bims-mikwok 2024-09-01 papers

bims-mikwok

Biomed News

on Mitochondrial quality control

Issue of 2024–09–01
28 papers selected by
Gavin McStay, Liverpool John Moores University

Drp1 depletion protects against ferroptotic cell death by preserving mitochondrial integrity and redox homeostasis.
Role of excessive mitochondrial fission in seawater immersion aggravated hemorrhagic shock-induced cardiac injury and the protective effect of Mdivi-1.
Taurine rescues intervertebral disc degeneration by activating mitophagy through the PINK1/Parkin pathway.
Mitochondrial dysfunction in acute kidney injury.
BNIP3-mediated mitophagy attenuates hypoxic-ischemic brain damage in neonatal rats by inhibiting ferroptosis through P62-KEAP1-NRF2 pathway activation to maintain iron and redox homeostasis.
Bunyavirus SFTSV nucleoprotein exploits tufm-mediated mitophagy to impair antiviral innate immunity.
The Mitochondrial Distribution and Morphology Family 33 Gene FgMDM33 Is Involved in Autophagy and Pathogenesis in Fusarium graminearum.
Coenzyme Q10 ameliorates lipopolysaccharide-induced acute lung injury by attenuating oxidative stress and NLRP3 inflammation through regulating mitochondrial dynamics.
Mitochondrial 'Birth-Death' coordinator: An intelligent hydrogen nanogenerator to enhance intervertebral disc regeneration.
Context-dependent roles of mitochondrial LONP1 in orchestrating the balance between airway progenitor versus progeny cells.
Lipophagy and mitophagy in renal pathophysiology.
SIRT6 prevent chronic cerebral hypoperfusion induced cognitive impairment by remodeling mitochondrial dynamics in a STAT5-PGAM5-Drp1 dependent manner.
Infection-induced peripheral mitochondria fission drives ER encapsulations and inter-mitochondria contacts that rescue bioenergetics.
Altered mitochondrial homeostasis on bisphenol-A exposure and its association in developing polycystic ovary syndrome: A comprehensive review.
Role of Mitofusin 1 in mediating reactive oxygen species in alveolar macrophages during Streptococcuspneumoniae.
Mitophagy in fibrotic diseases: molecular mechanisms and therapeutic applications.
The role of mitochondrial fusion and fission in immune-mediated inflammatory diseases.
Resveratrol stimulates brown of white adipose via regulating ERK/DRP1-mediated mitochondrial fission and improves systemic glucose homeostasis.
Mitochondrial Dynamics in Non-Small Cell Lung Cancer.
Mechanistic Insights into Metabolic Function of Dynamin-Related Protein 1 (DRP1).
Detailed analysis of Mdivi-1 effects on complex I and respiratory supercomplex assembly.
Pathological Role of High Sugar in Mitochondrial Respiratory Chain Defect-Augmented Mitochondrial Stress.
Cadmium causes spleen toxicity in chickens by regulating mitochondrial unfolded protein response and nuclear receptors response.
Scutellarin ameliorates mitochondrial dysfunction and apoptosis in OGD/R-insulted HT22 cells through mitophagy induction.
Drp1 splice variants regulate ovarian cancer mitochondrial dynamics and tumor progression.
RETRACTION: "Melatonin attenuates TNF-α-mediated hepatocytes damage via inhibiting mitochondrial stress and activating the Akt-Sirt3 signaling pathway".
The mitochondrial division inhibitor Mdivi-1 protected organ function and extended the treatment window in rats with uncontrolled haemorrhagic shock.
Identifying prognostic biomarkers in oral squamous cell carcinoma: an integrated single-cell and bulk RNA sequencing study on mitophagy-related genes.

Cell Death Dis. 2024 Aug 27. 15(8): 626

Drp1 depletion protects against ferroptotic cell death by preserving mitochondrial integrity and redox homeostasis.

Stephan Tang, Anneke Fuß, Zohreh Fattahi, Carsten Culmsee.

Mitochondria are highly dynamic organelles which undergo constant fusion and fission as part of the mitochondrial quality control. In genetic diseases and age-related neurodegenerative disorders, altered mitochondrial fission-fusion dynamics have been linked to impaired mitochondrial quality control, disrupted organelle integrity and function, thereby promoting neural dysfunction and death. The key enzyme regulating mitochondrial fission is the GTPase Dynamin-related Protein 1 (Drp1), which is also considered as a key player in mitochondrial pathways of regulated cell death. In particular, increasing evidence suggests a role for impaired mitochondrial dynamics and integrity in ferroptosis, which is an iron-dependent oxidative cell death pathway with relevance in neurodegeneration. In this study, we demonstrate that CRISPR/Cas9-mediated genetic depletion of Drp1 exerted protective effects against oxidative cell death by ferroptosis through preserved mitochondrial integrity and maintained redox homeostasis. Knockout of Drp1 resulted in mitochondrial elongation, attenuated ferroptosis-mediated impairment of mitochondrial membrane potential, and stabilized iron trafficking and intracellular iron storage. In addition, Drp1 deficiency exerted metabolic effects, with reduced basal and maximal mitochondrial respiration and a metabolic shift towards glycolysis. These metabolic effects further alleviated the mitochondrial contribution to detrimental ROS production thereby significantly enhancing neural cell resilience against ferroptosis. Taken together, this study highlights the key role of Drp1 in mitochondrial pathways of ferroptosis and expose the regulator of mitochondrial dynamics as a potential therapeutic target in neurological diseases involving oxidative dysregulation.

DOI: https://doi.org/10.1038/s41419-024-07015-8
Antioxid Redox Signal. 2024 Aug 24.

Role of excessive mitochondrial fission in seawater immersion aggravated hemorrhagic shock-induced cardiac injury and the protective effect of Mdivi-1.

Yanli Liu, Yue Wu, Yu Zhu, Qinghui Li, Xiaoyong Peng, Zisen Zhang, Lei Liu, Liangming Liu, Tao Li.

   AIMS: Seawater immersion significantly aggravated organ dysfunction following hemorrhagic shock, leading to higher mortality rate. However, the effective treatment are still unavailable in clinic. Mitochondria were involved in the onset and development of multiple organ function disorders, whether mitochondria participate in the cardiac dysfunction following seawater immersion combined with hemorrhagic shock remains poorly understood. Hence, we investigated the role and possible mechanism of mitochondria in seawater immersion combined with hemorrhage shock-induced cardiac dysfunction were observed.
RESULTS: Mitochondrial fission protein dynamin-related protein 1 (Drp1) was activated and translocated from the cytoplasm to mitochondria in the heart following seawater immersion combined with hemorrhagic shock, leading to excessive mito-chondrial fission. Excessive mitochondrial fission disrupted mitochondrial function and structure, activated mitophagy and apoptosis. At the same time, excessive mitochondrial fission resulted in disturbance of myocardial structure, hemodynamic disorders, and ultimately provoked multiple organ dysfunction and high mortality. Further studies showed that the mitochondrial division inhibitor Mdivi-1 can signifi-cantly reverse Drp1 mitochondrial translocation and inhibit mitochondrial fragmentation, reactive oxygen species (ROS) accumulation, mitophagy and apoptosis, and then protecting circulation and vital organ functions, prolonging animal survival.
INNOVATION: Our findings indicate that Drp1-mediated mitochondrial fission could be a novel therapeutic targets for the treatment of seawater immersion combined with hemorrhagic shock.
CONCLUSION: Drp1 mitochondrial translocation played an important role in the cardiac dysfunction after seawater immersion combined with hemorrhage shock. Drp1-mediated excessive mitochondrial fission leads to cardiac dysfunction, due to the mitochondrial structure and bioenergetics impairment.

Keywords:  Seawater immersion; hemorrhagic shock; mitochondrial fission; mitophagy Mdivi-1.

DOI:  https://doi.org/10.1089/ars.2022.0167
Biochem Biophys Res Commun. 2024 Aug 22. pii: S0006-291X(24)01123-9. [Epub ahead of print]739 150587

Taurine rescues intervertebral disc degeneration by activating mitophagy through the PINK1/Parkin pathway.

Shengyuan Lin, Tao Li, Bin Zhang, Peng Wang.

  Intervertebral disc degeneration (IDD) is a common cause of low back pain and disability. Recent studies have highlighted the critical role of mitochondrial dysfunction in the progression of IDD. In this study, we investigated the therapeutic potential of taurine in delaying IDD through the activation of mitophagy via the PINK1/Parkin pathway. Our in vitro and in vivo experiments demonstrate that taurine treatment significantly enhances mitophagy, reduces oxidative stress, delays cell senescence, and promotes the removal of damaged mitochondria in nucleus pulposus cells (NPC). Additionally, taurine-mediated activation of the PINK1/Parkin pathway leads to improved mitochondrial homeostasis and slows the progression of disc degeneration. These findings provide new insights into the protective effects of taurine and highlight its potential as a therapeutic agent for IDD.

Keywords:  Intervertebral disc degeneration; Mitophagy; PINK1/Parkin pathway; Taurine

DOI:  https://doi.org/10.1016/j.bbrc.2024.150587
Ren Fail. 2024 Dec;46(2): 2393262

Mitochondrial dysfunction in acute kidney injury.

Congcong Yao, Ziwei Li, Keke Sun, Yan Zhang, Songtao Shou, Heng Jin.

  Acute kidney injury (AKI) is a systemic clinical syndrome increasing morbidity and mortality worldwide in recent years. Renal tubular epithelial cells (TECs) death caused by mitochondrial dysfunction is one of the pathogeneses. The imbalance of mitochondrial quality control is the main cause of mitochondrial dysfunction. Mitochondrial quality control plays a crucial role in AKI. Mitochondrial quality control mechanisms are involved in regulating mitochondrial integrity and function, including antioxidant defense, mitochondrial quality control, mitochondrial DNA (mtDNA) repair, mitochondrial dynamics, mitophagy, and mitochondrial biogenesis. Currently, many studies have used mitochondrial dysfunction as a targeted therapeutic strategy for AKI. Therefore, this review aims to present the latest research advancements on mitochondrial dysfunction in AKI, providing a valuable reference and theoretical foundation for clinical prevention and treatment of this condition, ultimately enhancing patient prognosis.

Keywords:  Acute kidney injury; mitochondrial biogenesis; mitochondrial dynamics; mitochondrial quality control; mitophagy

DOI:  https://doi.org/10.1080/0886022X.2024.2393262
Acta Pharmacol Sin. 2024 Aug 23.

BNIP3-mediated mitophagy attenuates hypoxic-ischemic brain damage in neonatal rats by inhibiting ferroptosis through P62-KEAP1-NRF2 pathway activation to maintain iron and redox homeostasis.

Xin-Xin Wang, Mei Li, Xiao-Wen Xu, Wen-Bin Zhao, Yi-Ming Jin, Li-Li Li, Zheng-Hong Qin, Rui Sheng, Hong Ni.

  As a major contributor to neonatal death and neurological sequelae, hypoxic-ischemic encephalopathy (HIE) lacks a viable medication for treatment. Oxidative stress induced by hypoxic-ischemic brain damage (HIBD) predisposes neurons to ferroptosis due to the fact that neonates accumulate high levels of polyunsaturated fatty acids for their brain developmental needs but their antioxidant capacity is immature. Ferroptosis is a form of cell death caused by excessive accumulation of iron-dependent lipid peroxidation and is closely associated with mitochondria. Mitophagy is a type of mitochondrial quality control mechanism that degrades damaged mitochondria and maintains cellular homeostasis. In this study we employed mitophagy agonists and inhibitors to explore the mechanisms by which mitophagy exerted ferroptosis resistance in a neonatal rat HIE model. Seven-days-old neonatal rats were subjected to ligation of the right common carotid artery, followed by exposure to hypoxia for 2 h. The neonatal rats were treated with a mitophagy activator Tat-SPK2 peptide (0.5, 1 mg/kg, i.p.) 1 h before hypoxia, or in combination with mitochondrial division inhibitor-1 (Mdivi-1, 20 mg/kg, i.p.), and ferroptosis inhibitor Ferrostatin-1 (Fer-1) (2 mg/kg, i.p.) at the end of the hypoxia period. The regulation of ferroptosis by mitophagy was also investigated in primary cortical neurons or PC12 cells in vitro subjected to 4 or 6 h of OGD followed by 24 h of reperfusion. We showed that HIBD induced mitochondrial damage, ROS overproduction, intracellular iron accumulation, lipid peroxidation and ferroptosis, which were significantly reduced by the pretreatment with Tat-SPK2 peptide, and aggravated by the treatment with Mdivi-1 or BNIP3 knockdown. Ferroptosis inhibitors Fer-1 and deferoxamine B (DFO) reversed the accumulation of iron and lipid peroxides caused by Mdivi-1, hence reducing ferroptosis triggered by HI. We demonstrated that Tat-SPK2 peptide-activated BNIP3-mediated mitophagy did not alleviate neuronal ferroptosis through the GPX4-GSH pathway. BNIP3-mediated mitophagy drove the P62-KEAP1-NRF2 pathway, which conferred ferroptosis resistance by maintaining iron and redox homeostasis via the regulation of FTH1, HO-1, and DHODH/FSP1-CoQ10-NADH. This study may provide a new perspective and a therapeutic drug for the treatment of neonatal HIE.

Keywords:  P62-KEAP1-NRF2 pathway; Tat-SPK2 peptide; ferroptosis; hypoxic-ischemic brain damage; mitophagy

DOI:  https://doi.org/10.1038/s41401-024-01365-x
Autophagy. 2024 Aug 27.

Bunyavirus SFTSV nucleoprotein exploits tufm-mediated mitophagy to impair antiviral innate immunity.

Wen-Kang Zhang, Jia-Min Yan, Min Chu, Bang Li, Xiao-Lan Gu, Ze-Zheng Jiang, Ze-Min Li, Pan-Pan Liu, Tian-Mei Yu, Chuan-Min Zhou, Xue-Jie Yu.

  Severe fever with thrombocytopenia syndrome is an emerging viral hemorrhagic fever caused by a tick-borne bunyavirus, severe fever with thrombocytopenia syndrome virus (SFTSV), with a high case fatality. We previously found that SFTSV nucleoprotein (NP) induces macroautophagy/autophagy to facilitate virus replication. However, the role of NP in antagonizing host innate immunity remains unclear. Mitophagy, a selected form of autophagy, eliminates damaged mitochondria to maintain mitochondrial homeostasis. Here, we demonstrate that SFTSV NP triggers mitophagy to degrade MAVS (mitochondrial antiviral signaling protein), thereby blocking MAVS-mediated antiviral signaling to escape the host immune response. Mechanistically, SFTSV NP translocates to mitochondria by interacting with TUFM (Tu translation elongation factor, mitochondrial), and mediates mitochondrial sequestration into phagophores through interacting with LC3, thus inducing mitophagy. Notably, the N-terminal LC3-interacting region (LIR) motif of NP is essential for mitophagy induction. Collectively, our results demonstrated that SFTSV NP serves as a novel virulence factor, inducing TUFM-mediated mitophagy to degrade MAVS and evade the host immune response.

Keywords:  Bunyavirus; MAVS; SFTSV; interferon; mitophagy; nucleoprotein

DOI:  https://doi.org/10.1080/15548627.2024.2393067
J Fungi (Basel). 2024 Aug 16. pii: 579. [Epub ahead of print]10(8):

The Mitochondrial Distribution and Morphology Family 33 Gene FgMDM33 Is Involved in Autophagy and Pathogenesis in Fusarium graminearum.

Wuyun Lv, Yiyi Tu, Ting Xu, You Zhang, Junjie Chen, Nan Yang, Yuchun Wang.

  The mitochondrial distribution and morphology family 33 gene (MDM33) regulates mitochondrial homeostasis by mediating the mitochondrial fission process in yeast. The wheat head blight Fusarium graminearum contains an FgMdm33 protein that is orthologous to Saccharomyces cerevisiae Mdm33, albeit its function remains unknown. We have reported here the roles of FgMdm33 in regulating fungal morphogenesis, mitochondrial morphology, autophagy, apoptosis, and fungal pathogenicity. The ΔFgmdm33 mutants generated through a homologous recombination strategy in this study exhibited defects in terms of mycelial growth, conidia production, and virulence. Hyphal cells lacking FgMDM33 displayed elongated mitochondria and a dispensable respiratory-deficient growth phenotype, indicating the possible involvement of FgMDM33 in mitochondrial fission. The ΔFgmdm33 mutants displayed a remarkable reduction in the proteolysis of GFP-FgAtg8, whereas the formation of autophagic bodies in the hyphal cells of mutants was recorded under the induction of mitophagy. In addition, the transcriptional expression of the apoptosis-inducing factor 1 gene (FgAIF1) was significantly upregulated in the ΔFgmdm33 mutants. Cumulatively, these results indicate that FgMDM33 is involved in mitochondrial fission, non-selective macroautophagy, and apoptosis and that it regulates fungal growth, conidiation, and pathogenicity of the head blight pathogen.

Keywords:  Fusarium graminearum; MDM33; apoptosis; autophagy; mitochondrial fission; pathogenesis

DOI:  https://doi.org/10.3390/jof10080579
Int Immunopharmacol. 2024 Aug 26. pii: S1567-5769(24)01462-0. [Epub ahead of print]141 112941

Coenzyme Q10 ameliorates lipopolysaccharide-induced acute lung injury by attenuating oxidative stress and NLRP3 inflammation through regulating mitochondrial dynamics.

Yongping Chen, Haotian Yang, Xueyuan Hu, Tianyuan Yang, Yuan Zhao, Huanqi Liu, Honggang Fan.

  Increasing evidence has demonstrated that coenzyme Q10 (CoQ10) exhibits a range of biological properties. Herein, we explored the protective effect and potential molecular mechanism of CoQ10 on lipopolysaccharide (LPS)-induced acute lung injury (ALI). We found that medium (10 mg/kg) and high (50 mg/kg) doses of CoQ10 ameliorated LPS (50 µg/µL)-induced ALI to varying degrees, as demonstrated by reduced lung coefficient, lower wet/dry weight lung tissue ratio, decreased bronchoalveolar lavage fluid protein concentration, less anatomical and histopathological damage to the lung, and increased expression of proteins related to lung epithelial barrier structure. CoQ10 also alleviated LPS-induced oxidative stress and inflammation mediated by NOD-like receptor protein 3 (NLRP3) by reducing the reactive oxygen species (ROS), malondialdehyde, and mitochondrial ROS concentrations, increasing superoxide dismutase, glutathione, and catalase activity, and decreasing NLRP3 expression at the protein and mRNA levels. Moreover, CoQ10 alleviated structural and functional damage to the mitochondria, inhibited mitochondrial fission, and promoted mitochondrial fusion, mainly by inhibiting phosphorylation of dynamin-related protein 1 (Drp1) at Ser616 and Ser637. Correlation analysis revealed that mitochondrial fission (especially Drp1) was positively correlated with oxidative stress, NLRP3-mediated inflammation, and structural damage to the lung epithelial barrier. Molecular docking analysis showed that CoQ10 binds stably to Drp1, with a binding energy of -5.9 kcal/mol. Furthermore, the use of schaftoside (a Drp1 inhibitor) has further elucidated the mechanism of action of CoQ10. Together, these results suggest that CoQ10 alleviates LPS-induced ALI by regulating mitochondrial dynamics, attenuating oxidative stress, and decreasing NLRP3-medated inflammation, thereby promoting lung epithelial barrier structural remodeling.

Keywords:  Acute lung injury; Coenzyme Q10; Mitochondrial dynamics; NLRP3 inflammation; Oxidative stress

DOI:  https://doi.org/10.1016/j.intimp.2024.112941
Biomaterials. 2024 Aug 22. pii: S0142-9612(24)00298-9. [Epub ahead of print]313 122764

Mitochondrial 'Birth-Death' coordinator: An intelligent hydrogen nanogenerator to enhance intervertebral disc regeneration.

Yucheng Ji, Yuwei Hu, Yubo Feng, Lei Liu, Zhanyi Chen, Hongxing Shen, Yingchao Han, He Xu, Lifeng Lao.

  Currently, mitochondrial dysfunction caused by oxidative stress is a growing concern in degenerative diseases, notably intervertebral disc degeneration (IVDD). Dysregulation of the balance of mitochondrial quality control (MQC) has been considered the key contributor, while it's still challenging to effectively harmonize different MQC components in a simple and biologically safe way. Hydrogen gas (H2) is a promising mitochondrial therapeutic molecule due to its bio-reductivity and diffusibility across cellular membranes, yet its relationship with MQC regulation remains unknown. Herein, we propose a mitochondrial 'Birth-Death' coordinator achieved by an intelligent hydrogen nanogenerator (Fe@HP-OD), which can sustainably release H2 in response to the unique microenvironment in degenerated IVDs. Both in vitro and in vivo results prove alleviation of cellular oxidative stress and restoration of nucleus pulposus cells function, thereby facilitating successful IVD regeneration. Significantly, this study for the first time proposes the mitochondrial 'Birth-Death' coordination mechanism: 1) attenuation of overactivated mitochondrial 'Death' process (UPRmt and unselective mitophagy); and 2) activation of Adenosine 5'-monophosphate-activated protein kinase (AMPK) signaling pathway for mitochondrial 'Birth-Death' balance (mitochondrial biogenesis and controlled mitophagy). These pioneering findings can fill in the gaps in molecular mechanisms for H2 regulation on MQC homeostasis, and pave the way for future strategies towards restoring equilibrium of MQC system against degenerative diseases.

Keywords:  Dual-responsive hydrogel; Hydrogen therapy; Intervertebral disc degeneration; Mitochondrial quality control; Regenerative medicine

DOI:  https://doi.org/10.1016/j.biomaterials.2024.122764
Cell Stem Cell. 2024 Aug 16. pii: S1934-5909(24)00287-X. [Epub ahead of print]

Context-dependent roles of mitochondrial LONP1 in orchestrating the balance between airway progenitor versus progeny cells.

Le Xu, Chunting Tan, Justinn Barr, Nicole Talaba, Jamie Verheyden, Ji Sun Chin, Samvel Gaboyan, Nikita Kasaraneni, Ruth M Elgamal, Kyle J Gaulton, Grace Lin, Kamyar Afshar, Eugene Golts, Angela Meier, Laura E Crotty Alexander, Zea Borok, Yufeng Shen, Wendy K Chung, David J McCulley, Xin Sun.

  While all eukaryotic cells are dependent on mitochondria for function, in a complex tissue, which cell type and which cell behavior are more sensitive to mitochondrial deficiency remain unpredictable. Here, we show that in the mouse airway, compromising mitochondrial function by inactivating mitochondrial protease gene Lonp1 led to reduced progenitor proliferation and differentiation during development, apoptosis of terminally differentiated ciliated cells and their replacement by basal progenitors and goblet cells during homeostasis, and failed airway progenitor migration into damaged alveoli following influenza infection. ATF4 and the integrated stress response (ISR) pathway are elevated and responsible for the airway phenotypes. Such context-dependent sensitivities are predicted by the selective expression of Bok, which is required for ISR activation. Reduced LONP1 expression is found in chronic obstructive pulmonary disease (COPD) airways with squamous metaplasia. These findings illustrate a cellular energy landscape whereby compromised mitochondrial function could favor the emergence of pathological cell types.

Keywords:  ATF4; BOK; COPD; airway homeostasis; differentiated progeny cells; influenza infection; integrated stress response; lung epithelial cells; mitochondria; progenitor basal cells

DOI:  https://doi.org/10.1016/j.stem.2024.08.001
Nephron. 2024 Aug 23.

Lipophagy and mitophagy in renal pathophysiology.

Nicolas Dupont, Fabiola Terzi.

BACKGROUND: The lysosomal autophagic pathway plays a fundamental role in cellular and tissue homeostasis, its deregulation is linked to human pathologies including kidney diseases. Autophagy can randomly degrade cytoplasmic components in a non-selective manner commonly referred to as bulk autophagy. In contrast, selective forms of autophagy specifically target cytoplasmic structures such as organelles and protein aggregates thereby being important for cellular quality control and organelle homeostasis.
SUMMARY: Research during the past decades has begun to elucidate the role of selective autophagy in kidney physiology and kidney diseases.
KEY MESSAGES: In this review, we will summarize the knowledge on lipophagy and mitophagy, two forms of selective autophagy important in renal epithelium homeostasis and discuss how their deregulations contribute to renal disease progression.

DOI: https://doi.org/10.1159/000540688
J Transl Med. 2024 Aug 25. 22(1): 788

SIRT6 prevent chronic cerebral hypoperfusion induced cognitive impairment by remodeling mitochondrial dynamics in a STAT5-PGAM5-Drp1 dependent manner.

Yong Du, Jiaqing He, Yanni Xu, Xun Wu, Hongbo Cheng, Jiegang Yu, Xiaoliang Wang, Yaqing An, Yang Wu, Wei Guo.

  Vascular dementia (VaD) is a prevalent form of dementia resulting from chronic cerebral hypoperfusion (CCH). However, the pathogenic mechanisms of VaD and corresponding therapeutic strategies are not well understood. Sirtuin 6 (SIRT6) has been implicated in various biological processes, including cellular metabolism, DNA repair, redox homeostasis, and aging. Nevertheless, its functional relevance in VaD remains unexplored. In this study, we utilized a bilateral common carotid artery stenosis (BCAS) mouse model of VaD to investigate the role of SIRT6. We detected a significant decrease in neuronal SIRT6 protein expression following CCH. Intriguingly, neuron-specific ablation of Sirt6 in mice exacerbated neuronal damage and cognitive deficits after CCH. Conversely, treatment with MDL-800, an agonist of SIRT6, effectively mitigated neuronal loss and facilitated neurological recovery. Mechanistically, SIRT6 inhibited excessive mitochondrial fission by suppressing the CCH-induced STAT5-PGAM5-Drp1 signaling cascade. Additionally, the gene expression of monocyte SIRT6 in patients with asymptomatic carotid stenosis showed a correlation with cognitive outcomes, suggesting translational implications in human subjects. Our findings provide the first evidence that SIRT6 prevents cognitive impairment induced by CCH, and mechanistically, this protection is achieved through the remodeling of mitochondrial dynamics in a STAT5-PGAM5-Drp1-dependent manner.

Keywords:  Chronic cerebral hypoperfusion; Cognitive impairment; Drp1; Mitochondrial dynamics; SIRT6

DOI:  https://doi.org/10.1186/s12967-024-05566-0
Nat Commun. 2024 Aug 27. 15(1): 7352

Infection-induced peripheral mitochondria fission drives ER encapsulations and inter-mitochondria contacts that rescue bioenergetics.

William A Hofstadter, Katelyn C Cook, Elene Tsopurashvili, Robert Gebauer, Vojtěch Pražák, Emily A Machala, Ji Woo Park, Kay Grünewald, Emmanuelle R J Quemin, Ileana M Cristea.

The dynamic regulation of mitochondria shape via fission and fusion is critical for cellular responses to stimuli. In homeostatic cells, two modes of mitochondrial fission, midzone and peripheral, provide a decision fork between either proliferation or clearance of mitochondria. However, the relationship between specific mitochondria shapes and functions remains unclear in many biological contexts. While commonly associated with decreased bioenergetics, fragmented mitochondria paradoxically exhibit elevated respiration in several disease states, including infection with the prevalent pathogen human cytomegalovirus (HCMV) and metastatic melanoma. Here, incorporating super-resolution microscopy with mass spectrometry and metabolic assays, we use HCMV infection to establish a molecular mechanism for maintaining respiration within a fragmented mitochondria population. We establish that HCMV induces fragmentation through peripheral mitochondrial fission coupled with suppression of mitochondria fusion. Unlike uninfected cells, the progeny of peripheral fission enter mitochondria-ER encapsulations (MENCs) where they are protected from degradation and bioenergetically stabilized during infection. MENCs also stabilize pro-viral inter-mitochondria contacts (IMCs), which electrochemically link mitochondria and promote respiration. Demonstrating a broader relevance, we show that the fragmented mitochondria within metastatic melanoma cells also form MENCs. Our findings establish a mechanism where mitochondria fragmentation can promote increased respiration, a feature relevant in the context of human diseases.

DOI: https://doi.org/10.1038/s41467-024-51680-4
Reprod Toxicol. 2024 Aug 22. pii: S0890-6238(24)00167-9. [Epub ahead of print]130 108700

Altered mitochondrial homeostasis on bisphenol-A exposure and its association in developing polycystic ovary syndrome: A comprehensive review.

Supraja M Kodanch, Sayantani Mukherjee, Navya B Prabhu, Shama Prasada Kabekkodu, Shashikala K Bhat, Padmalatha S Rai.

  Polycystic ovary syndrome (PCOS) is a heterogeneous endocrinopathy that is known to be one of the most common reproductive pathologies observed in premenopausal women around the globe and is particularly complex as it affects various endocrine and reproductive metabolic pathways. Endocrine-disrupting chemicals (EDCs) are considered to be environmental toxicants as they have hazardous health effects on the functioning of the human endocrine system. Among various classes of EDCs, bisphenol A (BPA) has been under meticulous investigation due to its ability to alter the endocrine processes. As there is emerging evidence suggesting that BPA-induced mitochondrial homeostasis dysfunction in various pathophysiological conditions, this review aims to provide a detailed review of how various pathways associated with ovarian mitochondrial homeostasis are impaired on BPA exposure and its mirroring effects on the PCOS phenotype. BPA exposure might cause significant damage to the mitochondrial morphology and functions through the generation of reactive oxygen species (ROS) and simultaneously downregulates the total antioxidant capacity, thereby leading to oxidative stress. BPA disrupts the mitochondrial dynamics in human cells by altering the expressions of mitochondrial fission and fusion genes, increases the senescence marker proteins, along with significant alterations in the mTOR/AMPK pathway, upregulates the expression of autophagy mediating factors, and downregulates the autophagic suppressor. Furthermore, an increase in apoptosis of the ovarian granulosa cells indicates impaired folliculogenesis. As all these key features are associated with the pathogenesis of PCOS, this review can provide a better insight into the possible associations between BPA-induced dysregulation of mitochondrial homeostasis and PCOS.

Keywords:  Bisphenol A; Mitochondrial dynamics; Mitochondrial homeostasis; Oxidative stress; Polycystic ovary syndrome; Reactive oxygen species

DOI:  https://doi.org/10.1016/j.reprotox.2024.108700
Redox Biol. 2024 Aug 27. pii: S2213-2317(24)00307-0. [Epub ahead of print]76 103329

Role of Mitofusin 1 in mediating reactive oxygen species in alveolar macrophages during Streptococcuspneumoniae.

David Thomas, Jianjun Yang, Soo Jung Cho, Heather Stout-Delgado.

Alveolar macrophages (AM) are key effectors of the immune response and are essential for host responses to S. pneumoniae. Mitochondria are highly dynamic organelles whose function aids in regulating the cell cycle, innate immunity, autophagy, redox signaling, calcium homeostasis, and mitochondrial quality control in AM. In response to cellular stress, mitochondria can engage in stress-induced mitochondrial hyperfusion (SIMH). The current study aimed to investigate the role of Mfn1 on mitochondrial control of reactive oxygen species (ROS) in AMs and the role of Mfn1 deficiency on immune responses to S. pneumoniae. Compared to Mfn1FloxCre- controls, there were distinct histological differences in lung tissue collected from Mfn1Floxed; CreLysM mice, with less injury and inflammation observed in mice with Mfn1 deficient myeloid cells. There was a significant decrease in lipid peroxidation and ROS production in Mfn1 deficient AM that was associated with increased superoxide dismutase (SOD) and antioxidant activity. Our findings demonstrate that Mfn1 deficiency in myeloid cells decreased inflammation and lung tissue injury during S. pneumoniae infection.

DOI: https://doi.org/10.1016/j.redox.2024.103329
Front Physiol. 2024 ;15 1430230

Mitophagy in fibrotic diseases: molecular mechanisms and therapeutic applications.

Xinyan Cui, Zekun Zhou, Hua Tu, Jianjun Wu, Jian Zhou, Qiao Yi, Ousheng Liu, Xiaohan Dai.

  Mitophagy is a highly precise process of selective autophagy, primarily aimed at eliminating excess or damaged mitochondria to maintain the stability of both mitochondrial and cellular homeostasis. In recent years, with in-depth research into the association between mitophagy and fibrotic diseases, it has been discovered that this process may interact with crucial cellular biological processes such as oxidative stress, inflammatory responses, cellular dynamics regulation, and energy metabolism, thereby influencing the occurrence and progression of fibrotic diseases. Consequently, modulating mitophagy holds promise as a therapeutic approach for fibrosis. Currently, various methods have been identified to regulate mitophagy to prevent fibrosis, categorized into three types: natural drug therapy, biological therapy, and physical therapy. This review comprehensively summarizes the current understanding of the mechanisms of mitophagy, delves into its biological roles in fibrotic diseases, and introduces mitophagy modulators effective in fibrosis, aiming to provide new targets and theoretical basis for the investigation of fibrosis-related mechanisms and disease prevention.

Keywords:  energy metabolism; fibrosis; inflammation; mitophagy; oxidative stress; treatment

DOI:  https://doi.org/10.3389/fphys.2024.1430230
Cell Immunol. 2024 Aug 26. pii: S0008-8749(24)00067-4. [Epub ahead of print]403-404 104864

The role of mitochondrial fusion and fission in immune-mediated inflammatory diseases.

Yulai Fang, Shichen Min, Hong Shen.

  Mitochondria are highly dynamic organelles that maintain their homeostasis through mitochondrial dynamics. Mitochondrial fusion and fission are two important processes of mitochondrial dynamics. There is accumulating evidence that mitochondrial fusion and fission play an important role in the development of immune-mediated inflammatory diseases. This article provides a brief review of the essential role of mitochondrial fusion and fission in immune-mediated inflammatory diseases. It will provide a novel perspective and direction for the elucidation of the pathogenesis and treatment of immune-mediated inflammatory diseases.

Keywords:  Immune-mediated inflammatory diseases; Mitochondrial fission; Mitochondrial fusion

DOI:  https://doi.org/10.1016/j.cellimm.2024.104864
Endocrine. 2024 Aug 28.

Resveratrol stimulates brown of white adipose via regulating ERK/DRP1-mediated mitochondrial fission and improves systemic glucose homeostasis.

Hongjia Yan, Muqing Shao, Xiaoqian Lin, Ting Peng, Caiyu Chen, Mei Yang, Jian Zhong, Jian Yang, Suocheng Hui.

   PURPOSE: Diabetes mellitus and metabolic homeostasis disorders may benefit from white adipose tissue (WAT) browning, which is associated with mitochondrial fission. Resveratrol, a dietary polyphenol, exhibits beneficial effects against abnormalities related to metabolic diseases. However, it remains unknown whether resveratrol contributes to WAT browning by regulating mitochondrial fission.
METHODS: We administered resveratrol (0.4% mixed with control) to db/db mice for 12 weeks, measuring body weight, oral glucose tolerance, insulin tolerance, and histological changes. The uncoupling protein 1 (UCP1) and dynamin-related protein 1 (DRP1) expressions in the epididymal WAT were assessed via immunoblotting.
RESULTS: We found that resveratrol improved systemic glucose homeostasis and insulin resistance in db/db mice, which was associated with increased UCP1 in epididymal WAT. Resveratrol-treated mice exhibited more fragmented mitochondria and increased phosphorylation of DRP1 in the epididymal WAT of the db/db mice. These results were further confirmed in vitro, where resveratrol induced extracellular signal-regulated kinase (ERK) signaling activation, leading to phosphorylation of DRP1 at the S616 site (p-DRP1S616) and mitochondrial fission, which was reversed by an ERK inhibitor in 3T3-L1 adipocytes.
CONCLUSION: Resveratrol plays a role in regulating the phosphorylation of ERK and DRP1, resulting in the promotion of beige cells with epididymal WAT and the improvement of glucose homeostasis. Our present study provides novel insights into the potential mechanism of resveratrol-mediated effects on WAT browning, suggesting that it is, at least in part, mediated through ERK/DRP1-mediated mitochondrial fission.

Keywords:  Adipose browning; Glucose homeostasis; Mitochondrial fission; Resveratrol

DOI:  https://doi.org/10.1007/s12020-024-04008-7
Cancers (Basel). 2024 Aug 12. pii: 2823. [Epub ahead of print]16(16):

Mitochondrial Dynamics in Non-Small Cell Lung Cancer.

Agata Dutkowska, Daria Domańska-Senderowska, Karolina H Czarnecka-Chrebelska, Ewa Pikus, Aleksandra Zielińska, Laura Biskup, Agata Kołodziejska, Paulina Madura, Maria Możdżan, Urszula Załuska, Edward Zheng, Eliza Adamczyk, Konrad Kędzia, Szymon Wcisło, Marcin Wawrzycki, Ewa Brzeziańska-Lasota, Sławomir Jabłoński, Adam Antczak, Michał Poznański.

  In lung cancer patients, two complementary abnormalities were found that can cause disruption of the mitochondrial network: increased fusion and impaired fission, manifested by reduced levels of FIS1, a mitochondrial division regulator, and increased expression of MFN1, a mitochondrial fusion mediator. Immunoexpression studies of MFN1 and FIS1 proteins were performed in serum samples obtained from 47 patients with non-small cell lung cancer (NSCLC) and 21 controls. In the NSCLC patients, the immunoexpression of the MFN1 protein was significantly higher, and the FIS1 protein level was significantly lower than in the control group (p < 0.01; p < 0.001; UMW test). Patients with early, operable lung cancer had significantly lower levels of MFN1 immunoexpression compared to patients with advanced, metastatic lung cancer (p < 0.05; UMW test). This suggests that early stages of the disease are characterized by greater fragmentation of damaged mitochondria and apoptosis. In contrast, lower FIS1 protein levels were associated with a worse prognosis. Increased mitochondrial fusion in the blood of lung cancer patients may suggest an increase in protective and repair mechanisms. This opens up questions about why these mechanisms fail in the context of existing advanced cancer disease and is a starting point for further research into why protective mechanisms fail in lung cancer patients.

Keywords:  fission; fusion; lung cancer; mitochondrial dynamics

DOI:  https://doi.org/10.3390/cancers16162823
J Lipid Res. 2024 Aug 23. pii: S0022-2275(24)00138-X. [Epub ahead of print] 100633

Mechanistic Insights into Metabolic Function of Dynamin-Related Protein 1 (DRP1).

Xin Li, Katherine Pham, Jazmin Ysaguirre, Iqbal Mahmud, Lin Tan, Bo Wei, Long J Shao, Maryam Elizondo, Rabie Habib, Fathima Elizondo, Hiromi Sesaki, Philip L Lorenzi, Kai Sun.

  DRP1 plays crucial roles in mitochondrial and peroxisome fission. However, the mechanisms underlying the functional regulation of DRP1 in adipose tissue during obesity remain unclear. To elucidate the metabolic and pathological significance of diminished DRP1 in obese adipose tissue, we utilized adipose tissue-specific DRP1 KO mice challenged with an HFD. We observed significant metabolic dysregulations in the KO mice. Mechanistically, DRP1 exerts multifaceted functions in mitochondrial dynamics and ER-lipid droplet cross-talk in normal mice. Loss-of-function of DRP1 resulted in abnormally giant mitochondrial shapes, distorted mitochondrial membrane structure, and disrupted cristae architecture. Meanwhile, DRP1 deficiency induced the retention of nascent lipid droplets in ER, leading to perturbed overall lipid dynamics in the KO mice. Collectively, dysregulation of the dynamics of mitochondria, ER, and lipid droplets contributes to whole-body metabolic disorders, as evidenced by perturbations in energy metabolites. Our findings demonstrate that DRP1 plays a pivotal role in energy homeostasis in adipose tissue during obesity.

Keywords:  Dyslipidemias; Lipid droplets; Lipids; Mitochondria; Nutrition; Obesity

DOI:  https://doi.org/10.1016/j.jlr.2024.100633
Sci Rep. 2024 08 24. 14(1): 19673

Detailed analysis of Mdivi-1 effects on complex I and respiratory supercomplex assembly.

Nico Marx, Nadine Ritter, Paul Disse, Guiscard Seebohm, Karin B Busch.

  Several human diseases, including cancer and neurodegeneration, are associated with excessive mitochondrial fragmentation. In this context, mitochondrial division inhibitor (Mdivi-1) has been tested as a therapeutic to block the fission-related protein dynamin-like protein-1 (Drp1). Recent studies suggest that Mdivi-1 interferes with mitochondrial bioenergetics and complex I function. Here we show that the molecular mechanism of Mdivi-1 is based on inhibition of complex I at the IQ site. This leads to the destabilization of complex I, impairs the assembly of N- and Q-respirasomes, and is associated with increased ROS production and reduced efficiency of ATP generation. Second, the calcium homeostasis of cells is impaired, which for example affects the electrical activity of neurons. Given the results presented here, a potential therapeutic application of Mdivi-1 is challenging because of its potential impact on synaptic activity. Similar to the Complex I inhibitor rotenone, Mdivi-1 may lead to neurodegenerative effects in the long term.

Keywords:  Calcium metabolism; Inhibition; Mdivi-1; Mitochondria; Neuronal activity; Respiratory complex I; Respiratory supercomplexes

DOI:  https://doi.org/10.1038/s41598-024-69748-y
Biology (Basel). 2024 Aug 21. pii: 639. [Epub ahead of print]13(8):

Pathological Role of High Sugar in Mitochondrial Respiratory Chain Defect-Augmented Mitochondrial Stress.

Ebrima D Cham, Tsung-I Peng, Mei-Jie Jou.

  According to many research groups, high glucose induces the overproduction of superoxide anions, with reactive oxygen species (ROS) generally being considered the link between high glucose levels and the toxicity seen at cellular levels. Respiratory complex anomalies can lead to the production of ROS. Calcium [Ca2+] at physiological levels serves as a second messenger in many physiological functions. Accordingly, mitochondrial calcium [Ca2+]m overload leads to ROS production, which can be lethal to the mitochondria through various mechanisms. F1F0-ATPase (ATP synthase or complex V) is the enzyme responsible for catalyzing the final step of oxidative phosphorylation. This is achieved by F1F0-ATPase coupling the translocation of protons in the mitochondrial intermembrane space and shuttling them to the mitochondrial matrix for ATP synthesis to take place. Mitochondrial complex V T8993G mutation specifically blocks the translocation of protons across the intermembrane space, thereby blocking ATP synthesis and, in turn, leading to Neuropathy, Ataxia, and Retinitis Pigmentosa (NARP) syndrome. This study seeks to explore the possibility of [Ca2+]m overload mediating the pathological roles of high glucose in defective respiratory chain-mediated mitochondrial stress. NARP cybrids are the in vitro experimental models of cells with F1FO-ATPase defects, with these cells harboring 98% of mtDNA T8993G mutations. Their counterparts, 143B osteosarcoma cell lines, are the parental cell lines used for comparison. We observed that NARP cells mediated and enhanced the death of cells (apoptosis) when incubated with hydrogen peroxide (H2O2) and high glucose, as depicted using the MTT assay of cell viability. Furthermore, using fluorescence probe-coupled laser scanning confocal imaging microscopy, NARP cells were found to significantly enable mitochondrial reactive oxygen species (mROS) formation and enhance the depolarization of the mitochondrial membrane potential (ΔΨm). Elucidating the mechanisms of sugar-enhanced toxicity on the mitochondria may, in the future, help to alleviate the symptoms of patients with NARP syndromes and other neurodegenerative diseases.

Keywords:  cardiolipin; complex V; high glucose toxicity; mROS; mitochondrial DNA (mtDNA); mitochondrial calcium stress [Ca2+]m; mitochondrial permeability transition pore (MPTP); oxidative stress

DOI:  https://doi.org/10.3390/biology13080639
Poult Sci. 2024 Aug 03. pii: S0032-5791(24)00746-6. [Epub ahead of print]103(11): 104167

Cadmium causes spleen toxicity in chickens by regulating mitochondrial unfolded protein response and nuclear receptors response.

Wang-Ye Xu, Xiao-Wei Li, Jin-Xu Sun, Kanwar Kumar Malhi, Xue-Nan Li, Jin-Long Li.

  Cadmium (Cd) is a heavy metal that pollutes the environment and threatens human and animal health via the food chain. The spleen is one of the target organs affected by Cd toxicity. However, the mechanism of Cd toxicity is not fully understood. In this study, 80 chicks were allocated into 4 groups (n = 20) and exposed to different doses of CdCl2 (0 mg/kg, 35 mg/kg, 70 mg/kg and 140 mg/kg) for 90 d. The pathological changes in the spleen, mitochondrial dynamics-related factors, cytochrome P450 (CYP450) enzyme system contents, activities, transcription levels, nuclear receptors (NRs) response molecule levels, and mitochondrial unfolded protein-related factors were detected. The findings indicate that exposure to Cd significantly leads to spleen injury. In Cd groups, the total contents of CYP450 and cytochrome b5 (Cyt b5) increased, and the activities of the CYP450 enzyme system (APND, ERND, AH, and NCR) changed. The NRs response was induced, and the gene levels of AHR/CAR and corresponding CYP450 isoforms (CYP1B1, CYP1A5, CYP1A1, CYP2C18, CYP2D6 and CYP3A4) were found altered. The study found that Cd exposure altered the mRNA expression levels of mitochondrial dynamics-related factors, such as OPA1, Fis1, MFF, Mfn1, and Mfn2, breaking mitochondrial fusion and cleavage and ultimately leading to mitochondrial dysfunction. Changes were detected in the gene levels of several mitochondrial unfolded protein response (mtUPR)-related factors, namely (SIRT1, PGC-1α, NRF1, TFAM, SOD2, and HtrA2). Cd also altered the gene levels of mitochondrial function-related factors (VDAC1, Cyt-C, COA6, PRDX3, RAF and SIRT3). It is showed that Cd can initiate the NRs response, influence the homeostasis of the CPY450 enzyme system, trigger the mtUPR, impair mitochondrial function, and ultimately lead to Cd toxicity in the spleen of chickens.

Keywords:  CYP450s enzyme system; cadmium; mtUPR pathway; nuclear receptors (NR) response; spleen

DOI:  https://doi.org/10.1016/j.psj.2024.104167
Biomed Pharmacother. 2024 Aug 26. pii: S0753-3322(24)01225-3. [Epub ahead of print]179 117340

Scutellarin ameliorates mitochondrial dysfunction and apoptosis in OGD/R-insulted HT22 cells through mitophagy induction.

Lu Yang, Xianfeng Liu, Siyin Chen, Jiayi Sun, Yiwen Tao, Liyuan Ma, Yong Zeng, Kaipei Luo, Ruimin Tian, Xianli Meng.

  Scutellarin (Scu), a flavonoid from herbal Erigeron breviscapus (Vaniot) Hand-Mazz, exerts neuroprotective effects against cerebral ischemia. However, whether the effects of Scu are related to mitochondrial protection needs further investigation. In this study, we aimed to clarify the mechanisms of Scu against HT22 cells injury caused by oxygen-glucose deprivation and reperfusion (OGD/R). Our results proved that Scu significantly reduced the overload of intracellular reactive oxygen species (cellar ROS) and mitochondria reactive oxygen species (mito-ROS), ameliorating oxidative stress damage. TUNEL positive rate, Caspase-3 activity, and Cytochrome c (Cyto-c) expression remarkably decreased following Scu treatment. Meanwhile, Scu could maintain mitochondrial morphology and reverse ultrastructure changes. And mitochondrial membrane potential (MMP), oxygen consumption rate (OCR), adenosine triphosphate (ATP) production and Na+/K+-ATPase activity were obviously promoted. Additionally, Scu was found to stimulate mitophagy level by increasing the expression of LC3, Beclin1, PINK1 and Parkin proteins, as well as promoting the degradation of p62. More importantly, the regulatory effects of Scu on mito-ROS, MMP, ATP, Na+/K+-ATPase, cell viability and lactate dehydrogenase (LDH) were markedly limited by Mdivi-1 (a mitophagy inhibitor). Of note, the inhibitor also reversed Scu-mediated apoptosis suppression, evidenced by the diminished apoptosis rate, the down-regulated expression activities of Cyto-c, Bax and cleaved Caspase-3, as well as the elevated level of Bcl-2 protein. Collectively, Scu could improve mitochondrial dysfunction and inhibit apoptosis by stimulating mitophagy, thereby attenuating OGD/R-induced HT22 cells injury.

Keywords:  Hypoxia/ischemia; Mitochondria dysfunction; Mitochondria-mediated apoptosis; Mitophagy; Scutellarin

DOI:  https://doi.org/10.1016/j.biopha.2024.117340
EMBO Rep. 2024 Aug 27.

Drp1 splice variants regulate ovarian cancer mitochondrial dynamics and tumor progression.

Zaineb Javed, Dong Hui Shin, Weihua Pan, Sierra R White, Amal Taher Elhaw, Yeon Soo Kim, Shriya Kamlapurkar, Ya-Yun Cheng, J Cory Benson, Ahmed Emam Abdelnaby, Rébécca Phaëton, Hong-Gang Wang, Shengyu Yang, Mara L G Sullivan, Claudette M St Croix, Simon C Watkins, Steven J Mullett, Stacy L Gelhaus, Nam Lee, Lan G Coffman, Katherine M Aird, Mohamed Trebak, Karthikeyan Mythreye, Vonn Walter, Nadine Hempel.

  Aberrant mitochondrial fission/fusion dynamics are frequently associated with pathologies, including cancer. We show that alternative splice variants of the fission protein Drp1 (DNM1L) contribute to the complexity of mitochondrial fission/fusion regulation in tumor cells. High tumor expression of the Drp1 alternative splice variant lacking exon 16 relative to other transcripts is associated with poor outcome in ovarian cancer patients. Lack of exon 16 results in Drp1 localization to microtubules and decreased association with mitochondrial fission sites, culminating in fused mitochondrial networks, enhanced respiration, changes in metabolism, and enhanced pro-tumorigenic phenotypes in vitro and in vivo. These effects are inhibited by siRNAs designed to specifically target the endogenously expressed transcript lacking exon 16. Moreover, lack of exon 16 abrogates mitochondrial fission in response to pro-apoptotic stimuli and leads to decreased sensitivity to chemotherapeutics. These data emphasize the pathophysiological importance of Drp1 alternative splicing, highlight the divergent functions and consequences of changing the relative expression of Drp1 splice variants in tumor cells, and strongly warrant consideration of alternative splicing in future studies focused on Drp1.

Keywords:   DNM1L ; Alternative Splice Variants; Drp1; Mitochondrial Fission; Ovarian Cancer

DOI:  https://doi.org/10.1038/s44319-024-00232-4
J Cell Physiol. 2024 Aug 26.

RETRACTION: "Melatonin attenuates TNF-α-mediated hepatocytes damage via inhibiting mitochondrial stress and activating the Akt-Sirt3 signaling pathway".

RETRACTION: J. Song, C. Lu, W. Zhao, X. Shao, "Melatonin attenuates TNF-α-mediated hepatocytes damage via inhibiting mitochondrial stress and activating the Akt-Sirt3 signaling pathway," Journal of Cellular Physiology 234, no. 11 (2019): 20969-20979, https://doi.org/10.1002/jcp.28701. The above article, published online on 25 April 2019 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the authors; the journal's Editor in Chief, Alexander Hutchison; and Wiley Periodicals LLC. The retraction has been agreed due to concerns related to the data presented in the article. Several flaws and inconsistencies between results presented and experimental methods described were found. Additionally, several image elements of the experimental data were published elsewhere in a different scientific context. The authors stated that the data has been partially generated by a third-party company. Accordingly, the conclusions of this article are considered invalid.

DOI: https://doi.org/10.1002/jcp.31319
Shock. 2024 Aug 26.

The mitochondrial division inhibitor Mdivi-1 protected organ function and extended the treatment window in rats with uncontrolled haemorrhagic shock.

Yi Hu, He Fang, Lei Tan, Han She, Yuanlin Du, Yu Zhu, Yue Wu, Liangming Liu, Tao Li.

AIM: To elucidate whether the application of the mitochondrial division inhibitor Mdivi-1 can protect organ function and prolong the treatment window for traumatic hemorrhagic shock.
METHODS: Before definitive haemostasis treatment, Mdivi-1 (0.25 mg/kg, 0.5 mg/kg and 1 mg/kg) was administered to uncontrolled haemorrhagic shock (UHS) model rats. Lactate Ringer's solution plus hydroxyethyl starch (130/0.4) was used as a control. The effects of Mdivi-1 on blood loss, fluid demand, survival time, vital organ function, myocardial mitochondrial structure, and mitochondrial function of the heart, liver, kidney and intestine, and oxidative stress at 1 hour after hypotensive resuscitation (50-60 mmHg) were investigated. In addition, we investigated the effect of varying doses of Mdivi-1 on the maintenance time of hypotensive resuscitation without definitive haemostasis and the beneficial effect of Mdivi-1 after prolonging the duration of hypotensive resuscitation to 2 hours.
RESULTS: Compared to conventional resuscitative fluid, Mdivi-1 significantly reduced blood loss and fluid demand, improved important organ functions during hypotensive resuscitation, improved animal survival and reduced the incidence of early death. Mdivi-1 significantly alleviated oxidative stress injury, reduced mitochondrial damage and restored myocardial mitochondrial structure and mitochondrial function of the heart, liver, kidney and intestine. In addition, Mdivi-1 increased the maintenance time of hypotensive resuscitation and improved rat survival after the duration of hypotensive resuscitation was prolonged to 2 h.
CONCLUSIONS: Mdivi-1 significantly prolonged the treatment window for traumatic hemorrhagic shock to 2 hours in UHS model rats. The underlying mechanism may be that Mdivi-1 inhibits excessive mitochondrial fission and oxidative stress and improves the structure and function of mitochondria.

DOI: https://doi.org/10.1097/SHK.0000000000002459
Sci Rep. 2024 08 28. 14(1): 19992

Identifying prognostic biomarkers in oral squamous cell carcinoma: an integrated single-cell and bulk RNA sequencing study on mitophagy-related genes.

Minsi Li, Yi Wei, Wenhua Huang, Cen Wang, Shixi He, Shuwen Bi, Shuangyu Hu, Ling You, Xuanping Huang.

  Oral squamous cell carcinoma (OSCC) has an extremely poor prognosis. Recent studies have suggested that mitophagy-related genes (MRGs) are closely correlated with the development and occurrence of cancer, but the role they play in oral cancer has not yet been explained.We conducted a comprehensive analysis of integrated single-cell and bulk RNA sequencing (RNA-seq) data retrieved from Gene Expression Omnibus (GEO) datasets and The Cancer Genome Atlas (TCGA) database. Multiple methods were combined to provide a comprehensive understanding of the genetic expression patterns and biology of OSCC, such as analysis of pseudotime series, CellChat cell communication, immune infiltration, Gene Ontology (GO), LASSO Cox regression, gene set variation analysis (GSVA), Kyoto Encyclopedia of Genes and Genomes (KEGG), gene set enrichment analysis (GSEA), Tumor Mutation Burden (TMB) and drug sensitivity assessments. The findings of this study demonstrated significantly greater activity of MRGs in NK cells than in other cells in OSCC. A reliable prognostic model was developed using 12 candidate genes strongly associated with mitochondrial autophagy. T stage, N stage and risk score were revealed as independent prognostic factors. Distinctively enriched pathways and immune cells were observed in different risk groups. Notably, low-risk patients were more responsive to chemotherapy. In addition, a nomogram model with excellent predictive ability was established by combining the risk scores and clinical features. The activity of MRGs suggest the potential for the development of new targeted therapies. The construction of a robust prognostic model also provides reference value for individualized prediction and clinical decision-making in patients with OSCC.

Keywords:  Immune; Mitochondrial autophagy; Oral squamous cell carcinoma; Prognostic biomarkers; Single-cell RNA sequencing

DOI:  https://doi.org/10.1038/s41598-024-70498-0