bims-mikwok 2024-05-26 papers

bims-mikwok

Biomed News

on Mitochondrial quality control

Issue of 2024–05–26
34 papers selected by
Gavin McStay, Liverpool John Moores University

Conserved quality control mechanisms of mitochondrial protein import.
Mitophagy at the crossroads of cancer development: Exploring the role of mitophagy in tumor progression and therapy resistance.
Elimination of damaged mitochondria during UVB-induced senescence is orchestrated by NIX-dependent mitophagy.
KAT8 compound inhibition inhibits the initial steps of PINK1-dependant mitophagy.
Melatonin Mitigates Atrazine-Induced Renal Tubular Epithelial Cell Senescence by Promoting Parkin-Mediated Mitophagy.
Serine 39 in the GTP-binding domain of Drp1 is involved in shaping mitochondrial morphology.
Artificially transplanted mitochondria in endothelial cells promote mitophagy.
Impaired mitochondrial morphological plasticity and failure of mitophagy associated with the G11778A mutation of LHON.
Pyruvate kinase M2 sustains cardiac mitochondrial integrity in septic cardiomyopathy by regulating PHB2-dependent mitochondrial biogenesis.
Polydatin and Nicotinamide Rescue the Cellular Phenotype of Mitochondrial Diseases by Mitochondrial Unfolded Protein Response (mtUPR) Activation.
Zinc ions regulate mitochondrial quality control in neurons under oxidative stress and reduce PANoptosis in spinal cord injury models via the Lgals3-Bax pathway.
SIRT3 and RORα are two prospective targets against mitophagy during simulated ischemia/reperfusion injury in H9c2 cells.
Multifaceted role of dynamin-related protein 1 in cardiovascular disease: From mitochondrial fission to therapeutic interventions.
Opportunistic pathogen Porphyromonas gingivalis targets the LC3B-ceramide complex and mediates lethal mitophagy resistance in oral tumors.
Early Handling Exerts Anxiolytic Effects and Alters Brain Mitochondrial Dynamics in Adult High Anxiety Mice.
Mitochondrial clearance and increased HSF-1 activity are coupled to promote longevity in fasted Caenorhabditis elegans.
Anthracycline Cardiotoxicity Induces Progressive Changes in Myocardial Metabolism and Mitochondrial Quality Control: Novel Therapeutic Target.
MCU inhibition protects against intestinal ischemia‒reperfusion by inhibiting Drp1-dependent mitochondrial fission.
PRKN-linked familial Parkinson's disease: cellular and molecular mechanisms of disease-linked variants.
Tectorigenin improves metabolic dysfunction-associated steatohepatitis by down-regulating tRF-3040b and promoting mitophagy to inhibit pyroptosis pathway.
Rictor/mTORC2 signalling contributes to renal vascular endothelial-to-mesenchymal transition and renal allograft interstitial fibrosis by regulating BNIP3-mediated mitophagy.
Inhibition of Drp1-Filamin Protein Complex Prevents Hepatic Lipid Droplet Accumulation by Increasing Mitochondria-Lipid Droplet Contact.
Lon1 Inactivation Downregulates Autophagic Flux and Brassinosteroid Biogenesis, Modulating Mitochondrial Proportion and Seed Development in Arabidopsis.
SDHAF1 confers metabolic resilience to aging hematopoietic stem cells by promoting mitochondrial ATP production.
DEAD-box helicase 17 (DDX17) protects cardiac function by promoting mitochondrial homeostasis in heart failure.
Systemic phospho-defective and phospho-mimetic Drp1 mice exhibit normal growth and development with altered anxiety-like behavior.
UBXN1 promotes liver tumorigenesis by regulating mitochondrial homeostasis.
Melatonin Ameliorates Post-Stroke Cognitive Impairment in Mice by Inhibiting Excessive Mitophagy.
Lactate facilitated mitochondrial fission-derived ROS to promote pulmonary fibrosis via ERK/DRP-1 signaling.
Nlrp6 protects from corticosterone-induced NSPC ferroptosis by modulating RIG-1/MAVS-mediated mitophagy.
Imbalanced mitochondrial dynamics contributes to the pathogenesis of X-linked adrenoleukodystrophy.
[Prdx1 regulates macrophage polarization by maintaining mitochondrial homeostasis].
Mitophagy in spermatogenesis: Roles and mechanisms.
Roles of O-GlcNAcylation in Mitochondrial Homeostasis and Cardiovascular Diseases.

J Inherit Metab Dis. 2024 May 24.

Conserved quality control mechanisms of mitochondrial protein import.

Lion Borgert, Thomas Becker, Fabian den Brave.

  Mitochondria carry out essential functions for the cell, including energy production, various biosynthesis pathways, formation of co-factors and cellular signalling in apoptosis and inflammation. The functionality of mitochondria requires the import of about 900-1300 proteins from the cytosol in baker's yeast Saccharomyces cerevisiae and human cells, respectively. The vast majority of these proteins pass the outer membrane in a largely unfolded state through the translocase of the outer mitochondrial membrane (TOM) complex. Subsequently, specific protein translocases sort the precursor proteins into the outer and inner membranes, the intermembrane space and matrix. Premature folding of mitochondrial precursor proteins, defects in the mitochondrial protein translocases or a reduction of the membrane potential across the inner mitochondrial membrane can cause stalling of precursors at the protein import apparatus. Consequently, the translocon is clogged and non-imported precursor proteins accumulate in the cell, which in turn leads to proteotoxic stress and eventually cell death. To prevent such stress situations, quality control mechanisms remove non-imported precursor proteins from the TOM channel. The highly conserved ubiquitin-proteasome system of the cytosol plays a critical role in this process. Thus, the surveillance of protein import via the TOM complex involves the coordinated activity of mitochondria-localized and cytosolic proteins to prevent proteotoxic stress in the cell.

Keywords:  TOM complex; mitoTAD; mitochondria; protein quality control; protein sorting

DOI:  https://doi.org/10.1002/jimd.12756
Biochim Biophys Acta Mol Cell Res. 2024 May 20. pii: S0167-4889(24)00095-8. [Epub ahead of print] 119752

Mitophagy at the crossroads of cancer development: Exploring the role of mitophagy in tumor progression and therapy resistance.

K Deepak, Pritam Kumar Roy, Chandan Kanta Das, Budhaditya Mukherjee, Mahitosh Mandal.

  Preserving a functional mitochondrial network is crucial for cellular well-being, considering the pivotal role of mitochondria in ensuring cellular survival, especially under stressful conditions. Mitophagy, the selective removal of damaged mitochondria through autophagy, plays a pivotal role in preserving cellular homeostasis by preventing the production of harmful reactive oxygen species from dysfunctional mitochondria. While the involvement of mitophagy in neurodegenerative diseases has been thoroughly investigated, it is becoming increasingly evident that mitophagy plays a significant role in cancer biology. Perturbations in mitophagy pathways lead to suboptimal mitochondrial quality control, catalyzing various aspects of carcinogenesis, including establishing metabolic plasticity, stemness, metabolic reconfiguration of cancer-associated fibroblasts, and immunomodulation. While mitophagy performs a delicate balancing act at the intersection of cell survival and cell death, mounting evidence indicates that, particularly in the context of stress responses induced by cancer therapy, it predominantly promotes cell survival. Here, we showcase an overview of the current understanding of the role of mitophagy in cancer biology and its potential as a target for cancer therapy. Gaining a more comprehensive insight into the interaction between cancer therapy and mitophagy has the potential to reveal novel targets and pathways, paving the way for enhanced treatment strategies for therapy-resistant tumors in the near future.

Keywords:  Anticancer therapeutics; Drug resistance; Metabolic rewiring; Mitophagy; Pathway mechanism; Stemness maintenance

DOI:  https://doi.org/10.1016/j.bbamcr.2024.119752
Aging Cell. 2024 May 17. e14186

Elimination of damaged mitochondria during UVB-induced senescence is orchestrated by NIX-dependent mitophagy.

Maria Cavinato, Ines Martic, Sophia Wedel, Annabella Pittl, Rafal Koziel, Regina Weinmmüllner, Markus Schosserer, Brigitte Jenewein, Madhusudhan Reddy Bobbili, Elsa Arcalis, Johannes Haybaeck, Gerhard Pierer, Christian Ploner, Martin Hermann, Nikolaus Romani, Matthias Schmuth, Johannes Grillari, Pidder Jansen-Dürr.

  Skin aging is the result of two types of aging, "intrinsic aging" an inevitable consequence of physiologic and genetically determined changes and "extrinsic aging," which is dependent on external factors such as exposure to sunlight, smoking, and dietary habits. UVB causes skin injury through the generation of free radicals and other oxidative byproducts, also contributing to DNA damage. Appearance and accumulation of senescent cells in the skin are considered one of the hallmarks of aging in this tissue. Mitochondria play an important role for the development of cellular senescence, in particular stress-induced senescence of human cells. However, many aspects of mitochondrial physiology relevant to cellular senescence and extrinsic skin aging remain to be unraveled. Here, we demonstrate that mitochondria damaged by UVB irradiation of human dermal fibroblasts (HDF) are eliminated by NIX-dependent mitophagy and that this process is important for cell survival under these conditions. Additionally, UVB-irradiation of human dermal fibroblasts (HDF) induces the shedding of extracellular vesicles (EVs), and this process is significantly enhanced in UVB-irradiated NIX-depleted cells. Our findings establish NIX as the main mitophagy receptor in the process of UVB-induced senescence and suggest the release of EVs as an alternative mechanism of mitochondrial quality control in HDF.

Keywords:  NIX; UVB; mitochondria; mitophagy; senescence; skin aging; vesicles

DOI:  https://doi.org/10.1111/acel.14186
Sci Rep. 2024 05 22. 14(1): 11721

KAT8 compound inhibition inhibits the initial steps of PINK1-dependant mitophagy.

Capucine de Talhouët, Noemi Esteras, Marc P M Soutar, Benjamin O'Callaghan, Helene Plun-Favreau.

  It has recently been shown that KAT8, a genome-wide association study candidate risk gene for Parkinson's Disease, is involved in PINK1/Parkin-dependant mitophagy. The KAT8 gene encodes a lysine acetyltransferase and represents the catalytically active subunit of the non-specific lethal epigenetic remodelling complex. In the current study, we show that contrary to KAT5 inhibition, dual inhibition of KAT5 and KAT8 via the MG149 compound inhibits the initial steps of the PINK1-dependant mitophagy process. More specifically, our study shows that following mitochondrial depolarisation induced by mitochondrial toxins, MG149 treatment inhibits PINK1-dependant mitophagy initiation by impairing PINK1 activation, and subsequent phosphorylation of Parkin and ubiquitin. While this inhibitory effect of MG149 on PINK1-activation is potent, MG149 treatment in the absence of mitochondrial toxins is sufficient to depolarise the mitochondrial membrane, recruit PINK1 and promote partial downstream recruitment of the autophagy receptor p62, leading to an increase in mitochondrial delivery to the lysosomes. Altogether, our study provides additional support for KAT8 as a regulator of mitophagy and autophagy processes.

Keywords:  Autophagy; KAT8; MG149; Mitophagy; Parkinson’s disease

DOI:  https://doi.org/10.1038/s41598-024-60602-9
Research (Wash D C). 2024 ;7 0378

Melatonin Mitigates Atrazine-Induced Renal Tubular Epithelial Cell Senescence by Promoting Parkin-Mediated Mitophagy.

Yu-Sheng Shi, Tian-Ning Yang, Yu-Xiang Wang, Xiang-Yu Ma, Shuo Liu, Yi Zhao, Jin-Long Li.

The accumulation of senescent cells in kidneys is considered to contribute to age-related diseases and organismal aging. Mitochondria are considered a regulator of cell senescence process. Atrazine as a triazine herbicide poses a threat to renal health by disrupting mitochondrial homeostasis. Melatonin plays a critical role in maintaining mitochondrial homeostasis. The present study aims to explore the mechanism by which melatonin alleviates atrazine-induced renal injury and whether parkin-mediated mitophagy contributes to mitigating cell senescence. The study found that the level of parkin was decreased after atrazine exposure and negatively correlated with senescent markers. Melatonin treatment increased serum melatonin levels and mitigates atrazine-induced renal tubular epithelial cell senescence. Mechanistically, melatonin maintains the integrity of mitochondrial crista structure by increasing the levels of mitochondrial contact site and cristae organizing system, mitochondrial transcription factor A (TFAM), adenosine triphosphatase family AAA domain-containing protein 3A (ATAD3A), and sorting and assembly machinery 50 (Sam50) to prevent mitochondrial DNA release and subsequent activation of cyclic guanosine 5'-monophosphate-adenosine 5'-monophosphate synthase pathway. Furthermore, melatonin activates Sirtuin 3-superoxide dismutase 2 axis to eliminate the accumulation of reactive oxygen species in the kidney. More importantly, the antisenescence role of melatonin is largely determined by the activation of parkin-dependent mitophagy. These results offer novel insights into measures against cell senescence. Parkin-mediated mitophagy is a promising drug target for alleviating renal tubular epithelial cell senescence.

DOI: https://doi.org/10.34133/research.0378
FEBS Open Bio. 2024 May 17.

Serine 39 in the GTP-binding domain of Drp1 is involved in shaping mitochondrial morphology.

Marvi Ghani, Bernadett Szabó, Mahmoud Alkhatibe, Hailemariam Amsalu, Peleg Zohar, Eszter Anna Janka, János András Mótyán, Krisztina Tar.

  Continuous fusion and fission are critical for mitochondrial health. In this study, we further characterize the role played by dynamin-related protein 1 (Drp1) in mitochondrial fission. We show that a single amino acid change in Drp1 at position 39 from serine to alanine (S39A) within the GTP-binding (GTPase) domain results in a fused mitochondrial network in human SH-SY5Y neuroblastoma cells. Interestingly, the phosphorylation of Ser-616 and Ser-637 of Drp1 remains unaffected by the S39A mutation, and mitochondrial bioenergetic profile and cell viability in the S39A mutant were comparable to those observed in the control. This leads us to propose that the serine 39 residue of Drp1 plays a crucial role in mitochondrial distribution through its involvement in the GTPase activity. Furthermore, this amino acid mutation leads to structural anomalies in the mitochondrial network. Taken together, our results contribute to a better understanding of the function of the Drp1 protein.

Keywords:  Drp1; S39A; mitochondrial network collapse; single amino acid mutagenesis

DOI:  https://doi.org/10.1002/2211-5463.13820
Nat Rev Cardiol. 2024 May 21.

Artificially transplanted mitochondria in endothelial cells promote mitophagy.

Karina Huynh.

DOI: https://doi.org/10.1038/s41569-024-01041-x
Biochem Biophys Res Commun. 2024 May 14. pii: S0006-291X(24)00655-7. [Epub ahead of print]721 150119

Impaired mitochondrial morphological plasticity and failure of mitophagy associated with the G11778A mutation of LHON.

Bryce A Pasqualotto, Alexa Nelson, Samineh Deheshi, Claire A Sheldon, A Wayne Vogl, Gordon L Rintoul.

  Mitochondrial dynamics were examined in human dermal fibroblasts biopsied from a confirmed Leber's Hereditary Optic Neuropathy (LHON) patient with a homoplasmic G11778A mutation of the mitochondrial genome. Expression of the G11778A mutation did not impart any discernible difference in mitochondrial network morphology using widefield fluorescence microscopy. However, at the ultrastructural level, cells expressing this mutation exhibited an impairment of mitochondrial morphological plasticity when forced to utilize oxidative phosphorylation (OXPHOS) by transition to glucose-free, galactose-containing media. LHON fibroblasts also displayed a transient increase in mitophagy upon transition to galactose media. These results provide new insights into the consequences of the G11778A mutation of LHON and the pathological mechanisms underlying this disease.

Keywords:  G11778A; Galactose; LHON; Mitochondrial morphology; Mitophagy

DOI:  https://doi.org/10.1016/j.bbrc.2024.150119
Int J Med Sci. 2024 ;21(6): 983-993

Pyruvate kinase M2 sustains cardiac mitochondrial integrity in septic cardiomyopathy by regulating PHB2-dependent mitochondrial biogenesis.

Jiaxi Ren, Bin Ren, Tong Fu, Yanchun Ma, Ying Tan, Shuxiang Zhang, Yan Li, Qi Wang, Xing Chang, Ying Tong.

  Previous studies have highlighted the protective effects of pyruvate kinase M2 (PKM2) overexpression in septic cardiomyopathy. In our study, we utilized cardiomyocyte-specific PKM2 knockout mice to further investigate the role of PKM2 in attenuating LPS-induced myocardial dysfunction, focusing on mitochondrial biogenesis and prohibitin 2 (PHB2). Our findings confirmed that the deletion of PKM2 in cardiomyocytes significantly exacerbated LPS-induced myocardial dysfunction, as evidenced by impaired contractile function and relaxation. Additionally, the deletion of PKM2 intensified LPS-induced myocardial inflammation. At the molecular level, LPS triggered mitochondrial dysfunction, characterized by reduced ATP production, compromised mitochondrial respiratory complex I/III activities, and increased ROS production. Intriguingly, the absence of PKM2 further worsened LPS-induced mitochondrial damage. Our molecular investigations revealed that LPS disrupted mitochondrial biogenesis in cardiomyocytes, a disruption that was exacerbated by the absence of PKM2. Given that PHB2 is known as a downstream effector of PKM2, we employed PHB2 adenovirus to restore PHB2 levels. The overexpression of PHB2 normalized mitochondrial biogenesis, restored mitochondrial integrity, and promoted mitochondrial function. Overall, our results underscore the critical role of PKM2 in regulating the progression of septic cardiomyopathy. PKM2 deficiency impeded mitochondrial biogenesis, leading to compromised mitochondrial integrity, increased myocardial inflammation, and impaired cardiac function. The overexpression of PHB2 mitigated the deleterious effects of PKM2 deletion. This discovery offers a novel insight into the molecular mechanisms underlying septic cardiomyopathy and suggests potential therapeutic targets for intervention.

Keywords:  PHB2; PKM2; mitochondrial biogenesis; septic cardiomyopathy

DOI:  https://doi.org/10.7150/ijms.94577
Biomolecules. 2024 May 18. pii: 598. [Epub ahead of print]14(5):

Polydatin and Nicotinamide Rescue the Cellular Phenotype of Mitochondrial Diseases by Mitochondrial Unfolded Protein Response (mtUPR) Activation.

Paula Cilleros-Holgado, David Gómez-Fernández, Rocío Piñero-Pérez, José Manuel Romero Domínguez, Marta Talaverón-Rey, Diana Reche-López, Juan Miguel Suárez-Rivero, Mónica Álvarez-Córdoba, Ana Romero-González, Alejandra López-Cabrera, Marta Castro De Oliveira, Andrés Rodríguez-Sacristan, José Antonio Sánchez-Alcázar.

  Primary mitochondrial diseases result from mutations in nuclear DNA (nDNA) or mitochondrial DNA (mtDNA) genes, encoding proteins crucial for mitochondrial structure or function. Given that few disease-specific therapies are available for mitochondrial diseases, novel treatments to reverse mitochondrial dysfunction are necessary. In this work, we explored new therapeutic options in mitochondrial diseases using fibroblasts and induced neurons derived from patients with mutations in the GFM1 gene. This gene encodes the essential mitochondrial translation elongation factor G1 involved in mitochondrial protein synthesis. Due to the severe mitochondrial defect, mutant GFM1 fibroblasts cannot survive in galactose medium, making them an ideal screening model to test the effectiveness of pharmacological compounds. We found that the combination of polydatin and nicotinamide enabled the survival of mutant GFM1 fibroblasts in stress medium. We also demonstrated that polydatin and nicotinamide upregulated the mitochondrial Unfolded Protein Response (mtUPR), especially the SIRT3 pathway. Activation of mtUPR partially restored mitochondrial protein synthesis and expression, as well as improved cellular bioenergetics. Furthermore, we confirmed the positive effect of the treatment in GFM1 mutant induced neurons obtained by direct reprogramming from patient fibroblasts. Overall, we provide compelling evidence that mtUPR activation is a promising therapeutic strategy for GFM1 mutations.

Keywords:  EF-G1; GFM1; direct reprogramming; fibroblasts; induced neurons; mitochondria; mitochondrial diseases; mtUPR; treatment

DOI:  https://doi.org/10.3390/biom14050598
Free Radic Biol Med. 2024 May 21. pii: S0891-5849(24)00472-6. [Epub ahead of print]

Zinc ions regulate mitochondrial quality control in neurons under oxidative stress and reduce PANoptosis in spinal cord injury models via the Lgals3-Bax pathway.

Mingyu Bai, Yang Cui, Zelin Sang, Shuang Gao, Haosen Zhao, Xifan Mei.

  Spinal cord injury is a serious traumatic nervous system disorder characterized by extensive neuronal apoptosis. Oxidative stress, a key factor in neuronal apoptosis, leads to the accumulation of reactive oxygen species, making mitochondrial quality control within cells crucial. Previous studies have demonstrated zinc's anti-inflammatory and anti-apoptotic properties in protecting mitochondria during spinal cord injury treatment, yet the precise mechanisms remain elusive. Single-cell sequencing analysis has identified Lgals3 and Bax as core genes in apoptosis. This study aimed to investigate whether zinc ions protect intracellular mitochondria by inhibiting the apoptotic proteins Lgals3 and Bax. We elucidated zinc ions' key role in mitigating mitochondrial quality control dysfunction triggered by oxidative stress and confirmed this was achieved by targeting the Lgals3-Bax pathway. Zinc's inhibitory effect on this pathway not only preserved mitochondrial integrity but also significantly reduced PANoptosis after spinal cord injury . Under oxidative stress, zinc ion regulation of mitochondrial quality control reveals an organelle-targeted therapeutic strategy, offering a novel approach for more precise treatment of spinal cord injury.

Keywords:  Mitochondrial quality control; Oxidative stress; PANoptosis; Spinal cord injury; Zinc

DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.05.037
Heliyon. 2024 May 30. 10(10): e30568

SIRT3 and RORα are two prospective targets against mitophagy during simulated ischemia/reperfusion injury in H9c2 cells.

Jinjing Wu, Yanli Yang, Duomao Lin, Zhaoqi Wang, Jun Ma.

  Autophagy during myocardial ischemia/reperfusion (MI/R) exacerbates cardiomyocyte injury. Melatonin (Mel) alleviates myocardial damage by regulating mitochondrial function and mitophagy, but the role of mitophagy in melatonin-induced cardioprotection remains unclear. This study aimed to explore the roles of sirtuin3 (SIRT3) and retinoid-related orphan nuclear receptor-α (RORα) in mitophagy during simulated ischemia reperfusion (SIR) in H9c2 cells. Our data showed that mitophagy was excessively activated after SIR injury, which was consistent with reduced cell survival, enhanced oxidative responses and mitochondrial dysfunction in H9c2 myocytes. Melatonin greatly enhanced cell viability, reduced oxidative stress and improved mitochondrial function. The effects of melatonin protection were involved in excessive mitophagy inhibition, as demonstrated by the reduced levels of mitophagy-linked proteins, including Parkin, Beclin1, NIX and BNIP3, and the LC3 II/LC3 I ratio and elevations in p62. Additionally, the decreases in SIRT3 and RORα in H9c2 myocytes after SIR were reversed by melatonin, and the above effects of melatonin were eliminated by small interfering RNA (siRNA)-mediated knockdown of SIRT3 and RORα. In brief, SIRT3 and RORα are two prospective targets in the cardioprotection of melatonin against mitophagy during SIR in H9c2 myocytes.

Keywords:  Ischemia reperfusion; Melatonin; Mitophagy; Nuclear receptor; SIRT3

DOI:  https://doi.org/10.1016/j.heliyon.2024.e30568
Mitochondrion. 2024 May 17. pii: S1567-7249(24)00062-X. [Epub ahead of print] 101904

Multifaceted role of dynamin-related protein 1 in cardiovascular disease: From mitochondrial fission to therapeutic interventions.

Satinder Kaur, Naina Khullar, Umashanker Navik, Anjana Bali, Gurjit Kaur Bhatti, Jasvinder Singh Bhatti.

  Mitochondria are central to cellular energy production and metabolic regulation, particularly in cardiomyocytes. These organelles constantly undergo cycles of fusion and fission, orchestrated by key proteins like Dynamin-related Protein 1 (Drp-1). This review focuses on the intricate roles of Drp-1 in regulating mitochondrial dynamics, its implications in cardiovascular health, and particularly in myocardial infarction. Drp-1 is not merely a mediator of mitochondrial fission; it also plays pivotal roles in autophagy, mitophagy, apoptosis, and necrosis in cardiac cells. This multifaceted functionality is often modulated through various post-translational alterations, and Drp-1's interaction with intracellular calcium (Ca2 + ) adds another layer of complexity. We also explore the pathological consequences of Drp-1 dysregulation, including increased reactive oxygen species (ROS) production and endothelial dysfunction. Furthermore, this review delves into the potential therapeutic interventions targeting Drp-1 to modulate mitochondrial dynamics and improve cardiovascular outcomes. We highlight recent findings on the interaction between Drp-1 and sirtuin-3 and suggest that understanding this interaction may open new avenues for therapeutically modulating endothelial cells, fibroblasts, and cardiomyocytes. As the cardiovascular system increasingly becomes the focal point of aging and chronic disease research, understanding the nuances of Drp-1's functionality can lead to innovative therapeutic approaches.

Keywords:  Cardiovascular Diseases; Dynamin-related protein 1; Mitochondrial Dynamics; Reactive Oxygen Species; Therapeutics

DOI:  https://doi.org/10.1016/j.mito.2024.101904
iScience. 2024 Jun 21. 27(6): 109860

Opportunistic pathogen Porphyromonas gingivalis targets the LC3B-ceramide complex and mediates lethal mitophagy resistance in oral tumors.

Megan Sheridan, Nityananda Chowdhury, Bridgette Wellslager, Natalia Oleinik, Mohamed Faisal Kassir, Han G Lee, Mindy Engevik, Yuri Peterson, Subramanya Pandruvada, Zdzislaw M Szulc, Özlem Yilmaz, Besim Ogretmen.

  Mechanisms by which Porphyromonas gingivalis (P. gingivalis) infection enhances oral tumor growth or resistance to cell death remain elusive. Here, we determined that P. gingivalis infection mediates therapeutic resistance via inhibiting lethal mitophagy in cancer cells and tumors. Mechanistically, P. gingivalis targets the LC3B-ceramide complex by associating with LC3B via bacterial major fimbriae (FimA) protein, preventing ceramide-dependent mitophagy in response to various therapeutic agents. Moreover, ceramide-mediated mitophagy is induced by Annexin A2 (ANXA2)-ceramide association involving the E142 residue of ANXA2. Inhibition of ANXA2-ceramide-LC3B complex formation by wild-type P. gingivalis prevented ceramide-dependent mitophagy. Moreover, a FimA-deletion mutant P. gingivalis variant had no inhibitory effects on ceramide-dependent mitophagy. Further, 16S rRNA sequencing of oral tumors indicated that P. gingivalis infection altered the microbiome of the tumor macroenvironment in response to ceramide analog treatment in mice. Thus, these data provide a mechanism describing the pro-survival roles of P. gingivalis in oral tumors.

Keywords:  Bacteriology; Cancer; Cell biology; Microbiology; Molecular biology

DOI:  https://doi.org/10.1016/j.isci.2024.109860
Mol Neurobiol. 2024 May 18.

Early Handling Exerts Anxiolytic Effects and Alters Brain Mitochondrial Dynamics in Adult High Anxiety Mice.

Christina Thomou, Markus Nussbaumer, Eleni Grammenou, Chrysoula Komini, Angeliki-Maria Vlaikou, Maria P Papageorgiou, Michaela D Filiou.

  Early handling (EH), the brief separation of pups from their mother during early life, has been shown to exert beneficial effects. However, the impact of EH in a high anxiety background as well as the role of brain mitochondria in shaping EH-driven responses remain elusive.Here, we used a high (HAB) vs. normal (NAB) anxiety-related behavior mouse model to study how EH affects pup and dam behavior in divergent anxiety backgrounds. We also investigated EH-induced effects at the protein and mRNA levels in adult male HAB mice in the hypothalamus, the prefrontal cortex, and the hippocampus by examining the same mitochondrial/energy pathways and mitochondrial dynamics mechanisms (fission, fusion, biogenesis, and mitophagy) in all three brain regions.EH exerts anxiolytic effects in adult HAB but not NAB male mice and does not affect HAB or NAB maternal behavior, although basal HAB vs. NAB maternal behaviors differ. In adult HAB male mice, EH does not impact oxidative phosphorylation (OXPHOS) and oxidative stress in any of the brain regions studied but leads to increased protein expression of glycolysis enzymes and a correlation of anxiety-related behavior with Krebs cycle enzymes in HAB mice in the hypothalamus. Intriguingly, EH alters mitochondrial dynamics by increasing hypothalamic DRP1, OPA1, and PGC1a protein levels. At the mRNA level, we observe altered, EH-driven mitochondrial dynamics mRNA signatures which predominantly affect the prefrontal cortex.Taken together, our results show that EH exerts anxiolytic effects in adulthood in high anxiety and modulates mitochondrial dynamics pathways in a brain region-specific manner.

Keywords:  Early life; HAB; Maternal behavior; Mitochondria; Neonatal handling; Post-natal handling

DOI:  https://doi.org/10.1007/s12035-024-04116-5
iScience. 2024 Jun 21. 27(6): 109834

Mitochondrial clearance and increased HSF-1 activity are coupled to promote longevity in fasted Caenorhabditis elegans.

Nikolaos Tataridas-Pallas, Yahyah Aman, Rhianna Williams, Hannah Chapman, Kevin J H Cheng, Casandra Gomez-Paredes, Gillian P Bates, John Labbadia.

  Fasting has emerged as a potent means of preserving tissue function with age in multiple model organisms. However, our understanding of the relationship between food removal and long-term health is incomplete. Here, we demonstrate that in the nematode worm Caenorhabditis elegans, a single period of early-life fasting is sufficient to selectively enhance HSF-1 activity, maintain proteostasis capacity and promote longevity without compromising fecundity. These effects persist even when food is returned, and are dependent on the mitochondrial sirtuin, SIR-2.2 and the H3K27me3 demethylase, JMJD-3.1. We find that increased HSF-1 activity upon fasting is associated with elevated SIR-2.2 levels, decreased mitochondrial copy number and reduced H3K27me3 levels at the promoters of HSF-1 target genes. Furthermore, consistent with our findings in worms, HSF-1 activity is also enhanced in muscle tissue from fasted mice, suggesting that the potentiation of HSF-1 is a conserved response to food withdrawal.

Keywords:  Biological sciences; Physiology; cell biology; molecular biology

DOI:  https://doi.org/10.1016/j.isci.2024.109834
JACC CardioOncol. 2024 Apr;6(2): 217-232

Anthracycline Cardiotoxicity Induces Progressive Changes in Myocardial Metabolism and Mitochondrial Quality Control: Novel Therapeutic Target.

Anabel Díaz-Guerra, Rocío Villena-Gutiérrez, Agustín Clemente-Moragón, Mónica Gómez, Eduardo Oliver, Miguel Fernández-Tocino, Carlos Galán-Arriola, Laura Cádiz, Borja Ibáñez.

   Background: Anthracycline-induced cardiotoxicity (AIC) debilitates quality of life in cancer survivors. Serial characterizations are lacking of the molecular processes occurring with AIC.
Objectives: The aim of this study was to characterize AIC progression in a mouse model from early (subclinical) to advanced heart failure stages, with an emphasis on cardiac metabolism and mitochondrial structure and function.
Methods: CD1 mice received 5 weekly intraperitoneal doxorubicin injections (5 mg/kg) and were followed by serial echocardiography for 15 weeks. At 1, 9, and 15 weeks after the doxorubicin injections, mice underwent fluorodeoxyglucose positron emission tomography, and hearts were extracted for microscopy and molecular analysis.
Results: Cardiac atrophy was evident at 1 week post-doxorubicin (left ventricular [LV] mass 117 ± 26 mg vs 97 ± 25 mg at baseline and 1 week, respectively; P < 0.001). Cardiac mass nadir was observed at week 3 post-doxorubicin (79 ± 16 mg; P = 0.002 vs baseline), remaining unchanged thereafter. Histology confirmed significantly reduced cardiomyocyte area (167 ± 19 μm2 in doxorubicin-treated mice vs 211 ± 26 μm2 in controls; P = 0.004). LV ejection fraction declined from week 6 post-doxorubicin (49% ± 9% vs 61% ± 9% at baseline; P < 0.001) until the end of follow-up at 15 weeks (43% ± 8%; P < 0.001 vs baseline). At 1 week post-doxorubicin, when LV ejection fraction remained normal, reduced cardiac metabolism was evident from down-regulated markers of fatty acid oxidation and glycolysis. Metabolic impairment continued to the end of follow-up in parallel with reduced mitochondrial adenosine triphosphate production. A transient early up-regulation of nutrient-sensing and mitophagy markers were observed, which was associated with mitochondrial enlargement. Later stages, when mitophagy was exhausted, were characterized by overt mitochondrial fragmentation.
Conclusions: Cardiac atrophy, global hypometabolism, early transient-enhanced mitophagy, biogenesis, and nutrient sensing constitute candidate targets for AIC prevention.

Keywords:  anthracyclines; cancer; cardio-oncology; cardiotoxicity; doxorubicin; mitochondria

DOI:  https://doi.org/10.1016/j.jaccao.2024.02.005
Free Radic Biol Med. 2024 May 17. pii: S0891-5849(24)00459-3. [Epub ahead of print]221 111-124

MCU inhibition protects against intestinal ischemia‒reperfusion by inhibiting Drp1-dependent mitochondrial fission.

Tulanisa Kadier, Yi-Guo Zhang, Yi-Xin Jing, Zi-Yi Weng, Shi-Shi Liao, Jie Luo, Ke Ding, Chen Cao, Rong Chen, Qing-Tao Meng.

  Intestinal ischemia‒reperfusion (IIR) injury is a common complication of surgery, but clear molecular insights and valuable therapeutic targets are lacking. Mitochondrial calcium overload is an early sign of various diseases and is considered a vital factor in ischemia‒reperfusion injury. The mitochondrial calcium uniporter (MCU), which is located on the inner mitochondrial membrane, is the primary mediator of calcium ion entry into the mitochondria. However, the specific mechanism of MCU in IIR injury remains to be clarified. In this study, we generated an IIR model using C57BL/6 mice and Caco-2 cells and found increases in the calcium levels and MCU expression following IIR injury. The specific inhibition of MCU markedly attenuated IIR injury. Moreover, MCU knockdown alleviates mitochondrial dysfunction by reducing oxidative stress and apoptosis. Mechanistically, MCU knockdown substantially reduced the translocation of Drp1 and thus its binding to Fis1 receptors, resulting in decreased mitochondrial fission. Taken together, our findings demonstrated that MCU is a novel upstream regulator of Drp1 in ischemia‒reperfusion and represents a predictive and therapeutic target for IIR.

Keywords:  Intestinal ischemia-reperfusion injury; MCU; Mitochondrial calcium overload; Mitochondrial dynamics

DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.05.024
Cell Mol Life Sci. 2024 May 20. 81(1): 223

PRKN-linked familial Parkinson's disease: cellular and molecular mechanisms of disease-linked variants.

Lene Clausen, Justyna Okarmus, Vasileios Voutsinos, Morten Meyer, Kresten Lindorff-Larsen, Rasmus Hartmann-Petersen.

  Parkinson's disease (PD) is a common and incurable neurodegenerative disorder that arises from the loss of dopaminergic neurons in the substantia nigra and is mainly characterized by progressive loss of motor function. Monogenic familial PD is associated with highly penetrant variants in specific genes, notably the PRKN gene, where homozygous or compound heterozygous loss-of-function variants predominate. PRKN encodes Parkin, an E3 ubiquitin-protein ligase important for protein ubiquitination and mitophagy of damaged mitochondria. Accordingly, Parkin plays a central role in mitochondrial quality control but is itself also subject to a strict protein quality control system that rapidly eliminates certain disease-linked Parkin variants. Here, we summarize the cellular and molecular functions of Parkin, highlighting the various mechanisms by which PRKN gene variants result in loss-of-function. We emphasize the importance of high-throughput assays and computational tools for the clinical classification of PRKN gene variants and how detailed insights into the pathogenic mechanisms of PRKN gene variants may impact the development of personalized therapeutics.

Keywords:  AR-JP; DMS; MAVE; Mitochondria; PARK2; PRKN; Parkinson’s disease; Proteasome; Protein degradation; Protein folding; Protein quality control; Protein stability; Ubiquitin; VUS

DOI:  https://doi.org/10.1007/s00018-024-05262-8
Biochem Biophys Res Commun. 2024 May 16. pii: S0006-291X(24)00654-5. [Epub ahead of print]720 150118

Tectorigenin improves metabolic dysfunction-associated steatohepatitis by down-regulating tRF-3040b and promoting mitophagy to inhibit pyroptosis pathway.

Juanjuan Zhu, Wenmin Tang, Xian Wu, Mao Mu, Quan Zhang, Xueke Zhao.

  Tectorigenin (TEC) as a plant extract has the advantage of low side effects on metabolic dysfunction-associated steatohepatitis (MASH) treatment. Our previous study have shown that tRNA-derived RNA fragments (tRFs) associated with autophagy and pyroptosis in MASH, but whether TEC can mitigate MASH through tRFs-mediated mitophagy is not fully understood. This study aims to investigate whether TEC relies on tRFs to adjust the crosstalk of hepatocyte mitophagy with pyroptosis in MASH. Immunofluorescence results of PINK1 and PRKN with MitoTracker Green-labeled mitochondria verified that TEC enhanced mitophagy. Additionally, TEC inhibited pyroptosis, as reflected by the level of GSDME, NLRP3, IL-1β, and IL-18 decreased after TEC treatment, while the effect of pyroptosis inhibition by TEC was abrogated by Pink1 silencing. We found that the upregulation expression of tRF-3040b caused by MASH was suppressed by TEC. The promotion of mitophagy and the suppression of pyroptosis induced by TEC were abrogated by tRF-3040b mimics. TEC reduced lipid deposition, inflammation, and pyroptosis, and promoted mitophagy in mice, but tRF-3040b agomir inhibited these effects. In summary, our findings provided that TEC significantly reduced the expression of tRF-3040b to enhance mitophagy, thereby inhibiting pyroptosis in MASH. We elucidated a powerful theoretical basis and provided safe and effective potential drugs for MASH with the prevention and treatment.

Keywords:  Metabolic dysfunction-associated steatohepatitis; Mitophagy; Pyroptosis; Tectorigenin; tRNA-derived RNA fragments

DOI:  https://doi.org/10.1016/j.bbrc.2024.150118
Clin Transl Med. 2024 May;14(5): e1686

Rictor/mTORC2 signalling contributes to renal vascular endothelial-to-mesenchymal transition and renal allograft interstitial fibrosis by regulating BNIP3-mediated mitophagy.

Dengyuan Feng, Zeping Gui, Zhen Xu, Jianjian Zhang, Bin Ni, Zijie Wang, Jiawen Liu, Shuang Fei, Hao Chen, Li Sun, Min Gu, Ruoyun Tan.

   BACKGROUND: Renal allograft interstitial fibrosis/tubular atrophy (IF/TA) constitutes the principal histopathological characteristic of chronic allograft dysfunction (CAD) in kidney-transplanted patients. While renal vascular endothelial-mesenchymal transition (EndMT) has been verified as an important contributing factor to IF/TA in CAD patients, its underlying mechanisms remain obscure. Through single-cell transcriptomic analysis, we identified Rictor as a potential pivotal mediator for EndMT. This investigation sought to elucidate the role of Rictor/mTORC2 signalling in the pathogenesis of renal allograft interstitial fibrosis and the associated mechanisms.
METHODS: The influence of the Rictor/mTOR2 pathway on renal vascular EndMT and renal allograft fibrosis was investigated by cell experiments and Rictor depletion in renal allogeneic transplantation mice models. Subsequently, a series of assays were conducted to explore the underlying mechanisms of the enhanced mitophagy and the ameliorated EndMT resulting from Rictor knockout.
RESULTS: Our findings revealed a significant activation of the Rictor/mTORC2 signalling in CAD patients and allogeneic kidney transplanted mice. The suppression of Rictor/mTORC2 signalling alleviated TNFα-induced EndMT in HUVECs. Moreover, Rictor knockout in endothelial cells remarkably ameliorated renal vascular EndMT and allograft interstitial fibrosis in allogeneic kidney transplanted mice. Mechanistically, Rictor knockout resulted in an augmented BNIP3-mediated mitophagy in endothelial cells. Furthermore, Rictor/mTORC2 facilitated the MARCH5-mediated degradation of BNIP3 at the K130 site through K48-linked ubiquitination, thereby regulating mitophagy activity. Subsequent experiments also demonstrated that BNIP3 knockdown nearly reversed the enhanced mitophagy and mitigated EndMT and allograft interstitial fibrosis induced by Rictor knockout.
CONCLUSIONS: Consequently, our study underscores Rictor/mTORC2 signalling as a critical mediator of renal vascular EndMT and allograft interstitial fibrosis progression, exerting its impact through regulating BNIP3-mediated mitophagy. This insight unveils a potential therapeutic target for mitigating renal allograft interstitial fibrosis.

Keywords:  Rictor/mTORC2; mitophagy; renal allograft interstitial fibrosis; vascular endothelial cells

DOI:  https://doi.org/10.1002/ctm2.1686
Int J Mol Sci. 2024 May 17. pii: 5446. [Epub ahead of print]25(10):

Inhibition of Drp1-Filamin Protein Complex Prevents Hepatic Lipid Droplet Accumulation by Increasing Mitochondria-Lipid Droplet Contact.

Kohei Ariyoshi, Kazuhiro Nishiyama, Yuri Kato, Xinya Mi, Tomoya Ito, Yasu-Taka Azuma, Akiyuki Nishimura, Motohiro Nishida.

  Lipid droplet (LD) accumulation in hepatocytes is one of the major symptoms associated with fatty liver disease. Mitochondria play a key role in catabolizing fatty acids for energy production through β-oxidation. The interplay between mitochondria and LD assumes a crucial role in lipid metabolism, while it is obscure how mitochondrial morphology affects systemic lipid metabolism in the liver. We previously reported that cilnidipine, an already existing anti-hypertensive drug, can prevent pathological mitochondrial fission by inhibiting protein-protein interaction between dynamin-related protein 1 (Drp1) and filamin, an actin-binding protein. Here, we found that cilnidipine and its new dihydropyridine (DHP) derivative, 1,4-DHP, which lacks Ca2+ channel-blocking action of cilnidipine, prevent the palmitic acid-induced Drp1-filamin interaction, LD accumulation and cytotoxicity of human hepatic HepG2 cells. Cilnidipine and 1,4-DHP also suppressed the LD accumulation accompanied by reducing mitochondrial contact with LD in obese model and high-fat diet-fed mouse livers. These results propose that targeting the Drp1-filamin interaction become a new strategy for the prevention or treatment of fatty liver disease.

Keywords:  cilnidipine; fatty liver disease; lipid droplet; mitochondria fission

DOI:  https://doi.org/10.3390/ijms25105446
Int J Mol Sci. 2024 May 16. pii: 5425. [Epub ahead of print]25(10):

Lon1 Inactivation Downregulates Autophagic Flux and Brassinosteroid Biogenesis, Modulating Mitochondrial Proportion and Seed Development in Arabidopsis.

Ce Song, Yuqi Hou, Tiantian Li, Yinyin Liu, Xian-Ao Wang, Wumei Qu, Lei Li.

  Mitochondrial protein homeostasis is crucially regulated by protein degradation processes involving both mitochondrial proteases and cytosolic autophagy. However, it remains unclear how plant cells regulate autophagy in the scenario of lacking a major mitochondrial Lon1 protease. In this study, we observed a notable downregulation of core autophagy proteins in Arabidopsis Lon1 knockout mutant lon1-1 and lon1-2, supporting the alterations in the relative proportions of mitochondrial and vacuolar proteins over total proteins in the plant cells. To delve deeper into understanding the roles of the mitochondrial protease Lon1 and autophagy in maintaining mitochondrial protein homeostasis and plant development, we generated the lon1-2atg5-1 double mutant by incorporating the loss-of-function mutation of the autophagy core protein ATG5, known as atg5-1. The double mutant exhibited a blend of phenotypes, characterized by short plants and early senescence, mirroring those observed in the individual single mutants. Accordingly, distinct transcriptome alterations were evident in each of the single mutants, while the double mutant displayed a unique amalgamation of transcriptional responses. Heightened severity, particularly evident in reduced seed numbers and abnormal embryo development, was observed in the double mutant. Notably, aberrations in protein storage vacuoles (PSVs) and oil bodies were evident in the single and double mutants. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses of genes concurrently downregulated in lon1-2, atg5-1, and lon1-2atg5-1 unveiled a significant suppression of genes associated with brassinosteroid (BR) biosynthesis and homeostasis. This downregulation likely contributes to the observed abnormalities in seed and embryo development in the mutants.

Keywords:  Arabidopsis; Lon1; autophagy; brassinosteroid; mitochondrion

DOI:  https://doi.org/10.3390/ijms25105425
Cell Stem Cell. 2024 May 14. pii: S1934-5909(24)00176-0. [Epub ahead of print]

SDHAF1 confers metabolic resilience to aging hematopoietic stem cells by promoting mitochondrial ATP production.

Shintaro Watanuki, Hiroshi Kobayashi, Yuki Sugiura, Masamichi Yamamoto, Daiki Karigane, Kohei Shiroshita, Yuriko Sorimachi, Takayuki Morikawa, Shinya Fujita, Kotaro Shide, Miho Haraguchi, Shinpei Tamaki, Takumi Mikawa, Hiroshi Kondoh, Hiroyasu Nakano, Kenta Sumiyama, Go Nagamatsu, Nobuhito Goda, Shinichiro Okamoto, Ayako Nakamura-Ishizu, Kazuya Shimoda, Makoto Suematsu, Toshio Suda, Keiyo Takubo.

  Aging generally predisposes stem cells to functional decline, impairing tissue homeostasis. Here, we report that hematopoietic stem cells (HSCs) acquire metabolic resilience that promotes cell survival. High-resolution real-time ATP analysis with glucose tracing and metabolic flux analysis revealed that old HSCs reprogram their metabolism to activate the pentose phosphate pathway (PPP), becoming more resistant to oxidative stress and less dependent on glycolytic ATP production at steady state. As a result, old HSCs can survive without glycolysis, adapting to the physiological cytokine environment in bone marrow. Mechanistically, old HSCs enhance mitochondrial complex II metabolism during stress to promote ATP production. Furthermore, increased succinate dehydrogenase assembly factor 1 (SDHAF1) in old HSCs, induced by physiological low-concentration thrombopoietin (TPO) exposure, enables rapid mitochondrial ATP production upon metabolic stress, thereby improving survival. This study provides insight into the acquisition of resilience through metabolic reprogramming in old HSCs and its molecular basis to ameliorate age-related hematopoietic abnormalities.

Keywords:  SDHAF1; adenosine triphosphate; hematopoietic stem cell; mitochondria; stem cell aging; stem cell metabolism; thrombopoietin

DOI:  https://doi.org/10.1016/j.stem.2024.04.023
Signal Transduct Target Ther. 2024 May 24. 9(1): 127

DEAD-box helicase 17 (DDX17) protects cardiac function by promoting mitochondrial homeostasis in heart failure.

Mingjing Yan, Junpeng Gao, Ming Lan, Que Wang, Yuan Cao, Yuxuan Zheng, Yao Yang, Wenlin Li, Xiaoxue Yu, Xiuqing Huang, Lin Dou, Bing Liu, Junmeng Liu, Hongqiang Cheng, Kunfu Ouyang, Kun Xu, Shenghui Sun, Jin Liu, Weiqing Tang, Xiyue Zhang, Yong Man, Liang Sun, Jianping Cai, Qing He, Fuchou Tang, Jian Li, Tao Shen.

DEAD-box helicase 17 (DDX17) is a typical member of the DEAD-box family with transcriptional cofactor activity. Although DDX17 is abundantly expressed in the myocardium, its role in heart is not fully understood. We generated cardiomyocyte-specific Ddx17-knockout mice (Ddx17-cKO), cardiomyocyte-specific Ddx17 transgenic mice (Ddx17-Tg), and various models of cardiomyocyte injury and heart failure (HF). DDX17 is downregulated in the myocardium of mouse models of heart failure and cardiomyocyte injury. Cardiomyocyte-specific knockout of Ddx17 promotes autophagic flux blockage and cardiomyocyte apoptosis, leading to progressive cardiac dysfunction, maladaptive remodeling and progression to heart failure. Restoration of DDX17 expression in cardiomyocytes protects cardiac function under pathological conditions. Further studies showed that DDX17 can bind to the transcriptional repressor B-cell lymphoma 6 (BCL6) and inhibit the expression of dynamin-related protein 1 (DRP1). When DDX17 expression is reduced, transcriptional repression of BCL6 is attenuated, leading to increased DRP1 expression and mitochondrial fission, which in turn leads to impaired mitochondrial homeostasis and heart failure. We also investigated the correlation of DDX17 expression with cardiac function and DRP1 expression in myocardial biopsy samples from patients with heart failure. These findings suggest that DDX17 protects cardiac function by promoting mitochondrial homeostasis through the BCL6-DRP1 pathway in heart failure.

DOI: https://doi.org/10.1038/s41392-024-01831-2
iScience. 2024 Jun 21. 27(6): 109874

Systemic phospho-defective and phospho-mimetic Drp1 mice exhibit normal growth and development with altered anxiety-like behavior.

Arisa Ikeda, Miho Iijima, Hiromi Sesaki.

  Mitochondrial division controls the size, distribution, and turnover of this essential organelle. A dynamin-related GTPase, Drp1, drives membrane division as a force-generating mechano-chemical enzyme. Drp1 is regulated by multiple mechanisms, including phosphorylation at two primary sites: serine 579 and serine 600. While previous studies in cell culture systems have shown that Drp1 S579 phosphorylation promotes mitochondrial division, its physiological functions remained unclear. Here, we generated phospho-mimetic Drp1 S579D and phospho-defective Drp1 S579R mice using the CRISPR-Cas system. Both mouse models exhibited normal growth, development, and breeding. We found that Drp1 is highly phosphorylated at S579 in brain neurons. Notably, the Drp1 S579D mice showed decreased anxiety-like behaviors, whereas the Drp1 S579R mice displayed increased anxiety-like behaviors. These findings suggest a critical role for Drp1 S579 phosphorylation in brain function. The Drp1 S579D and S579R mice thus offer valuable in vivo models for specific analysis of Drp1 S579 phosphorylation.

Keywords:  Behavioral neuroscience; Biochemistry; Developmental neuroscience; Molecular biology; Molecular neuroscience; Neuroscience

DOI:  https://doi.org/10.1016/j.isci.2024.109874
J Transl Med. 2024 May 21. 22(1): 485

UBXN1 promotes liver tumorigenesis by regulating mitochondrial homeostasis.

Kun Jiao, Guiqin Xu, Yun Liu, Zhaojuan Yang, Lvzhu Xiang, Zehong Chen, Chen Xu, You Zuo, Zhibai Wu, Ningqian Zheng, Wangjie Xu, Li Zhang, Yongzhong Liu.

   BACKGROUND: The maintenance of mitochondrial homeostasis is critical for tumor initiation and malignant progression because it increases tumor cell survival and growth. The molecular events controlling mitochondrial integrity that facilitate the development of hepatocellular carcinoma (HCC) remain unclear. Here, we report that UBX domain-containing protein 1 (UBXN1) hyperactivation is essential for mitochondrial homeostasis and liver tumorigenesis.
METHODS: Oncogene-induced mouse liver tumor models were generated with the Sleeping Beauty (SB) transposon delivery system. Assessment of HCC cell growth in vivo and in vitro, including tumour formation, colony formation, TUNEL and FACS assays, was conducted to determine the effects of UBXN1 on HCC cells, as well as the involvement of the UBXN1-prohibitin (PHB) interaction in mitochondrial function. Coimmunoprecipitation (Co-IP) was used to assess the interaction between UBXN1 and PHB. Liver hepatocellular carcinoma (LIHC) datasets and HCC patient samples were used to assess the expression of UBXN1.
RESULTS: UBXN1 expression is commonly upregulated in human HCCs and mouse liver tumors and is associated with poor overall survival in HCC patients. UBXN1 facilitates the growth of human HCC cells and promotes mouse liver tumorigenesis driven by the NRas/c-Myc or c-Myc/shp53 combination. UBXN1 interacts with the inner mitochondrial membrane protein PHB and sustains PHB expression. UBXN1 inhibition triggers mitochondrial damage and liver tumor cell apoptosis.
CONCLUSIONS: UBXN1 interacts with PHB and promotes mitochondrial homeostasis during liver tumorigenesis.

Keywords:  Apoptosis; Hepatocellular carcinoma; Mitochondrial homeostasis; PHB; UBXN1

DOI:  https://doi.org/10.1186/s12967-024-05208-5
Cells. 2024 May 18. pii: 872. [Epub ahead of print]13(10):

Melatonin Ameliorates Post-Stroke Cognitive Impairment in Mice by Inhibiting Excessive Mitophagy.

Yan Shi, Qian Fang, Yue Hu, Zhaoyu Mi, Shuting Luo, Yaoxue Gan, Shishan Yuan.

  Post-stroke cognitive impairment (PSCI) remains the most common consequence of ischemic stroke. In this study, we aimed to investigate the role and mechanisms of melatonin (MT) in improving cognitive dysfunction in stroke mice. We used CoCl2-induced hypoxia-injured SH-SY5Y cells as a cellular model of stroke and photothrombotic-induced ischemic stroke mice as an animal model. We found that the stroke-induced upregulation of mitophagy, apoptosis, and neuronal synaptic plasticity was impaired both in vivo and in vitro. The results of the novel object recognition test and Y-maze showed significant cognitive deficits in the stroke mice, and Nissl staining showed a loss of neurons in the stroke mice. In contrast, MT inhibited excessive mitophagy both in vivo and in vitro and decreased the levels of mitophagy proteins PINK1 and Parkin, and immunofluorescence staining showed reduced co-localization of Tom20 and LC3. A significant inhibition of mitophagy levels could be directly observed under transmission electron microscopy. Furthermore, behavioral experiments and Nissl staining showed that MT ameliorated cognitive deficits and reduced neuronal loss in mice following a stroke. Our results demonstrated that MT inhibits excessive mitophagy and improves PSCI. These findings highlight the potential of MT as a preventive drug for PSCI, offering promising therapeutic implications.

Keywords:  melatonin; mitophagy; neuroprotective; post-stroke cognitive impairment; synaptic plasticity

DOI:  https://doi.org/10.3390/cells13100872
J Transl Med. 2024 May 21. 22(1): 479

Lactate facilitated mitochondrial fission-derived ROS to promote pulmonary fibrosis via ERK/DRP-1 signaling.

Zhiheng Sun, Zhihua Ji, Huiwen Meng, Wanyu He, Bin Li, Xiaoyue Pan, Yanlin Zhou, Guoying Yu.

  Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrotic interstitial lung diseases, which mainly existed in middle-aged and elderly people. The accumulation of reactive oxygen species (ROS) is a common characteristic of IPF. Previous research also shown that lactate levels can be abnormally elevated in IPF patients. Emerging evidence suggested a relationship between lactate and ROS in IPF which needs further elucidation. In this article, we utilized a mouse model of BLM-induced pulmonary fibrosis to detect alterations in ROS levels and other indicators associated with fibrosis. Lactate could induce mitochondrial fragmentation by modulating expression and activity of DRP1 and ERK. Moreover, Increased ROS promoted P65 translocation into nucleus, leading to expression of lung fibrotic markers. Finally, Ulixertinib, Mdivi-1 and Mito-TEMPO, which were inhibitor activity of ERK, DRP1 and mtROS, respectively, could effectively prevented mitochondrial damage and production of ROS and eventually alleviate pulmonary fibrosis. Taken together, these findings suggested that lactate could promote lung fibrosis by increasing mitochondrial fission-derived ROS via ERK/DRP1 signaling, which may provide novel therapeutic solutions for IPF.

Keywords:  DRP1; Idiopathic pulmonary fibrosis; Lactate; Mitochondrial fission; Reactive oxygen species

DOI:  https://doi.org/10.1186/s12967-024-05289-2
Redox Biol. 2024 May 16. pii: S2213-2317(24)00174-5. [Epub ahead of print]73 103196

Nlrp6 protects from corticosterone-induced NSPC ferroptosis by modulating RIG-1/MAVS-mediated mitophagy.

Jingyan Shen, Pengfei Xie, Junhan Wang, Fan Yang, Shengjie Li, Haitao Jiang, Xuefeng Wu, Feng Zhou, Jianmei Li.

  Hippocampal neural stem/progenitor cells (NSPCs) are highly vulnerable to different stress stimuli, resulting in adult neurogenesis decline and eventual cognitive defects. Our previous study demonstrated that NOD-like receptor family pyrin domain-containing 6 (Nlrp6) highly expressed in NSPCs played a critical role in sustaining hippocampal neurogenesis to resist stress-induced depression, but the underlying mechnistms are still unclear. Here, we found that Nlrp6 depletion led to cognitive defects and hippocampal NSPC loss in mice. RNA-sequencing analysis of the primary NSPCs revealed that Nlrp6 deficiency altered gene expression profiles of mitochondrial energy generation and ferroptotic process. Upon siNlrp6 transfection, as well as corticosterone (CORT) exposure, downregulation of Nlrp6 suppressed retinoic acid-inducible gene I (RIG-1)/mitochondrial antiviral signaling proteins (MAVS)-mediated autophagy, but drove NSPC ferroptotic death. More interesting, short chain fatty acids (SCFAs) upregulated Nlrp6 expression and promoted RIG-1/MAVS-mediated mitophagy, preventing CORT-induced NSPC ferroptosis. Our study further demonstrates that Nlrp6 should be a sensor for RIG-1/MAVS-mediated mitophagy and play a critical role in maintain mitochondrial homeostasis of hippocampal NSPCs. These results suggests that Nlrp6 should be a potential drug target to combat neurodegenerative diseases relative with chronic stress.

Keywords:  Cognitive defects; Mitochondrial disorders; Mitophagy; NOD-Like receptor family pyrin domain-containing 6; NSPC ferroptosis

DOI:  https://doi.org/10.1016/j.redox.2024.103196
Brain. 2024 May 20. pii: awae038. [Epub ahead of print]

Imbalanced mitochondrial dynamics contributes to the pathogenesis of X-linked adrenoleukodystrophy.

Nathalie Launay, Jone Lopez-Erauskin, Patrizia Bianchi, Sanjib Guha, Janani Parameswaran, Andrea Coppa, Lorenzo Torreni, Agatha Schlüter, Stéphane Fourcade, Abraham J Paredes-Fuentes, Rafael Artuch, Carlos Casasnovas, Montserrat Ruiz, Aurora Pujol.

  The peroxisomal disease adrenoleukodystrophy (X-ALD) is caused by loss of the transporter of very-long-chain fatty acids (VLCFAs), ABCD1. An excess of VLCFAs disrupts essential homeostatic functions crucial for axonal maintenance, including redox metabolism, glycolysis and mitochondrial respiration. As mitochondrial function and morphology are intertwined, we set out to investigate the role of mitochondrial dynamics in X-ALD models. Using quantitative 3D transmission electron microscopy, we revealed mitochondrial fragmentation in corticospinal axons in Abcd1- mice. In patient fibroblasts, an excess of VLCFAs triggers mitochondrial fragmentation through the redox-dependent phosphorylation of DRP1 (DRP1S616). The blockade of DRP1-driven fission by the peptide P110 effectively preserved mitochondrial morphology. Furthermore, mRNA inhibition of DRP1 not only prevented mitochondrial fragmentation but also protected axonal health in a Caenorhabditis elegans model of X-ALD, underscoring DRP1 as a potential therapeutic target. Elevated levels of circulating cell-free mtDNA in patients' CSF align this leukodystrophy with primary mitochondrial disorders. Our findings underscore the intricate interplay between peroxisomal dysfunction, mitochondrial dynamics and axonal integrity in X-ALD, shedding light on potential avenues for therapeutic intervention.

Keywords:  DRP1; P110; VLCFA; X-ALD; ccfmtDNA; mitochondrial dynamics

DOI:  https://doi.org/10.1093/brain/awae038
Sheng Wu Gong Cheng Xue Bao. 2024 May 25. 40(5): 1509-1522

[Prdx1 regulates macrophage polarization by maintaining mitochondrial homeostasis].

Xiang Zhang, Ziyue Zhang, Yiming Qi, Xiaona Zhang, Songna Yin.

  In order to investigate the role of Prdx1 in macrophage polarization, mouse leukemia cells of monocyte macrophage (RAW264.7) were treated with lipopolysaccharides (LPS)+ interferon gamma (IFNγ) or IL-4 to induce type 1 macrophage (M1) and type 1 macrophage (M2) macrophages, respectively. The Prdx1 gene knockout cells (Prdx1-/-) were used for the study. Flow cytometry was conducted to detect M1/M2 macrophage markers, and ELISA kits were used to measure M1/M2 cytokine levels. Inducible nitric-oxide synthase (iNOS) activity, arginase-1 (Arg-1) activity, and oxidative damage were also assessed. The Seahorse XFe24 Extracellular Flux Analyzer was employed to measure extracellular acidification rate and oxygen consumption rate. The mitochondrial membrane potential was analyzed using the mitochondrial membrane potential dye (JC-1) fluorescent probe, and mitochondrial superoxide was detected through fluorescence staining. Additionally, the impact of adding a mitochondrial reactive oxygen species (ROS) scavenger on RAW264.7 macrophage polarization was examined. The results demonstrated an increase in ROS, hydrogen peroxide, and 8-hydroxy-2 deoxyguanosine (8-OHDG). Cytotoxicity and mitochondrial toxic effects, including mitochondrial superoxide accumulation, decreased adenosine-triphosphate (ATP) production, reduced mitochondrial membrane potential, and decreased mitochondrial DNA copy number, were observed. Furthermore, down-regulation of translocase of inner mitochondrial membrane 23 (TIM23) mitochondrial protein and mitochondrial stress protein heat shock protein 60 (HSP60) was noted. The extra cellular acidification rate (ECAR) in M1 macrophage polarization in RAW264.7 cells was increased, while oxygen consumption rate (OCR) in M2 macrophages was reduced. These findings indicate that Prdx1 knockout in RAW264.7 cells can inhibit M2 macrophage polarization but promote M1 macrophage polarization by impairing mitochondrial function and reducing oxidative phosphorylation.

Keywords:  Prdx1; macrophage; mitochondria; polarization

DOI:  https://doi.org/10.13345/j.cjb.230667
Biochem Biophys Rep. 2024 Jul;38 101730

Mitophagy in spermatogenesis: Roles and mechanisms.

Nabil Eid, Md Abdul Alim Al-Bari.

DOI: https://doi.org/10.1016/j.bbrep.2024.101730
Antioxidants (Basel). 2024 May 06. pii: 571. [Epub ahead of print]13(5):

Roles of O-GlcNAcylation in Mitochondrial Homeostasis and Cardiovascular Diseases.

Zhen Qiu, Jiahui Cui, Qin Huang, Biao Qi, Zhongyuan Xia.

  Protein posttranslational modifications are important factors that mediate the fine regulation of signaling molecules. O-linked β-N-acetylglucosamine-modification (O-GlcNAcylation) is a monosaccharide modification on N-acetylglucosamine linked to the hydroxyl terminus of serine and threonine of proteins. O-GlcNAcylation is responsive to cellular stress as a reversible and posttranslational modification of nuclear, mitochondrial and cytoplasmic proteins. Mitochondrial proteins are the main targets of O-GlcNAcylation and O-GlcNAcylation is a key regulator of mitochondrial homeostasis by directly regulating the mitochondrial proteome or protein activity and function. Disruption of O-GlcNAcylation is closely related to mitochondrial dysfunction. More importantly, the O-GlcNAcylation of cardiac proteins has been proven to be protective or harmful to cardiac function. Mitochondrial homeostasis is crucial for cardiac contractile function and myocardial cell metabolism, and the imbalance of mitochondrial homeostasis plays a crucial role in the pathogenesis of cardiovascular diseases (CVDs). In this review, we will focus on the interactions between protein O-GlcNAcylation and mitochondrial homeostasis and provide insights on the role of mitochondrial protein O-GlcNAcylation in CVDs.

Keywords:  O-GlcNAcylation; cardiovascular diseases; mitochondrial homeostasis; mitochondrial protein; posttranslational modification

DOI:  https://doi.org/10.3390/antiox13050571