that FH1 expression was significantly downregulated in thyroid papillary carcinoma cell lines compared to the normal thyroid cell line. Overexpression of FH1 reduced cell viability and inhibited cell proliferation rate in TPC-1 cells. Furthermore, FH1 overexpression suppressed cell invasion and migration abilities. Abnormal mitochondrial morphological changes were observed in TPC-1 and K-1 cells, whereas FH1 overexpression resulted in relatively normal mitochondria. FH1 overexpression also affected the expression of fusion and fission genes, promoting fission and inhibiting fusion in thyroid cancer cells. Moreover, FH1 overexpression led to increased inflammation and pyroptosis. These conclusions were further verified by in vitro tumor formation experiments.
CONCLUSION: FH1 promoted thyroid cancer progression by regulating mitochondrial homeostasis via the PGC-1α-dependent pathway, which affected pyroptosis and apoptosis.

Keywords:  FH1; Thyroid cancer; apoptosis.; cell fission; mitochondrial homeostasis; pyroptosis

DOI:  https://doi.org/10.2174/0115748928282936240530105434