bims-mikwok 2024-08-18 papers

bims-mikwok

Biomed News

on Mitochondrial quality control

Issue of 2024–08–18
28 papers selected by
Gavin McStay, Liverpool John Moores University

Phosphoglycerate mutase 5 exacerbates alcoholic cardiomyopathy in male mice by inducing prohibitin-2 dephosphorylation and impairing mitochondrial quality control.
Mitochondrial-derived compartments remove surplus proteins from the outer mitochondrial membrane.
Benzopyrene represses mitochondrial fission factors and PINK1/Parkin-mediated mitophagy in primary astrocytes.
Deficiency in the mitophagy mediator Parkin accelerates murine skin allograft rejection.
PKD regulates mitophagy to prevent oxidative stress and mitochondrial dysfunction during mouse oocyte maturation.
GPR50 regulates neuronal development as a mitophagy receptor.
M6A RNA methylation-mediated TUG1 stability maintains mitochondrial homeostasis during kidney aging by epigenetically regulating PGC1-α expression.
JAK2 inhibitor protects the septic heart through enhancing mitophagy in cardiomyocytes.
Endothelial Birc3 promotes renal fibrosis through modulating Drp1-mediated mitochondrial fission via MAPK/PI3K/Akt pathway.
OPA1 promotes ferroptosis by augmenting mitochondrial ROS and suppressing an integrated stress response.
Selenomethionine supplementation mitigates fluoride-induced liver apoptosis and inflammatory reactions by blocking Parkin-mediated mitophagy in mice.
The Role of Endothelial Cell Mitophagy in Age-Related Cardiovascular Diseases.
Involvement of Sirt1-FoxO3a-Bnip3 axis and autophagy mediated mitochondrial turnover in according protection to hyperglycemic NRK-52E cells by Berberine.
MANF facilitates breast cancer cell survival under glucose-starvation conditions via prkn-mediated mitophagy regulation.
Insufficient FUNDC1-dependent mitophagy due to early environmental cadmium exposure triggers mitochondrial redox imbalance to aggravate diet-induced lipotoxicity.
Inherited mitochondrial dysfunction triggered by OPA1 mutation impacts the sensory innervation fibre identity, functionality and regenerative potential in the cornea.
Mitochondrial network reorganization and transient expansion during oligodendrocyte generation.
Electroacupuncture protects against cerebral ischemia-reperfusion injury through mitochondrial dynamics.
Dysregulation of mitochondria, apoptosis and mitophagy in Leber's hereditary optic neuropathy with MT-ND1 3635G>A mutation.
Canagliflozin mediates mitophagy through the AMPK/PINK1/PARKIN pathway to alleviate isoprenaline-induced cardiac remodelling.
An Engineered Cellular Carrier Delivers miR-138-5p to Enhance Mitophagy and Protect Hypoxic-Injured Neurons via the DNMT3A/Rhebl1 Axis.
Ciclopirox platinum(IV) conjugates suppress tumors by promoting mitophagy and provoking immune responses.
Gentiana decoction inhibits liver fibrosis and the activation of hepatic stellate cells via upregulating the expression of Parkin.
Regimen on Dnaja3 haploinsufficiency mediated sarcopenic obesity with imbalanced mitochondrial homeostasis and lipid metabolism.
COX-2 optimizes cardiac mitochondrial biogenesis and exerts a cardioprotective effect during sepsis.
Reduced FNDC5-AMPK signaling in diabetic atrium increases the susceptibility of atrial fibrillation by impairing mitochondrial dynamics and activating NLRP3 inflammasome.
FDX1 downregulation activates mitophagy and the PI3K/AKT signaling pathway to promote hepatocellular carcinoma progression by inducing ROS production.
β-Hydroxybutyrate enhances chondrocyte mitophagy and reduces cartilage degeneration in osteoarthritis via the HCAR2/AMPK/PINK1/Parkin pathway.

Clin Transl Med. 2024 Aug;14(8): e1806

Phosphoglycerate mutase 5 exacerbates alcoholic cardiomyopathy in male mice by inducing prohibitin-2 dephosphorylation and impairing mitochondrial quality control.

Jun Tao, Junxiong Qiu, Junmeng Zheng, Ruibing Li, Xing Chang, Qingyong He.

   BACKGROUND: The induction of mitochondrial quality control (MQC) mechanisms is essential for the re-establishment of mitochondrial homeostasis and cellular bioenergetics during periods of stress. Although MQC activation has cardioprotective effects in various cardiovascular diseases, its precise role and regulatory mechanisms in alcoholic cardiomyopathy (ACM) remain incompletely understood.
METHODS: We explored whether two mitochondria-related proteins, phosphoglycerate mutase 5 (Pgam5) and prohibitin 2 (Phb2), influence MQC in male mice during ACM.
RESULTS: Myocardial Pgam5 expression was upregulated in a male mouse model of ACM. Notably, following ACM induction, heart dysfunction was markedly reversed in male cardiomyocyte-specific Pgam5 knockout (Pgam5cKO) mice. Meanwhile, in alcohol-treated male mouse-derived neonatal cardiomyocytes, Pgam5 depletion preserved cell survival and restored mitochondrial dynamics, mitophagy, mitochondrial biogenesis and the mitochondrial unfolded protein response (mtUPR). We further found that in alcohol-treated cardiomyocyte, Pgam5 binds Phb2 and induces its dephosphorylation at Ser91. Alternative transduction of phospho-mimetic (Phb2S91D) and phospho-defective (Phb2S9A) Phb2 mutants attenuated and enhanced, respectively, alcohol-related mitochondrial dysfunction in cardiomyocytes. Moreover, transgenic male mice expressing Phb2S91D were resistant to alcohol-induced heart dysfunction.
CONCLUSIONS: We conclude that ACM-induced Pgam5 upregulation results in Pgam5-dependent Phb2S91 dephosphorylation, leading to MQC destabilisation and mitochondrial dysfunction in heart. Therefore, modulating the Pgam5/Phb2 interaction could potentially offer a novel therapeutic strategy for ACM in male mice.
HIGHLIGHTS: Pgam5 knockout attenuates alcohol-induced cardiac histopathology and heart dysfunction in male mice. Pgam5 KO reduces alcohol-induced myocardial inflammation, lipid peroxidation and metabolic dysfunction in male mice. Pgam5 depletion protects mitochondrial function in alcohol-exposed male mouse cardiomyocytes. Pgam5 depletion normalises MQC in ACM. EtOH impairs MQC through inducing Phb2 dephosphorylation at Ser91. Pgam5 interacts with Phb2 and induces Phb2 dephosphorylation. Transgenic mice expressing a Ser91 phospho-mimetic Phb2 mutant are resistant to ACM.

Keywords:  MQC; Pgam5; Phb2; alcoholic cardiomyopathy

DOI:  https://doi.org/10.1002/ctm2.1806
J Cell Biol. 2024 Nov 04. pii: e202307036. [Epub ahead of print]223(11):

Mitochondrial-derived compartments remove surplus proteins from the outer mitochondrial membrane.

Zachary N Wilson, Sai Sangeetha Balasubramaniam, Sara Wong, Max-Hinderk Schuler, Mitchell J Wopat, Adam L Hughes.

The outer mitochondrial membrane (OMM) creates a boundary that imports most of the mitochondrial proteome while removing extraneous or damaged proteins. How the OMM senses aberrant proteins and remodels to maintain OMM integrity remains unresolved. Previously, we identified a mitochondrial remodeling mechanism called the mitochondrial-derived compartment (MDC) that removes a subset of the mitochondrial proteome. Here, we show that MDCs specifically sequester proteins localized only at the OMM, providing an explanation for how select mitochondrial proteins are incorporated into MDCs. Remarkably, selective sorting into MDCs also occurs within the OMM, as subunits of the translocase of the outer membrane (TOM) complex are excluded from MDCs unless assembly of the TOM complex is impaired. Considering that overloading the OMM with mitochondrial membrane proteins or mistargeted tail-anchored membrane proteins induces MDCs to form and sequester these proteins, we propose that one functional role of MDCs is to create an OMM-enriched trap that segregates and sequesters excess proteins from the mitochondrial surface.

DOI: https://doi.org/10.1083/jcb.202307036
Toxicology. 2024 Aug 13. pii: S0300-483X(24)00207-5. [Epub ahead of print] 153926

Benzopyrene represses mitochondrial fission factors and PINK1/Parkin-mediated mitophagy in primary astrocytes.

Yunn Me Me Paing, Yunkyung Eom, Sung Hoon Lee.

  Mitochondria are essential for various physiological functions in astrocytes in the brain, such as maintaining ion and pH homeostasis, regulating neurotransmission, and modulating neuroinflammation. Mitophagy, a form of autophagy specific to mitochondria, is essential for ensuring mitochondrial quality and function. Benzo[a]pyrene (BaP) accumulates in the brain, and exposure to it is recognized as an environmental risk factor for neurodegenerative diseases. However, while the toxic mechanisms of BaP have been investigated in neurons, their effects on astrocytes-the most prevalent glial cells in the brain-are not clearly understood. Therefore, this study aims to investigate the toxic effects of exposure to BaP on mitochondria in primary astrocytes. Fluorescent probes and genetically encoded indicators were utilized to visualize mitochondrial morphology and physiology, and regulatory factors involved in mitochondrial morphology and mitophagy were assessed. Additionally, the mitochondrial respiration rate was measured in BaP-exposed astrocytes. BaP exposure resulted in mitochondrial enlargement owing to the suppression of mitochondrial fission factors. Furthermore, BaP-exposed astrocytes demonstrated reduced mitophagy and exhibited aberrant mitochondrial function and physiology, such as altered mitochondrial respiration rates, increased mitochondrial superoxide, disrupted mitochondrial membrane potential, and dysregulated mitochondrial Ca2+. These findings offer insights into the underlying toxic mechanisms of BaP exposure in neurodegenerative diseases by inducing aberrant mitophagy and mitochondrial dysfunction in astrocytes.

Keywords:  astrocytes; benzo[a]pyrene; fission factor; mitochondria; mitophagy

DOI:  https://doi.org/10.1016/j.tox.2024.153926
Am J Transplant. 2024 Aug 12. pii: S1600-6135(24)00491-X. [Epub ahead of print]

Deficiency in the mitophagy mediator Parkin accelerates murine skin allograft rejection.

Kathleen M Wragg, Matthew J Worley, Jane C Deng, Morgan Salmon, Daniel R Goldstein.

Alterations in mitochondrial function and associated quality control programs, including mitochondrial-specific autophagy, termed mitophagy, are gaining increasing recognition in the context of disease. However, the role of mitophagy in organ transplant rejection remains poorly understood. Using mice deficient in Parkin, a ubiquitin-ligase which tags damaged or dysfunctional mitochondria for autophagic clearance, we assessed the impact of Parkin-dependent mitophagy on skin-graft rejection. We observed accelerated graft loss in Parkin-deficient mice across multiple-skin graft models. Immune cell distributions post-transplantation were largely unperturbed compared to wild-type; however, the CD8+ T cells of Parkin-deficient mice expressed more T-bet, IFNγ and Ki67, indicating greater priming towards effector function. This was accompanied by increased circulating levels of IL-12p70 in Parkin-deficient mice. Using a mixed leukocyte reaction, we demonstrated that naïve Parkin-deficient CD4+ and CD8+ T cells exhibit enhanced activation marker expression and proliferative responses to alloantigen, which were attenuated with administration of a pharmacological mitophagy inducer (p62-mediated mitophagy inducer), known to increase mitophagy in the absence of a functional PINK1-Parkin pathway. These findings indicate a role for Parkin-dependent mitophagy in curtailing skin-graft rejection.

DOI: https://doi.org/10.1016/j.ajt.2024.08.005
Mitochondrion. 2024 Aug 13. pii: S1567-7249(24)00104-1. [Epub ahead of print] 101946

PKD regulates mitophagy to prevent oxidative stress and mitochondrial dysfunction during mouse oocyte maturation.

Ya-Ping Liu, Bing He, Wen-Xin Wang, Wen-Lin Pan, Le Jiao, Jing-Jing Yan, Shao-Chen Sun, Yu Zhang.

  Mitochondria play dominant roles in various cellular processes such as energy production, apoptosis, calcium homeostasis, and oxidation-reduction balance. Maintaining mitochondrial quality through mitophagy is essential, especially as its impairment leads to the accumulation of dysfunctional mitochondria in aging oocytes. Our previous research revealed that PKD expression decreases in aging oocytes, and its inhibition negatively impacts oocyte quality. Given PKD's role in autophagy mechanisms, this study investigates whether PKD regulates mitophagy to maintain mitochondrial function and support oocyte maturation. When fully grown oocytes were treated with CID755673, a potent PKD inhibitor, we observed meiosis arrest at the metaphase I stage, along with decreased spindle stability. Our results demonstrate an association with mitochondrial dysfunction, including reduced ATP production and fluctuations in Ca2+ homeostasis, which ultimately lead to increased ROS accumulation, stimulating oxidative stress-induced apoptosis and DNA damage. Further research has revealed that these phenomena result from PKD inhibition, which affects the phosphorylation of ULK, thereby reducing autophagy levels. Additionally, PKD inhibition leads to decreased Parkin expression, which directly and negatively affects mitophagy. These defects result in the accumulation of damaged mitochondria in oocytes, which is the primary cause of mitochondrial dysfunction. Taken together, these findings suggest that PKD regulates mitophagy to support mitochondrial function and mouse oocyte maturation, offering insights into potential targets for improving oocyte quality and addressing mitochondrial-related diseases in aging females.

Keywords:  Mitochondria; Mitophagy; Oocyte maturation; PKD; Parkin; ULK

DOI:  https://doi.org/10.1016/j.mito.2024.101946
Cell Death Dis. 2024 Aug 15. 15(8): 591

GPR50 regulates neuronal development as a mitophagy receptor.

Ji-Chuan Liu, Xiu-Yun Zhao, Ming-Lei Wu, Yi-Fan Shi, Ze-Ping Huang, Li-Pao Fang, Chao Zhu, Xuan Peng, Zi-Ling Shi, Li-Jun Lan, Wen-Li Ji, Li Luo, Lei Feng, Zeng-Li Zhang, De-En Xu, Shao Li, Zheng-Hong Qin, Yan-Yun Sun, Melitta Schachner, Quan-Hong Ma.

Neurons rely heavily on high mitochondrial metabolism to provide sufficient energy for proper development. However, it remains unclear how neurons maintain high oxidative phosphorylation (OXPHOS) during development. Mitophagy plays a pivotal role in maintaining mitochondrial quality and quantity. We herein describe that G protein-coupled receptor 50 (GPR50) is a novel mitophagy receptor, which harbors the LC3-interacting region (LIR) and is required in mitophagy under stress conditions. Although it does not localize in mitochondria under normal culturing conditions, GPR50 is recruited to the depolarized mitochondrial membrane upon mitophagy stress, which marks the mitochondrial portion and recruits the assembling autophagosomes, eventually facilitating the mitochondrial fragments to be engulfed by the autophagosomes. Mutations Δ502-505 and T532A attenuate GPR50-mediated mitophagy by disrupting the binding of GPR50 to LC3 and the mitochondrial recruitment of GPR50. Deficiency of GPR50 causes the accumulation of damaged mitochondria and disrupts OXPHOS, resulting in insufficient ATP production and excessive ROS generation, eventually impairing neuronal development. GPR50-deficient mice exhibit impaired social recognition, which is rescued by prenatal treatment with mitoQ, a mitochondrially antioxidant. The present study identifies GPR50 as a novel mitophagy receptor that is required to maintain mitochondrial OXPHOS in developing neurons.

DOI: https://doi.org/10.1038/s41419-024-06978-y
Antioxid Redox Signal. 2024 Aug 12.

M6A RNA methylation-mediated TUG1 stability maintains mitochondrial homeostasis during kidney aging by epigenetically regulating PGC1-α expression.

Yonghong Zhu, Bowen Yang, Suyun Chen, Guanqing Chen, Xiaobian Zeng, Hui Min, Li Xu.

Aging is a significant risk factor for the increased incidence of acute kidney injury and chronic kidney disease, posing significant challenges to global public health. The role of N6-methyladenosine (m6A) in the development of chronic kidney disease has been reported, but the regulatory mechanism of m6A in kidney aging remains unclear. In this study, we identified a long non-coding RNA (lncRNA), called TUG1, which exhibited a significantly decreased level of m6A modification in human aged kidney through the m6A-lncRNA epitranscriptome microarray. Bioinformatics analysis and machine learning predicted that TUG1 formed potentially strong interaction with PGC1-α. RIP and ChIP analysis supported that TUG1 promoted proliferator-activated receptor γ coactivator-1α (PGC1-α) expression by directly interact with its TBE region, thereby impacting mitochondrial quality control, cellular senescence and renal fibrosis. Silencing the RNA m6A methylase METTL14 or the reader protein IGF2BP2 resulted in the weakened stability of LncRNA TUG1, contributing to an imbalance in mitochondrial quality control. Our study demonstrated that Our study demonstrated that the m6A modification and stability of TUG1 was mediated by METTL14 in an IGF2BP2-dependent manner, and modulate the mitochondrial homeostasis in kidney aging by direct targeting PGC-1α. These findings provide a new perspective on potential therapeutic targets for kidney aging.

DOI: https://doi.org/10.1089/ars.2024.0631
Biomed Pharmacother. 2024 Aug 08. pii: S0753-3322(24)01163-6. [Epub ahead of print]178 117279

JAK2 inhibitor protects the septic heart through enhancing mitophagy in cardiomyocytes.

Dafei Han, Tiantian Su, Mingzhu Wang, Renhao Zhang, Huihui Xu, Rui Chu, Zhenduo Zhu, Yawei Shen, Nan Wang, Shufang He, Yongsheng Wang, Yongsheng Han, Qingtong Wang.

  Sepsis-induced myocardial dysfunction (SIMD) is a severe complication in sepsis, manifested as myocardial systolic dysfunction, which is associated with poor prognosis and higher mortality. Mitophagy, a self-protective mechanism maintaining cellular homeostasis, plays an indispensable role in cardioprotection. This study aimed to unveil the cardioprotective effects of Baricitinib on LPS-induced myocardial dysfunction and its effect on mitophagy. Herein, we demonstrated that LPS induced severe myocardial dysfunction and initiated mitophagy in septic mice hearts. Despite the initiation of mitophagy, a significant number of apoptotic cells and damaged mitochondria persisted in the myocardium, and myocardial energy metabolism remained impaired, indicating that the limited mitophagy was insufficient to mitigate LPS-induced damage. The JAK2-AKT-mTOR signaling pathway is activated in LPS-induced cardiomyocytes and in the hearts of septic mice. Baricitinib administration remarkably improved cardiac function, suppressed systemic inflammatory response, attenuated histopathological changes, inhibited cardiac cell apoptosis and alleviated myocardial damage in septic mice. Furthermore, Baricitinib treatment significantly enhanced PINK1-Parkin-mediated mitophagy, increased autophagosomes, decreased impaired mitochondria, and restored myocardial energy metabolism. Mechanically, the limited mitophagy in septic myocardium was associated with increased p-ULK1 (Ser757), which was regulated by p-mTOR. Baricitinib reduced p-ULK1 (Ser757) and enhanced mitophagy by inhibiting the JAK2-AKT-mTOR signaling pathway. Inhibition of mitophagy with Mdivi-1 reversed the cardiac protective and anti-inflammatory effects of Baricitinib in septic mice. These findings suggest that Baricitinib attenuates SIMD by enhancing mitophagy in cardiomyocytes via the JAK2-AKT-mTOR signaling pathway, providing a novel mechanistic and therapeutic insight into the SIMD.

Keywords:  Baricitinib; JAK2-AKT-mTOR signaling pathway; Mitophagy; Sepsis-induced myocardial dysfunction

DOI:  https://doi.org/10.1016/j.biopha.2024.117279
Biochem Pharmacol. 2024 Aug 10. pii: S0006-2952(24)00460-X. [Epub ahead of print]229 116477

Endothelial Birc3 promotes renal fibrosis through modulating Drp1-mediated mitochondrial fission via MAPK/PI3K/Akt pathway.

Shuai Chen, Qingqing He, Huaiyu Yang, Hongxing Huang.

  Renal fibrosis serves as the shared pathway in chronic kidney disease (CKD) progression towards end-stage renal disease (ESRD). Endothelial-mesenchymal transition (EndMT) is a vital mechanism leading to the generation of myofibroblasts, thereby contributing to the advancement of fibrogenesis. Baculoviral IAP Repeat Containing 3(Birc3) was identified as a crucial inhibitor of cell death and a significant mediator in inflammatory signaling and immunity. However, its involvement in the development of renal interstitial fibrosis via EndMT still needs to be clarified. Herein, elevated levels of Birc3 expression along with EndMT-associated alterations, including increased α-smooth muscle actin (α-SMA) levels and decreased CD31 expression, were observed in fibrotic kidneys of Unilateral Ureteral Obstruction (UUO)-induced mouse models and transforming growth factor-β (TGF-β)-induced EndMT in Human Umbilical Vein Endothelial Cells (HUVECs). Functionally, Birc3 knockdown inhibited EndMT and mitochondrial fission mediated by dynamin-related protein 1 (Drp1) both in vivo and in vitro. Mechanistically, endothelial Birc3 exacerbated Drp-1-induced mitochondrial fission through the MAPK/PI3K/Akt signaling pathway in endothelial cell models stimulated TGF-β. Collectively, these findings illuminate the mechanisms and indicate that targeting Birc3 could offer a promising therapeutic strategy to improve endothelial cell survival and mitigate the progression of CKD.

Keywords:  Birc3; Endothelial-mesenchymal transition; MAPK/PI3K/Akt signaling pathway; Mitochondrial fission; Renal fibrosis

DOI:  https://doi.org/10.1016/j.bcp.2024.116477
Mol Cell. 2024 Aug 09. pii: S1097-2765(24)00618-X. [Epub ahead of print]

OPA1 promotes ferroptosis by augmenting mitochondrial ROS and suppressing an integrated stress response.

Felix G Liang, Fereshteh Zandkarimi, Jaehoon Lee, Joshua L Axelrod, Ryan Pekson, Yisang Yoon, Brent R Stockwell, Richard N Kitsis.

  Ferroptosis, an iron-dependent form of nonapoptotic cell death mediated by lipid peroxidation, has been implicated in the pathogenesis of multiple diseases. Subcellular organelles play pivotal roles in the regulation of ferroptosis, but the mechanisms underlying the contributions of the mitochondria remain poorly defined. Optic atrophy 1 (OPA1) is a mitochondrial dynamin-like GTPase that controls mitochondrial morphogenesis, fusion, and energetics. Here, we report that human and mouse cells lacking OPA1 are markedly resistant to ferroptosis. Reconstitution with OPA1 mutants demonstrates that ferroptosis sensitization requires the GTPase activity but is independent of OPA1-mediated mitochondrial fusion. Mechanistically, OPA1 confers susceptibility to ferroptosis by maintaining mitochondrial homeostasis and function, which contributes both to the generation of mitochondrial lipid reactive oxygen species (ROS) and suppression of an ATF4-mediated integrated stress response. Together, these results identify an OPA1-controlled mitochondrial axis of ferroptosis regulation and provide mechanistic insights for therapeutically manipulating this form of cell death in diseases.

Keywords:  ATF4; GPx4; OPA1; cell death; ferroptosis; integrated stress response; mitochondria; system X(c)(−); xCT

DOI:  https://doi.org/10.1016/j.molcel.2024.07.020
Sci Total Environ. 2024 Aug 12. pii: S0048-9697(24)05608-0. [Epub ahead of print] 175458

Selenomethionine supplementation mitigates fluoride-induced liver apoptosis and inflammatory reactions by blocking Parkin-mediated mitophagy in mice.

Tianyu Wang, Haojei Li, Yuanyuan Li, Meng Li, Hui Zhao, Wenhui Zhang, Tianrui Zhao, Yinghui Wang, Jundong Wang, Jinming Wang.

  As an environmental pollutant, fluoride-induced liver damage is directly linked to mitochondrial alteration and oxidative stress. Selenium's antioxidant capacity has been shown to alleviate liver damage. Emerging research proves that E3 ubiquitin ligase Park2 (Parkin)-mediated mitophagy may be a therapeutic target for fluorosis. The current study explored the effect of diverse selenium sources on fluoride-caused liver injury and the role of Parkin-mediated mitophagy in this intervention process. Therefore, this study established a fluoride-different selenium sources co-intervention wild-type (WT) mouse model and a fluoride-optimum selenium sources co-intervention Parkin gene knockout (Parkin-/-) mouse model. Our results show that selenomethionine (SeMet) is the optimum selenium supplementation form for mice suffering from fluorosis when compared to sodium selenite and chitosan nano‑selenium because mice from the F-SeMet group showed more closely normal growth and development levels of liver function, antioxidant capacity, and anti-inflammatory ability. Explicitly, SeMet ameliorated liver inflammation and cell apoptosis in fluoride-toxic mice, accomplished through downregulating the mRNA and protein expression levels associated with mitochondrial fusion and fission, mitophagy, apoptosis, inflammatory signalling pathway of nuclear factor-kappa B (NF-κB), reducing the protein expression levels of PARKIN, PTEN-induced putative kinase1 (PINK1), SQSTM1/p62 (P62), microtubule-associated protein light chain 3 (LC3), cysteinyl aspartate specific proteinase 3 (CASPAS3), as well as restraining the content of interleukin-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor α (TNF-α), and interferon-γ (IFN-γ). The Parkin-/- showed comparable positive effects to the SeMet in the liver of fluorosis mice. The structure of the mitochondria, mRNA, protein expression levels, and the content of proinflammatory factors in mice from the FParkin-/- and F + SeMetParkin-/- groups closely resembled those in the F + SeMetWT group. Overall, the above results indicated that SeMet could alleviate fluoride-triggered inflammation and apoptosis in mice liver via blocking Parkin-mediated mitophagy.

Keywords:  Fluorosis; Liver; Mitophagy; Parkin; Selenomethionine

DOI:  https://doi.org/10.1016/j.scitotenv.2024.175458
Aging Dis. 2024 Jul 29.

The Role of Endothelial Cell Mitophagy in Age-Related Cardiovascular Diseases.

Quancheng Han, Yiding Yu, Xiujuan Liu, Yonghong Guo, Jingle Shi, Yitao Xue, Yan Li.

Aging is a major risk factor for cardiovascular diseases (CVD), and mitochondrial autophagy impairment is considered a significant physiological change associated with aging. Endothelial cells play a crucial role in maintaining vascular homeostasis and function, participating in various physiological processes such as regulating vascular tone, coagulation, angiogenesis, and inflammatory responses. As aging progresses, mitochondrial autophagy impairment in endothelial cells worsens, leading to the development of numerous cardiovascular diseases. Therefore, regulating mitochondrial autophagy in endothelial cells is vital for preventing and treating age-related cardiovascular diseases. However, there is currently a lack of systematic reviews in this area. To address this gap, we have written this review to provide new research and therapeutic strategies for managing aging and age-related cardiovascular diseases.

DOI: https://doi.org/10.14336/AD.2024.0788
Toxicol In Vitro. 2024 Aug 08. pii: S0887-2333(24)00146-2. [Epub ahead of print] 105916

Involvement of Sirt1-FoxO3a-Bnip3 axis and autophagy mediated mitochondrial turnover in according protection to hyperglycemic NRK-52E cells by Berberine.

Sugandh Saxena, Sumit Kumar Anand, Ankita Sharma, Poonam Kakkar.

  Aberrant accumulation of dysfunctional mitochondria in renal cells during hyperglycemia signifies perturbed autophagy and mitochondrial turnover. This study aims to focus on the underlying mechanism involved in autophagy and mitophagy inducing efficacy of Berberine (isoquinoline alkaloid) in hyperglycemic NRK-52E cells. Berberine mediated protection to hyperglycemic cells prevented alteration in mitochondrial structure and function. Treatment with SRT-1720 (Sirt1 activator) enhanced autophagy, decreased apoptosis, upregulated expression of downstream moieties (FoxO3a and Bnip3) and ameliorated mitochondria related anomalies while nicotinamide (Sirt1 inhibitor) treatment exhibited reversal of the same. GFP reporter assay ascertained enhanced transcriptional activity of FoxO in Berberine treated hyperglycemic cells, which was found to be correlated to increased expression of downstream protein Bnip3. Knocking down FoxO3a disrupted autophagy and stimulated apoptosis. N-acetyl-L-cysteine pre-treatment confirmed that generation of ROS intervened high glucose induced toxicity in NRK-52E cells. Berberine co-treatment resulted in differential expressions of key proteins involved in autophagy and mitophagy like LC3B, ATGs, Beclin1, Sirt1, Bnip3, FoxO3a and Parkin. Further, enhanced mitophagy in Berberine treated cells was confirmed by transmission electron microscopy. Thus, our findings give evidence that the protection accorded by Berberine against hyperglycemia in renal proximal tubular cells (NRK-52E) involves instigation of Sirt1-FoxO3a-Bnip3 axis and autophagy mediated mitophagy induction.

Keywords:  Autophagy; Berberine; Diabetic nephropathy; Mitochondrial dysfunction; Mitophagy

DOI:  https://doi.org/10.1016/j.tiv.2024.105916
Autophagy. 2024 Aug 15.

MANF facilitates breast cancer cell survival under glucose-starvation conditions via prkn-mediated mitophagy regulation.

Zhenchong Xiong, Lin Yang, Chao Zhang, Weiling Huang, Wenjing Zhong, Jiarong Yi, Jikun Feng, Xiazi Zouxu, Libing Song, Xi Wang.

  During tumor expansion, breast cancer (BC) cells often experience reactive oxygen species accumulation and mitochondrial damage because of glucose shortage. However, the mechanism by which BC cells deal with the glucose-shortage-induced oxidative stress remains unclear. Here, we showed that MANF (mesencephalic astrocyte derived neurotrophic factor)-mediated mitophagy facilitates BC cell survival under glucose-starvation conditions. MANF-mediated mitophagy also promotes fatty acid oxidation in glucose-starved BC cells. Moreover, during glucose starvation, SENP1-mediated de-SUMOylation of MANF increases cytoplasmic MANF expression through the inhibition of MANF's nuclear translocation and hence renders mitochondrial distribution of MANF. MANF mediates mitophagy by binding to PRKN (parkin RBR E3 ubiquitin protein ligase), a key mitophagy regulator, in the mitochondria. Under conditions of glucose starvation, protein oxidation inhibits PRKN activity; nevertheless, the CXXC motif of MANF alleviates protein oxidation in RING II-domain of PRKN and restores its E3 ligase activity. Furthermore, MANF-PRKN interactions are essential for BC tumor growth and metastasis. High MANF expression predicts poor outcomes in patients with BC. Our results highlight the prosurvival role of MANF-mediated mitophagy in BC cells during glucose starvation, suggesting MANF as a potential therapeutic target.

Keywords:  Breast cancer; MANF; PRKN; ROS; glucose starvation; mitophagy

DOI:  https://doi.org/10.1080/15548627.2024.2392415
Environ Pollut. 2024 Aug 12. pii: S0269-7491(24)01438-6. [Epub ahead of print] 124724

Insufficient FUNDC1-dependent mitophagy due to early environmental cadmium exposure triggers mitochondrial redox imbalance to aggravate diet-induced lipotoxicity.

Cai-Yu Lian, Hui-Jia Li, Wei-Hao Xia, Yue Li, Xue-Lei Zhou, Du-Bao Yang, Xue-Mei Wan, Lin Wang.

  Cadmium (Cd) is a toxic contaminant widely spread in natural and industrial environments. Adolescent exposure to Cd increases risk for obesity-related morbidity in young adults including type 2 diabetes and metabolic dysfunction-associated steatotic liver disease (MASLD). Despite this recognition, the direct impact of adolescent Cd exposure on the progression of MASLD later in life, and the mechanisms underlying these effects, remain unclear. Here, adolescent rats received control diet or diets containing 2 mg Cd2+/kg feed for 4 weeks, and then HFD containing 15% lard or control diet in young adult rats was selected for 6 weeks to clarify this issue. Data firstly showed that HFD-fed rats in young adulthood due to adolescent Cd exposure exhibited more severe MASLD, evidenced by increased liver damage, disordered serum and hepatic lipid levels, and activated NLRP3 inflammasome. Hepatic transcriptome analysis revealed the potential effects of mitochondrial dysfunction in aggravated MASLD due to Cd exposure. Verification data further confirmed that mitochondrial structure and function were targeted and disrupted during this process, shown by broken mitochondrial ridges, decreased mitochondrial membrane potential, imbalanced mitochondrial dynamic, insufficient ATP concentration, and enhanced mitochondrial ROS generation. However, mitophagy is inactively involved in clearance of damaged mitochondria induced by early Cd in HFD condition due to inhibited mitophagy receptor FUNDC1. In contrast, FUNDC1-dependent mitophagy activation prevents lipotoxicity aggravated by early Cd via suppressing mitochondrial ROS generation. Collectively, our data show that insufficient FUNDC1-dependent mitophagy can drive the transition from HFD-induced MASLD to MASH, and accordingly, these findings will provide a better understanding of potential mechanism of diet-induced metabolic diseases in the context of early environmental Cd exposure.

Keywords:  Cadmium; High fat diet; Mitophagy; NAFLD; lipotoxicity

DOI:  https://doi.org/10.1016/j.envpol.2024.124724
Sci Rep. 2024 08 13. 14(1): 18794

Inherited mitochondrial dysfunction triggered by OPA1 mutation impacts the sensory innervation fibre identity, functionality and regenerative potential in the cornea.

Léna Meneux, Nadège Feret, Sarah Pernot, Mélissa Girard, Solange Sarkis, Alicia Caballero Megido, Melanie Quiles, Agnès Müller, Laura Fichter, Jerome Vialaret, Christophe Hirtz, Cecile Delettre, Frederic Michon.

  Mitochondrial dysfunctions are detrimental to organ metabolism. The cornea, transparent outmost layer of the eye, is prone to environmental aggressions, such as UV light, and therefore dependent on adequate mitochondrial function. While several reports have linked corneal defects to mitochondrial dysfunction, the impact of OPA1 mutation, known to induce such dysfunction, has never been studied in this context. We used the mouse line carrying OPA1delTTAG mutation to investigate its impact on corneal biology. To our surprise, neither the tear film composition nor the corneal epithelial transcriptomic signature were altered upon OPA1 mutation. However, when analyzing the corneal innervation, we discovered an undersensitivity of the cornea upon the mutation, but an increased innervation volume at 3 months. Furthermore, the fibre identity changed with a decrease of the SP + axons. Finally, we demonstrated that the innervation regeneration was less efficient and less functional in OPA1+/- corneas. Altogether, our study describes the resilience of the corneal epithelial biology, reflecting the mitohormesis induced by the OPA1 mutation, and the adaptation of the corneal innervation to maintain its functionality despite its morphogenesis defects. These findings will participate to a better understanding of the mitochondrial dysfunction on peripheral innervation.

Keywords:  Cornea; Epithelium; Innervation; Mitochondria; OPA1; Proteomic; Tear film; Transcriptomic

DOI:  https://doi.org/10.1038/s41598-024-68994-4
Nat Commun. 2024 Aug 14. 15(1): 6979

Mitochondrial network reorganization and transient expansion during oligodendrocyte generation.

Xhoela Bame, Robert A Hill.

Oligodendrocyte precursor cells (OPCs) give rise to myelinating oligodendrocytes of the brain. This process persists throughout life and is essential for recovery from neurodegeneration. To better understand the cellular checkpoints that occur during oligodendrogenesis, we determined the mitochondrial distribution and morphometrics across the oligodendrocyte lineage in mouse and human cerebral cortex. During oligodendrocyte generation, mitochondrial content expands concurrently with a change in subcellular partitioning towards the distal processes. These changes are followed by an abrupt loss of mitochondria in the oligodendrocyte processes and myelin, coinciding with sheath compaction. This reorganization and extensive expansion and depletion take 3 days. Oligodendrocyte mitochondria are stationary over days while OPC mitochondrial motility is modulated by animal arousal state within minutes. Aged OPCs also display decreased mitochondrial size, volume fraction, and motility. Thus, mitochondrial dynamics are linked to oligodendrocyte generation, dynamically modified by their local microenvironment, and altered in the aging brain.

DOI: https://doi.org/10.1038/s41467-024-51016-2
Heliyon. 2024 Jul 30. 10(14): e34986

Electroacupuncture protects against cerebral ischemia-reperfusion injury through mitochondrial dynamics.

Cheng-Long Li, Wei Mao, Li-da Zhang, Hai-Sheng Ji, Ting-Ting Tong, Jun-Li Wang, Xiao-Qing Wu, Kui-Wu Li, Hai-Yang Wu, Guo-Qing Zhang, Jun-Yu Zhang, Wei Han, Ying Wang.

   Background: Electroacupuncture (EA) has been shown to promote functional recovery after cerebral ischemia-reperfusion (I/R) injury. However, the contribution of mitochondrial dynamics to recovery remains unclear. The aim of this study was to investigate whether mitochondrial dynamics are involved in the effects of EA on cerebral I/R injury.
Methods: The rats with cerebral I/R injury were established by the middle cerebral artery occlusion/reperfusion. Subsequently, EA was applied to Baihui (GV20) and Dazhui (GV14) acupoints, with 2 Hz/5 Hz in frequency, 1.0 mA in intensity, 20 min each time, once a day for seven consecutive days. The therapeutic outcomes were assessed by modified neurological severity score (mNSS), 2,3,5-Triphenyte-trazolium chloride (TTC) staining, and hematoxylin-eosin (HE) staining. Mitochondrial morphology was observed under transmission electron microscopy. Adenosine triphosphate (ATP) content and ATP synthases (ATPases) activity were evaluated to measure mitochondrial function using ELISA. Finally, mitochondrial dynamics-related molecules, including dynamin-related protein 1 (Drp1), fission 1 (Fis1), mitofusin 1 (Mfn1), mitofusin 2 (Mfn2), and optic atrophy 1 (OPA1), were detected by Western blot and immunofluorescence staining.
Results: Cerebral I/R injury induced neurological dysfunction, cerebral infarction and neuronal injury, all of which were ameliorated by EA. And EA improved mitochondrial morphology and function. Moreover, EA altered the balance of mitochondrial dynamics. Specifically, the data showed a significant decrease in the expression of Drp1 and Fis1, leading to the inhibition of mitochondrial fission. Additionally, Mfn1, Mfn2 and Opa1, which are related to mitochondrial fusion, were effectively promoted after EA treatment. However, sham EA did not show any neuroprotective effects in rats with cerebral I/R injury.
Conclusions: In summary, our study indicates that the balance of mitochondrial dynamics is crucial for EA therapy to treat cerebral I/R injury.

Keywords:  Cerebral ischemia–reperfusion injury; Electroacupuncture; Mitochondrial dynamics; Neurological deficits

DOI:  https://doi.org/10.1016/j.heliyon.2024.e34986
Gene. 2024 Aug 13. pii: S0378-1119(24)00734-0. [Epub ahead of print] 148853

Dysregulation of mitochondria, apoptosis and mitophagy in Leber's hereditary optic neuropathy with MT-ND1 3635G>A mutation.

Yingqi Chen, Xiaoyang Wei, Xiaorui Ci, Yanchun Ji, Juanjuan Zhang.

  Leber's hereditary optic neuropathy (LHON) is a maternal inherited disorder, primarily due to mitochondrial DNA (mtDNA) mutations. This investigation aimed to assess the pathogenicity of m.3635G>A alteration known to confer susceptibility to LHON. The disruption of electrostatic interactions among S110 of the MT-ND1 and the side chain of E4, along with the carbonyl backbone of M1 in the NDUFA1, was observed in complex I of cybrids with m.3635G>A. This disturbance affected the complex I assembly activity by changing the mitochondrial respiratory chain composition and function. In addition, the affected cybrids exhibited notable deficiencies in complex I activities, including impaired mitochondrial respiration and depolarization of its membrane potential. Apoptosis was also stimulated in the mutant group, as witnessed by the secretion of cytochrome c and activation of PARP, caspase 3, 7, and 9 compared to the control. Furthermore, the mutant group exhibited decreased levels of autophagy protein light chain 3, accumulation of autophagic substrate P62, and impaired PINK1/Parkin-dependent mitophagy. Overall, the current study has confirmed the crucial involvement of the alteration of the m.3635G>A gene in the development of LHON. These findings contribute to a deeper comprehension of the pathophysiological mechanisms underlying LHON, providing a fundamental basis for further research.

Keywords:  Apoptosis; Leber’s hereditary optic neuropathy (LHON); MT-ND1 mutation; Mitochondrial dysfunction; Mitophagy

DOI:  https://doi.org/10.1016/j.gene.2024.148853
J Cardiovasc Pharmacol. 2024 Aug 13.

Canagliflozin mediates mitophagy through the AMPK/PINK1/PARKIN pathway to alleviate isoprenaline-induced cardiac remodelling.

Shaolin Gong, Yuan Sui, Mengxuan Xiao, Daoyao Fu, Zhiping Xiong, Liuping Zhang, Qingshan Tian, Yongnan Fu, Wenjun Xiong.

Heart failure has always been a prevalent, disabling, and potentially life-threatening disease. For the treatment of heart failure, controlling cardiac remodeling is very important. In recent years, clinical trials have shown that SGLT-2 inhibitors not only excel in lowering glucose levels but also demonstrate favorable cardiovascular protective effects. However, the precise mechanisms behind the cardiovascular benefits of SGLT-2 inhibitors remain elusive. In our current research, we assessed the impact of canagliflozin (CANA, an SGLT-2 inhibitor) on cardiac remodeling progression in mice, and preliminarily elucidated the possible mechanism of action of SGLT-2 inhibitor. Our results indicate that the administration of canagliflozin significantly attenuates myocardial hypertrophy and fibrosis and enhances cardiac ejection function in mice with isoprenaline (ISO)-induced cardiac remodeling. Notably, excessive mitophagy, along with mitochondrial structural abnormalities observed in ISO-induced cardiac remodeling, were mitigated by canagliflozin treatment, thereby attenuating cardiac remodeling progression. Furthermore, the differential expression of AMPK/PINK1/Parkin pathway-related proteins in ISO-induced cardiac remodeling was effectively reversed by canagliflozin, suggesting the therapeutic potential of targeting this pathway with the drug. Thus, our study indicates that canagliflozin holds promise in mitigating cardiac injury, enhancing cardiac function, and potentially exerting cardioprotective effects by modulating mitochondrial function and mitophagy through the AMPK/PINK1/Parkin pathway.

DOI: https://doi.org/10.1097/FJC.0000000000001625
Acta Biomater. 2024 Aug 07. pii: S1742-7061(24)00442-2. [Epub ahead of print]

An Engineered Cellular Carrier Delivers miR-138-5p to Enhance Mitophagy and Protect Hypoxic-Injured Neurons via the DNMT3A/Rhebl1 Axis.

Xingjia Zhu, Qianqian Liu, Fengwei Zhu, Rui Jiang, Zhichao Lu, Chenxing Wang, Peipei Gong, Qi Yao, Tian Xia, Jie Sun, Fei Ju, Defeng Wang, Ruifan Sun, Youlang Zhou, Bo You, Wei Shi.

  Mitophagy influences the progression and prognosis of ischemic stroke (IS). However, whether DNA methylation in the brain is associated with altered mitophagy in hypoxia-injured neurons remains unclear. Here, miR-138-5p was found to be highly expressed in exosomes secreted by astrocytes stimulated with oxygen and glucose deprivation/re-oxygenation (OGD/R), which could influence the recovery of OGD/R-injured neurons through autophagy. Mechanistically, miR-138-5p promotes the stable expression of Ras homolog enriched in brain like 1(Rhebl1) through DNA-methyltransferase-3a (DNMT3A), thereby enhancing ubiquitin-dependent mitophagy to maintain mitochondrial homeostasis. Furthermore, we employed glycosylation engineering and bioorthogonal click reactions to load mirna onto the surface of microglia and deliver them to injured region utilising the inflammatory chemotactic properties of microglia to achieve drug-targeted delivery to the central nervous system (CNS). Our findings demonstrate miR-138-5p improves mitochondrial function in neurons through the miR-138-5p/DNMT3A/Rhebl1 axis. Additionally, our engineered cell vector-targeted delivery system could be promising for treating IS. STATEMENT OF SIGNIFICANCE: : In this study, we demonstrated that miR-138-5p in exosomes secreted by astrocytes under hypoxia plays a critical role in the treatment of hypoxia-injured neurons. And we find a new target of miR-138-5p, DNMT3A, which affects neuronal mitophagy and thus exerts a protective effect by regulating the methylation of Rbebl1. Furthermore, we have developed a carrier delivery system by combining miR-138-5p with the cell membrane of microglia and utilized the inflammatory chemotactic properties of microglia to deliver this system to the brain via intravenous injection. This groundbreaking study not only provides a novel therapeutic approach for ischemia-reperfusion treatment but also establishes a solid theoretical foundation for further research on targeted drug delivery for central nervous system diseases with promising clinical applications.

Keywords:  MCAO; OGD/R; astrocyte; miR-138-5p; mitophagy; neuron

DOI:  https://doi.org/10.1016/j.actbio.2024.07.059
J Inorg Biochem. 2024 Aug 11. pii: S0162-0134(24)00220-4. [Epub ahead of print]260 112696

Ciclopirox platinum(IV) conjugates suppress tumors by promoting mitophagy and provoking immune responses.

Suying Li, Shuaiqi Feng, Yan Chen, Bin Sun, Ning Zhang, Yanna Zhao, Jun Han, Zhifang Liu, Yan-Qin He, Qingpeng Wang.

  Mitophagy is an important target for antitumor drugs development. A series of ciclopirox (CPX) platinum(IV) hybrids targeting PTEN induced putative kinase 1 (PINK1)/Parkin mediated mitophagy were designed and prepared as antitumor agents. The dual CPX platinum(IV) complex with cisplatin core was screened out as a candidate, which displayed promising antitumor activities both in vitro and in vivo. Mechanistically, it caused serious DNA damage in tumor cells. Then, remarkable mitochondrial damage was induced accompanied by the mitochondrial membrane depolarization and reactive oxygen species generation, which further promoted apoptosis through the Bcl-2/Bax/Caspase3 pathway. Furthermore, mitophagy was ignited via the PINK1/Parkin/P62/LC3 axis, and exhibited positive influence on promoting the apoptosis of tumor cells. The antitumor immunity was boosted by the block of immune check point programmed cell death ligand-1 (PD-L1), which further increased the density of T cells in tumors. Subsequently, the metastasis of tumor cells was inhibited by inhibiting angiogenesis in tumors.

Keywords:  Angiogenesis inhibition; Antitumor; Biochemistry; Ciclopirox; Mitophagy; Platinum(IV)

DOI:  https://doi.org/10.1016/j.jinorgbio.2024.112696
Fitoterapia. 2024 Aug 07. pii: S0367-326X(24)00353-8. [Epub ahead of print]178 106170

Gentiana decoction inhibits liver fibrosis and the activation of hepatic stellate cells via upregulating the expression of Parkin.

Jing Deng, Jun Long, Yang Yang, Fengyu Yang, Yongjie Wei.

  Liver fibrosis is a wound-healing process. It can be induced by various chronic liver diseases. Liver fibrosis is characterized by the activation of hepatic stellate cells (HSCs), a key event. However, no effective treatment strategies to cure or alleviate liver fibrosis-induced pathologic changes have yet been developed. Traditional Chinese medicine (TCM) exhibits a good anti-fibrosis action, with few side effects. Gentiana decoction, a TCM also called Longdan Xiegan Tang (LXT), is used for purging the liver in clinical settings. However, the role of LXT in preventing liver fibrosis and the underlying regulatory mechanism have not yet been investigated. This study demonstrates that LXT treatment can protect the liver from the injuries resulting from CCl4-induced liver fibrosis in mice and suppress the activation of HSCs. The mice in the LXT group exhibit litter collagen I and HSC activation marker α-smooth muscle actin (α-SMA) expression. Transcriptome sequencing of the mouse liver tissue reveals that the level of Parkin, a mitophagy marker, decreased in CCl4-induced liver fibrosis. Further study shows that the injection of Parkin-overexpression adeno-associated virus (Parkin-AAV) via the tail vein can reduce CCl4-induced liver fibrogenesis in mice. We conducted a mechanistic study also, which suggests that LXT treatment suppresses the activation of HSCs by upregulating the expression of Parkin. Hence, it can be suggested that LXT inhibits liver fibrosis by activating the Parkin signaling pathway.

Keywords:  Gentiana decoction; Hepatic stellate cells; Liver fibrosis; Parkin

DOI:  https://doi.org/10.1016/j.fitote.2024.106170
J Cachexia Sarcopenia Muscle. 2024 Aug 12.

Regimen on Dnaja3 haploinsufficiency mediated sarcopenic obesity with imbalanced mitochondrial homeostasis and lipid metabolism.

Yu-Ning Fann, Wan-Huai Teo, Hsin-Chen Lee, Chen-Chung Liao, Yeou-Guang Tsay, Tung-Fu Huang, Jeng-Fan Lo.

   BACKGROUND: Sarcopenic obesity is characterized by excess fat mass and diminished muscular mass/function. DNAJA3, a mitochondrial co-chaperone protein, plays a crucial role in skeletal muscle development. GMI, an immunomodulatory protein, promotes myogenic differentiation through DNAJA3 activation. This study aims to elucidate the physiological effects of muscular Dnaja3 haploinsufficiency on mitochondrial dysfunction and dysregulated lipid metabolism and to assess the efficacy of GMI in rescuing sarcopenic obesity both in vitro and in vivo.
METHODS: We generated mouse strain with Dnaja3 heterozygosity (HSA-Dnaja3f/+) specifically in skeletal muscle. The body weight, body composition, and locomotor activity of WT and HSA-Dnaja3f/+ mice were examined. The isolated skeletal muscles and primary myoblasts from the WT and HSA-Dnaja3f/+ mice, at young or old age, were utilized to study the molecular mechanisms, mitochondrial respiration and ROS level, mitochondrial proteomes, and serological analyses, respectively. To evaluate the therapeutic efficacy of GMI, both short-term and long-term GMI treatment were administrated intraperitoneally to the HSA-Dnaja3f/+ young (4 weeks old) or adult (3 months old) mice for a duration of either 1 or 6 months, respectively.
RESULTS: Muscular Dnaja3 heterozygosity resulted in impaired locomotor activity (P < 0.05), reduced muscular cross-sectional area (P < 0.0001), and up-regulation of lipogenesis (ACC2) and pro-inflammation (STAT3) in skeletal muscles (P < 0.05). Primary myoblasts from the HSA-Dnaja3f/+ mice displayed impaired mitochondrial respiration (P < 0.01) and imbalanced mitochondrial ROS levels. A systemic proteomic analysis of the purified mitochondria from the primary myoblasts was conducted to show the abnormalities in mitochondrial function and fatty acid metabolism (P < 0.0001). At age of 13 to 14 months, the HSA-Dnaja3f/+ mice displayed increased body fat mass (P < 0.001), reduced fat-free mass (P < 0.01), and impaired glucose and insulin tolerance (P < 0.01). The short-term GMI treatment improved locomotor activity (P < 0.01) and down-regulated the protein levels of STAT3 (P < 0.05), ACC2, and mitochondrial respiratory complex III (UQCRC2) (P < 0.01) via DNAJA3 activation. The long-term GMI treatment ameliorated fat mass accumulation, glucose intolerance, and systemic inflammation (AST) (P < 0.05) in skeletal muscle, while enhancing thermogenesis (UCP1) (P < 0.01) in eWAT. GMI treatment promoted myogenesis, enhanced oxygen consumption, and ameliorated STAT3 (P < 0.01) through DNAJA3 activation (P < 0.05) in vitro.
CONCLUSIONS: Muscular Dnaja3 haploinsufficiency dysregulates mitochondrial function and lipid metabolism then leads to sarcopenic obesity. GMI emerges as a therapeutic regimen for sarcopenic obesity treatment through DNAJA3 activation.

Keywords:  DNAJA3; Lipid metabolism; Mitochondrial homeostasis; Sarcopenic obesity; Skeletal muscle homeostasis

DOI:  https://doi.org/10.1002/jcsm.13549
Cytokine. 2024 Aug 10. pii: S1043-4666(24)00236-9. [Epub ahead of print]182 156733

COX-2 optimizes cardiac mitochondrial biogenesis and exerts a cardioprotective effect during sepsis.

Leijing Yin, Ludong Yuan, Zhengyang Luo, Yuting Tang, Xiaofang Lin, Shuxin Wang, Pengfei Liang, Lingjin Huang, Bimei Jiang.

   BACKGROUND: Septic cardiomyopathy is a component of multiple organ dysfunction in sepsis. Mitochondrial dysfunction plays an important role in septic cardiomyopathy. Studies have shown that cyclooxygenase-2 (COX-2) had a protective effect on the heart, and prostaglandin E2 (PGE2), the downstream product of COX-2, was increasingly recognized to have a protective effect on mitochondrial function.
OBJECTIVE: This study aims to demonstrate that COX-2/PGE2 can protect against septic cardiomyopathy by regulating mitochondrial function.
METHODS: Cecal ligation and puncture (CLP) was used to establish a mouse model of sepsis and RAW264.7 macrophages and H9C2 cells were used to simulate sepsis in vitro. The NS-398 and celecoxib were used to inhibit the activity of COX-2. ZLN005 and SR18292 were used to activate or inhibit the PGC-1α activity. The mitochondrial biogenesis was examined through the Mitotracker Red probe, mtDNA copy number, and ATP content detection.
RESULTS: The experimental data suggested that COX-2 inhibition attenuated PGC-1α expression thus decreasing mitochondrial biogenesis, whereas increased PGE2 could promote mitochondrial biogenesis by activating PGC-1α. The results also showed that the effect of COX-2/PGE2 on PGC-1α was mediated by the activation of cyclic adenosine monophosphate (cAMP) response element binding protein (CREB). Finally, the effect of COX-2/PGE2 on the heart was also verified in the septic mice.
CONCLUSION: Collectively, these results suggested that COX-2/PGE2 pathway played a cardioprotective role in septic cardiomyopathy through improving mitochondrial biogenesis, which has changed the previous understanding that COX-2/PGE2 only acted as an inflammatory factor.

Keywords:  COX-2; Celecoxib; Mitochondrial biogenesis; PGC-1α; PGE(2); Septic cardiomyopathy

DOI:  https://doi.org/10.1016/j.cyto.2024.156733
Biochem Pharmacol. 2024 Aug 10. pii: S0006-2952(24)00459-3. [Epub ahead of print]229 116476

Reduced FNDC5-AMPK signaling in diabetic atrium increases the susceptibility of atrial fibrillation by impairing mitochondrial dynamics and activating NLRP3 inflammasome.

Shan Meng, Xin Chen, Jikai Zhao, Xinyi Huang, Yuting Huang, Tao Huang, Zijun Zhou, Wenpu Ren, Tao Hong, Jinfeng Duan, Liming Yu, Huishan Wang.

  Fibronectin type III domain-containing protein 5 (FNDC5) exerts potential anti-arrhythmic effects. However, the function and mechanism of FNDC5 in diabetes-associated atrial fibrillation (AF) remain unknown. In this study, bioinformatics analysis, in vivo and in vitro experiments were conducted to explore the alteration and role of FNDC5 in diabetes-related atrial remodeling and AF susceptibility. RNA sequencing data from atrial samples of permanent AF patients and diabetic mice exhibited significantly decreased FNDC5 at the transcriptional level, which was in line with the protein expression in diabetic mice as well as high glucose and palmitic acid (HG+PA) injured atrial myocytes. Diabetic mice exhibited adverse atrial remodeling and increased AF inducibility. Moreover, reduced atrial FNDC5 was accompanied with exacerbated NOD-like receptor pyrin domain containing 3 (NLRP3) activation and disturbed mitochondrial fission and fusion processes, as evidenced by decreased expressions of optic atrophy 1 (OPA-1), mitofusin (MFN-1, MFN-2) and increased phosphorylation of dynamin-related protein 1 (Ser616). These effects were validated in HG+PA-treated atrial myocytes. Critically, FNDC5 overexpression remarkably enhanced cellular antioxidant capacity by upregulating the expressions of superoxide dismutase (SOD1, SOD2) level. In addition, HG+PA-induced mitochondrial dysfunction was ameliorated by FNDC5 overexpression as evidenced by improved mitochondrial dynamics and membrane potential. Moreover, NLRP3 inflammasome-mediated inflammation was reduced by FNDC5 overexpression, and AMPK signaling might serve as the key down-stream effector. The present study demonstrated that reduced atrial FNDC5-AMPK signaling contributed to the pathogenesis of diabetes- associated AF by impairing mitochondrial dynamics and activating the NLRP3 inflammasome. These findings provide promising therapeutic avenues for diabetes-associated AF.

Keywords:  Atrial fibrillation; Diabetes; FNDC5; Mitochondrial dynamics; NLRP3 inflammasome

DOI:  https://doi.org/10.1016/j.bcp.2024.116476
Redox Biol. 2024 Aug 05. pii: S2213-2317(24)00280-5. [Epub ahead of print]75 103302

FDX1 downregulation activates mitophagy and the PI3K/AKT signaling pathway to promote hepatocellular carcinoma progression by inducing ROS production.

Bo Sun, Peng Ding, Yinghui Song, Jia Zhou, Xu Chen, Chuang Peng, Sulai Liu.

   BACKGROUND: Mitochondrial dysfunction and metabolic reprogramming can lead to the development and progression of hepatocellular carcinoma (HCC). Ferredoxin 1 (FDX1) is a small mitochondrial protein and recent studies have shown that FDX1 plays an important role in tumor cuproptosis, but its role in HCC is still elusive. In this study, we aim to investigate the expression and novel functions of FDX1 in HCC.
METHODS: FDX1 expression was first analyzed in publicly available datasets and verified by immunohistochemistry, qRT-PCR and Western blot. In vitro and in vivo experiments were applied to explore the functions of FDX1. Non-targeted metabolomics and RNA-sequencing were used to determine molecular mechanism. mRFP-GFP-LC3 lentivirus transfection, Mito-Tracker Red and Lyso-Tracker Green staining, transmission electron microscopy, flow cytometry, JC-1 staining, etc. were used to analyze mitophagy or ROS levels. Hydrodynamic tail vein injection (HTVi) and patient-derived organoid (PDO) models were used to analyze effect of FDX1 overexpression.
RESULTS: FDX1 expression is significantly downregulated in HCC tissues. FDX1 downregulation promotes HCC cell proliferation, invasion in vitro and growth, metastasis in vivo. In addition, FDX1 affects metabolism of HCC cells and is associated with autophagy. We then confirmed that FDX1 deficiency increases ROS levels, activates mitophagy and the PI3K/AKT signaling pathway in HCC cells. Interestingly, scavenging ROS attenuates the tumor-promoting role and mitophagy of FDX1 downregulation. The results of HTVi and PDO models both find that FDX1 elevation significantly inhibits HCC progression. Moreover, low FDX1 expression is associated with shorter survival and is an independent risk factor for prognosis in HCC patients.
CONCLUSIONS: Our research had investigated novel functions of FDX1 in HCC. Downregulation of FDX1 contributes to metabolic reprogramming and leads to ROS-mediated activation of mitophagy and the PI3K/AKT signaling pathway. FDX1 is a potential prognostic biomarker and increasing FDX1 expression may be a potential therapeutic approach to inhibit HCC progression.

Keywords:  Ferredoxin 1; Hepatocellular carcinoma; Mitophagy; PI3K/AKT signaling pathway; Reactive oxygen species

DOI:  https://doi.org/10.1016/j.redox.2024.103302
Aging Cell. 2024 Aug 09. e14294

β-Hydroxybutyrate enhances chondrocyte mitophagy and reduces cartilage degeneration in osteoarthritis via the HCAR2/AMPK/PINK1/Parkin pathway.

Huangming Zhuang, Xunshan Ren, Yuelong Zhang, Huajie Li, Panghu Zhou.

  Osteoarthritis (OA) is widely recognized as the prevailing joint disease associated with aging. The ketogenic diet (KD) has been postulated to impede the advancement of various inflammatory ailments. β-Hydroxybutyrate (βOHB), a prominent constituent of ketone bodies, has recently been proposed to possess crucial signaling capabilities. In this study, we propose to explore the role and mechanism of βOHB in OA. Tissue staining and inflammatory factor assay were employed to evaluate the impacts of KD and βOHB on OA rats. The oxidative stress conditions in chondrocytes were induced using tert-butyl hydroperoxide (TBHP). The mechanisms were determined using the siRNA of hydroxycarboxylic acid receptor 2 (HCAR2), the antagonist of adenosine monophosphate-activated protein kinase (AMPK), and the inhibitor of mitophagy. The administration of KD demonstrated a reduction in pathological damage to cartilage, as well as a decrease in plasma levels of inflammatory factors. Furthermore, it resulted in an increase in the concentration of βOHB in the blood and synovial fluid. In vitro experiments showed that βOHB facilitated mitophagy and adenosine triphosphate production. Besides, βOHB mitigated chondrocyte senescence, inflammatory factors secretion, extracellular matrix degradation, and apoptosis induced by TBHP. Subsequent investigations indicated that the protective effects of βOHB were no longer observed following the knockdown of HCAR2, the antagonist of AMPK, or the inhibitor of mitophagy. Moreover, in vivo studies suggested that βOHB played a protective role by targeting the HCAR2-AMPK-PINK1 axis. In conclusion, βOHB enhanced chondrocyte mitophagy through the HCAR2/AMPK/PINK1/Parkin pathway, offering a potential therapeutic approach for the treatment of OA.

Keywords:  hydroxycarboxylic acid receptor 2; mitophagy; osteoarthritis; senescence; β‐Hydroxybutyrate

DOI:  https://doi.org/10.1111/acel.14294