bims-mikwok 2024-02-25 papers

bims-mikwok

Biomed News

on Mitochondrial quality control

Issue of 2024‒02‒25
28 papers selected by
Gavin McStay, Liverpool John Moores University

Exposure of the inner mitochondrial membrane triggers apoptotic mitophagy.
Notoginsenoside R1 improves intestinal microvascular functioning in sepsis by targeting Drp1-mediated mitochondrial quality imbalance.
Effect of CB1 Receptor Deficiency on Mitochondrial Quality Control Pathways in Gastrocnemius Muscle.
Identification of MIMAS, a multifunctional mega-assembly integrating metabolic and respiratory biogenesis factors of mitochondria.
Stalled translation by mitochondrial stress upregulates a CNOT4-ZNF598 ribosomal quality control pathway important for tissue homeostasis.
MIMAS is a new giant multifunctional player in the mitochondrial megacomplex playground.
The role of mitochondrial quality control mechanisms in chondrocyte senescence.
Mechanism and role of mitophagy in the development of severe infection.
ALLO-1- and IKKE-1-dependent positive feedback mechanism promotes the initiation of paternal mitochondrial autophagy.
MFN2 overexpression in skeletal muscles of young and old mice causes a mild hypertrophy without altering mitochondrial respiration and H2 O2 emission.
Gonococcal OMV-delivered PorB induces epithelial cell mitophagy.
Baicalein ameliorated obesity-induced cardiac dysfunction by regulating the mitochondrial unfolded protein response through NRF2 signaling.
Mitochondrial fission inhibition protects against hypertension induced by angiotensin II.
Mitochondria and MICOS - function and modeling.
GOLPH3 Participates in Mitochondrial Fission and Is Necessary to Sustain Bioenergetic Function in MDA-MB-231 Breast Cancer Cells.
Mitophagy regulates mitochondrial number following pharmacological induction of mitochondrial biogenesis in renal proximal tubule cells.
Role of the small protein Mco6 in the mitochondrial sorting and assembly machinery.
Mitochondrial quality control alterations and placenta-related disorders.
A New Mitochondrial Uncoupler Improves Metabolic Homeostasis in Mice.
Author Correction: Mitophagy curtails cytosolic mtDNA-dependent activation of cGAS/STING inflammation during aging.
Disturbance of mitochondrial dynamics in myocardium of broilers with pulmonary hypertension syndrome.
Mitochondrial Quantity and Quality in Age-Related Sarcopenia.
Pulsed Hyperoxia Acts on Plasmatic Advanced Glycation End Products and Advanced Oxidation Protein Products and Modulates Mitochondrial Biogenesis in Human Peripheral Blood Mononuclear Cells: A Pilot Study on the "Normobaric Oxygen Paradox".
Ubiquitin Ligase Parkin Regulates the Stability of SARS-CoV-2 Main Protease and Suppresses Viral Replication.
Regulatory mechanism of perinatal nonylphenol exposure on cardiac mitochondrial autophagy and the PINK1/Parkin signaling pathway in male offspring rats.
Targeting SIRT3 sensitizes glioblastoma to ferroptosis by promoting mitophagy and inhibiting SLC7A11.
Transcription Factor TFAP2B Exerts Neuroprotective Effects Targeting BNIP3-Mediated Mitophagy in Ischemia/Reperfusion Injury.
Identification of mitophagy-related hub genes during the progression of spinal cord injury by integrated multinomial bioinformatics analysis.

Cell Death Differ. 2024 Feb 23.

Exposure of the inner mitochondrial membrane triggers apoptotic mitophagy.

Tahnee L Saunders, Simon P Windley, Gediminas Gervinskas, Katherine R Balka, Caitlin Rowe, Rachael Lane, Maximilien Tailler, Thanh Ngoc Nguyen, Georg Ramm, Michael Lazarou, Dominic De Nardo, Benjamin T Kile, Kate McArthur.

During apoptosis mediated by the intrinsic pathway, BAX/BAK triggers mitochondrial permeabilization and the release of cytochrome-c, followed by a dramatic remodelling of the mitochondrial network that results in mitochondrial herniation and the subsequent release of pro-inflammatory mitochondrial components. Here, we show that mitochondrial herniation and subsequent exposure of the inner mitochondrial membrane (IMM) to the cytoplasm, initiates a unique form of mitophagy to deliver these damaged organelles to lysosomes. IMM-induced mitophagy occurs independently of canonical PINK1/Parkin signalling and is driven by ubiquitination of the IMM. Our data suggest IMM-induced mitophagy is an additional safety mechanism that cells can deploy to contain damaged mitochondria. It may have particular relevance in situations where caspase activation is incomplete or inhibited, and in contexts where PINK1/Parkin-mitophagy is impaired or overwhelmed.

DOI: https://doi.org/10.1038/s41418-024-01260-2
Pharm Biol. 2024 Dec;62(1): 250-260

Notoginsenoside R1 improves intestinal microvascular functioning in sepsis by targeting Drp1-mediated mitochondrial quality imbalance.

Dongyao Hou, Ruixue Liu, Shuai Hao, Yong Dou, Guizhen Chen, Liangming Liu, Tao Li, Yunxing Cao, He Huang, Chenyang Duan.

  CONTEXT: Sepsis can result in critical organ failure, and notoginsenoside R1 (NGR1) offers mitochondrial protection.OBJECTIVE: To determine whether NGR1 improves organ function and prognosis after sepsis by protecting mitochondrial quality.
MATERIALS AND METHODS: A sepsis model was established in C57BL/6 mice using cecum ligation puncture (CLP) and an in vitro model with lipopolysaccharide (LPS, 10 µg/mL)-stimulated primary intestinal microvascular endothelial cells (IMVECs) and then determine NGR1's safe dosage. Groups for each model were: in vivo-a control group, a CLP-induced sepsis group, and a CLP + NGR1 treatment group (30 mg/kg/d for 3 d); in vitro-a control group, a LPS-induced sepsis group, and a LPS + NGR1 treatment group (4 μM for 30 min). NGR1's effects on survival, intestinal function, mitochondrial quality, and mitochondrial dynamic-related protein (Drp1) were evaluated.
RESULTS: Sepsis resulted in approximately 60% mortality within 7 days post-CLP, with significant reductions in intestinal microvascular perfusion and increases in vascular leakage. Severe mitochondrial quality imbalance was observed in IMVECs. NGR1 (IC50 is 854.1 μM at 30 min) targeted Drp1, inhibiting mitochondrial translocation, preventing mitochondrial fragmentation and restoring IMVEC morphology and function, thus protecting against intestinal barrier dysfunction, vascular permeability, microcirculatory flow, and improving sepsis prognosis.
DISCUSSION AND CONCLUSIONS: Drp1-mediated mitochondrial quality imbalance is a potential therapeutic target for sepsis. Small molecule natural drugs like NGR1 targeting Drp1 may offer new directions for organ protection following sepsis. Future research should focus on clinical trials to evaluate NGR1's efficacy across various patient populations, potentially leading to novel treatments for sepsis.

Keywords:  Drp1; Traditional Chinese medicine; mitochondria; sepsis

DOI:  https://doi.org/10.1080/13880209.2024.2318349
Biology (Basel). 2024 Feb 11. pii: 116. [Epub ahead of print]13(2):

Effect of CB1 Receptor Deficiency on Mitochondrial Quality Control Pathways in Gastrocnemius Muscle.

Rosalba Senese, Giuseppe Petito, Elena Silvestri, Maria Ventriglia, Nicola Mosca, Nicoletta Potenza, Aniello Russo, Francesco Manfrevola, Gilda Cobellis, Teresa Chioccarelli, Veronica Porreca, Vincenza Grazia Mele, Rosanna Chianese, Pieter de Lange, Giulia Ricci, Federica Cioffi, Antonia Lanni.

  This study aims to explore the complex role of cannabinoid type 1 receptor (CB1) signaling in the gastrocnemius muscle, assessing physiological processes in both CB1+/+ and CB1-/- mice. The primary focus is to enhance our understanding of how CB1 contributes to mitochondrial homeostasis. At the tissue level, CB1-/- mice exhibit a substantial miRNA-related alteration in muscle fiber composition, characterized by an enrichment of oxidative fibers. CB1 absence induces a significant increase in the oxidative capacity of muscle, supported by elevated in-gel activity of Complex I and Complex IV of the mitochondrial respiratory chain. The increased oxidative capacity is associated with elevated oxidative stress and impaired antioxidant defense systems. Analysis of mitochondrial biogenesis markers indicates an enhanced capacity for new mitochondria production in CB1-/- mice, possibly adapting to altered muscle fiber composition. Changes in mitochondrial dynamics, mitophagy response, and unfolded protein response (UPR) pathways reveal a dynamic interplay in response to CB1 absence. The interconnected mitochondrial network, influenced by increased fusion and mitochondrial UPR components, underlines the dual role of CB1 in regulating both protein quality control and the generation of new mitochondria. These findings deepen our comprehension of the CB1 impact on muscle physiology, oxidative stress, and MQC processes, highlighting cellular adaptability to CB1-/-. This study paves the way for further exploration of intricate signaling cascades and cross-talk between cellular compartments in the context of CB1 and mitochondrial homeostasis.

Keywords:  cannabinoid type 1 receptor (CB1); miRNA; mitochondria; mitochondrial quality control (MQC); mitochondrial unfolded protein response (UPRmt); skeletal muscle

DOI:  https://doi.org/10.3390/biology13020116
Cell Rep. 2024 Feb 21. pii: S2211-1247(24)00100-1. [Epub ahead of print]43(3): 113772

Identification of MIMAS, a multifunctional mega-assembly integrating metabolic and respiratory biogenesis factors of mitochondria.

Patrick Horten, Kuo Song, Joshua Garlich, Robert Hardt, Lilia Colina-Tenorio, Susanne E Horvath, Uwe Schulte, Bernd Fakler, Martin van der Laan, Thomas Becker, Rosemary A Stuart, Nikolaus Pfanner, Heike Rampelt.

  The mitochondrial inner membrane plays central roles in bioenergetics and metabolism and contains several established membrane protein complexes. Here, we report the identification of a mega-complex of the inner membrane, termed mitochondrial multifunctional assembly (MIMAS). Its large size of 3 MDa explains why MIMAS has escaped detection in the analysis of mitochondria so far. MIMAS combines proteins of diverse functions from respiratory chain assembly to metabolite transport, dehydrogenases, and lipid biosynthesis but not the large established supercomplexes of the respiratory chain, ATP synthase, or prohibitin scaffold. MIMAS integrity depends on the non-bilayer phospholipid phosphatidylethanolamine, in contrast to respiratory supercomplexes whose stability depends on cardiolipin. Our findings suggest that MIMAS forms a protein-lipid mega-assembly in the mitochondrial inner membrane that integrates respiratory biogenesis and metabolic processes in a multifunctional platform.

Keywords:  CP: Metabolism; CP: Molecular biology; membrane protein complex; metabolism; metabolite carriers; mitochondria; phosphatidylethanolamine; phospholipids; protein assembly; respiratory chain

DOI:  https://doi.org/10.1016/j.celrep.2024.113772
Nat Commun. 2024 Feb 22. 15(1): 1637

Stalled translation by mitochondrial stress upregulates a CNOT4-ZNF598 ribosomal quality control pathway important for tissue homeostasis.

Ji Geng, Shuangxi Li, Yu Li, Zhihao Wu, Sunil Bhurtel, Suman Rimal, Danish Khan, Rani Ohja, Onn Brandman, Bingwei Lu.

Translational control exerts immediate effect on the composition, abundance, and integrity of the proteome. Ribosome-associated quality control (RQC) handles ribosomes stalled at the elongation and termination steps of translation, with ZNF598 in mammals and Hel2 in yeast serving as key sensors of translation stalling and coordinators of downstream resolution of collided ribosomes, termination of stalled translation, and removal of faulty translation products. The physiological regulation of RQC in general and ZNF598 in particular in multicellular settings is underexplored. Here we show that ZNF598 undergoes regulatory K63-linked ubiquitination in a CNOT4-dependent manner and is upregulated upon mitochondrial stresses in mammalian cells and Drosophila. ZNF598 promotes resolution of stalled ribosomes and protects against mitochondrial stress in a ubiquitination-dependent fashion. In Drosophila models of neurodegenerative diseases and patient cells, ZNF598 overexpression aborts stalled translation of mitochondrial outer membrane-associated mRNAs, removes faulty translation products causal of disease, and improves mitochondrial and tissue health. These results shed lights on the regulation of ZNF598 and its functional role in mitochondrial and tissue homeostasis.

DOI: https://doi.org/10.1038/s41467-024-45525-3
Cell Rep. 2024 Feb 21. pii: S2211-1247(24)00202-X. [Epub ahead of print]43(3): 113874

MIMAS is a new giant multifunctional player in the mitochondrial megacomplex playground.

Kostas Tokatlidis.

Mitochondria are rich in multi-protein assemblies that are usually dedicated to one function. In this issue of Cell Reports, Horten et al.1 describe a 3-nanometer megacomplex in the mitochondrial inner membrane, which serves multiple functions integrating mitochondria biogenesis and metabolism.

DOI: https://doi.org/10.1016/j.celrep.2024.113874
Exp Gerontol. 2024 Feb 18. pii: S0531-5565(24)00021-4. [Epub ahead of print] 112379

The role of mitochondrial quality control mechanisms in chondrocyte senescence.

Tianlei Zhao, Dawei Niu, Yancheng Chen, Peiliang Fu.

  Chondrocytes are the exclusive cellular constituents of articular cartilage, and their functional status governs the health of the cartilage. The primary factor contributing to the deterioration of cartilage structure and function is chondrocyte senescence. In hypoxia and hypodextrose environment, chondrocytes heavily rely on glycolysis for energy metabolism. Mitochondria, acting as the regulatory hub for chondrocyte energy metabolism, exhibit dysfunction before chondrocyte senescence, indicating their crucial involvement in the process. Previous research has suggested that molecules associated with mitochondrial quality control mechanisms can effectively restore mitochondrial function and alleviate chondrocyte senescence. However, there remains to be clarity regarding the relationship between mitochondrial quality control mechanisms and differences in efficacy among various target molecules, which pose challenges when evaluating them in chondrocytes. By conducting a comprehensive review of the existing literature on mitochondrial quality control mechanisms and chondrocyte senescence, we gain further insights into this intricate relationship while identifying promising targets that could potentially open up novel avenues for the treatment of chondrocyte senescence.

Keywords:  Aging; Articular cartilage; Cellular senescence; Mitochondrial quality control; Osteoarthritis

DOI:  https://doi.org/10.1016/j.exger.2024.112379
Cell Death Discov. 2024 Feb 19. 10(1): 88

Mechanism and role of mitophagy in the development of severe infection.

Lixiu Ma, Tianyu Han, Yi-An Zhan.

Mitochondria produce adenosine triphosphate and potentially contribute to proinflammatory responses and cell death. Mitophagy, as a conservative phenomenon, scavenges waste mitochondria and their components in the cell. Recent studies suggest that severe infections develop alongside mitochondrial dysfunction and mitophagy abnormalities. Restoring mitophagy protects against excessive inflammation and multiple organ failure in sepsis. Here, we review the normal mitophagy process, its interaction with invading microorganisms and the immune system, and summarize the mechanism of mitophagy dysfunction during severe infection. We highlight critical role of normal mitophagy in preventing severe infection.

DOI: https://doi.org/10.1038/s41420-024-01844-4
Nat Commun. 2024 Feb 17. 15(1): 1460

ALLO-1- and IKKE-1-dependent positive feedback mechanism promotes the initiation of paternal mitochondrial autophagy.

Taeko Sasaki, Yasuharu Kushida, Takuya Norizuki, Hidetaka Kosako, Ken Sato, Miyuki Sato.

Allophagy is responsible for the selective removal of paternally inherited organelles, including mitochondria, in Caenorhabditis elegans embryos, thereby facilitating the maternal inheritance of mitochondrial DNA. We previously identified two key factors in allophagy: an autophagy adaptor allophagy-1 (ALLO-1) and TBK1/IKKε family kinase IKKE-1. However, the precise mechanisms by which ALLO-1 and IKKE-1 regulate local autophagosome formation remain unclear. In this study, we identify two ALLO-1 isoforms with different substrate preferences during allophagy. Live imaging reveals a stepwise mechanism of ALLO-1 localization with rapid cargo recognition, followed by ALLO-1 accumulation around the cargo. In the ikke-1 mutant, the accumulation of ALLO-1, and not the recognition of cargo, is impaired, resulting in the failure of isolation membrane formation. Our results also suggest a feedback mechanism for ALLO-1 accumulation via EPG-7/ATG-11, a worm homolog of FIP200, which is a candidate for IKKE-1-dependent phosphorylation. This feedback mechanism may underlie the ALLO-1-dependent initiation and progression of autophagosome formation around paternal organelles.

DOI: https://doi.org/10.1038/s41467-024-45863-2
Acta Physiol (Oxf). 2024 Feb 23. e14119

MFN2 overexpression in skeletal muscles of young and old mice causes a mild hypertrophy without altering mitochondrial respiration and H2 O2 emission.

Marina Cefis, Manon Dargegen, Vincent Marcangeli, Shima Taherkhani, Maude Dulac, Jean-Philippe Leduc-Gaudet, Dominique Mayaki, Sabah N A Hussain, Gilles Gouspillou.

  AIM: Sarcopenia, the aging-related loss of muscle mass and function, is a debilitating process negatively impacting the quality of life of affected individuals. Although the mechanisms underlying sarcopenia are incompletely understood, impairments in mitochondrial dynamics, including mitochondrial fusion, have been proposed as a contributing factor. However, the potential of upregulating mitochondrial fusion proteins to alleviate the effects of aging on skeletal muscles remains unexplored. We therefore hypothesized that overexpressing Mitofusin 2 (MFN2) in skeletal muscle in vivo would mitigate the effects of aging on muscle mass and improve mitochondrial function.METHODS: MFN2 was overexpressed in young (7 mo) and old (24 mo) male mice for 4 months through intramuscular injections of an adeno-associated viruses. The impacts of MFN2 overexpression on muscle mass and fiber size (histology), mitochondrial respiration, and H2 O2 emission (Oroboros fluororespirometry), and various signaling pathways (qPCR and western blotting) were investigated.
RESULTS: MFN2 overexpression increased muscle mass and fiber size in both young and old mice. No sign of fibrosis, necrosis, or inflammation was found upon MFN2 overexpression, indicating that the hypertrophy triggered by MFN2 overexpression was not pathological. MFN2 overexpression even reduced the proportion of fibers with central nuclei in old muscles. Importantly, MFN2 overexpression had no impact on muscle mitochondrial respiration and H2 O2 emission in both young and old mice. MFN2 overexpression attenuated the increase in markers of impaired autophagy in old muscles.
CONCLUSION: MFN2 overexpression may be a viable approach to mitigate aging-related muscle atrophy and may have applications for other muscle disorders.

Keywords:  autophagy; mitochondria; mitochondrial dynamics; mitochondrial fusion; mitofusin 2; sarcopenia; skeletal muscle aging

DOI:  https://doi.org/10.1111/apha.14119
Nat Commun. 2024 Feb 23. 15(1): 1669

Gonococcal OMV-delivered PorB induces epithelial cell mitophagy.

Shuai Gao, Lingyu Gao, Dailin Yuan, Xu'ai Lin, Stijn van der Veen.

The bacterial pathogen Neisseria gonorrhoeae is able to invade epithelial cells and survive intracellularly. During this process, it secretes outer membrane vesicles (OMVs), however, the mechanistic details for interactions between gonococcal OMVs and epithelial cells and their impact on intracellular survival are currently not established. Here, we show that gonococcal OMVs induce epithelial cell mitophagy to reduce mitochondrial secretion of reactive oxygen species (ROS) and enhance intracellular survival. We demonstrate that OMVs deliver PorB to mitochondria to dissipate the mitochondrial membrane potential, resulting in mitophagy induction through a conventional PINK1 and OPTN/NDP52 mechanism. Furthermore, PorB directly recruits the E3 ubiquitin ligase RNF213, which decorates PorB lysine residue 171 with K63-linked polyubiquitin to induce mitophagy in a p62-dependent manner. These results demonstrate a mechanism in which polyubiquitination of a bacterial virulence factor that targets mitochondria directs mitophagy processes to this organelle to prevent its secretion of deleterious ROS.

DOI: https://doi.org/10.1038/s41467-024-45961-1
Phytomedicine. 2024 Feb 10. pii: S0944-7113(24)00106-5. [Epub ahead of print]126 155441

Baicalein ameliorated obesity-induced cardiac dysfunction by regulating the mitochondrial unfolded protein response through NRF2 signaling.

Lulu Guo, Junle Yang, Wenting Yuan, Chongyao Li, Hui Li, Yang Yang, Runqing Xue, Kangkang Yan.

  BACKGROUND: The mitochondrial unfolded protein response (UPRmt) is the first line of defense against mitochondrial dysfunction in several diseases. Baicalein, which is an extract of Scutellaria baicalensis Georgi roots, exerts mitoprotective effects on metabolic disorders and cardiovascular diseases. However, it remains unclear whether baicalein alleviates obesity-induced cardiac damage through the UPRmt.PURPOSE: The present research designed to clarify the role of baicalein in lipotoxicity-induced myocardial apoptosis and investigated the UPRmt-related mechanism.
METHODS: In the in vitro experiment, palmitic acid (PA)-treated AC16 cardiomyocytes were established to mimic obesity-induced myocardial injury. After pretreatment of AC16 cells with baicalein, the levels of cell vitality, apoptosis, mitochondrial membrane potential, mitochondrial oxidative stress, and UPRmt-related proteins were determined. Additionally, AC16 cells were treated with ML385 or siRNA to explore the regulation of the UPRmt by NRF2 signaling. In the in vivo experiment, male db/db mice administered with baicalein for 8 weeks were used to validate the effects of baicalein on cardiac damage induced by obesity, the UPRmt, and the NRF2-related pathway.
RESULTS: In AC16 cardiomyocytes, PA dose-dependently increased the expression of UPRmt markers (HSP60, LONP1, ATF4, and ATF5). This increase was accompanied by enhanced production of mitochondrial ROS, reduced mitochondrial membrane potential, and elevated the expression levels of cytochrome c, cleaved caspase-3, and Bax/Bcl2, eventually leading to cell apoptosis. Baicalein treatment reversed UPRmt activation and mitochondrial damage and impeded mitochondrial-mediated cell apoptosis. Moreover, NRF2 downregulation by its inhibitor ML385 or siRNA diminished baicalein-mediated NRF2 signaling activation and UPRmt inhibition and triggered mitochondrial dysfunction. Additionally, NRF2 deficiency more intensely activated the UPRmt, resulting in mitochondrial oxidative stress and apoptosis of PA-induced cardiomyocytes, thus indicating that NRF2 plays a vital role in mitochondrial homeostasis regulation. In the in vivo study in db/db mice, baicalein inhibited the UPRmt, enhanced the antioxidant capacity, and attenuated cardiac dysfunction through a NRF2-activated pathway.
CONCLUSION: To our best knowledge, these results provide the first insight that baicalein inhibits the UPRmt to induce a protective effect against lipotoxicity-induced mitochondrial damage and cardiomyocyte apoptosis via activating NRF2 signaling and suggest a new role of NRF2 in UPRmt regulation.

Keywords:  Baicalein; Cardiomyocyte apoptosis; NRF2; Obesity; UPR(mt)

DOI:  https://doi.org/10.1016/j.phymed.2024.155441
Hypertens Res. 2024 Feb 21.

Mitochondrial fission inhibition protects against hypertension induced by angiotensin II.

Kyle J Preston, Tatsuo Kawai, Keiichi Torimoto, Ryohei Kuroda, Yuki Nakayama, Tomoko Akiyama, Yayoi Kimura, Rosario Scalia, Michael V Autieri, Victor Rizzo, Tomoki Hashimoto, Patrick Osei-Owusu, Satoru Eguchi.

  Mitochondrial dysfunction has been implicated in various types of cardiovascular disease including hypertension. Mitochondrial fission fusion balance is critical to mitochondrial quality control, whereas enhanced fission has been reported in several models of cardiovascular disease. However, limited information is available regarding the contribution of mitochondrial fission in hypertension. Here, we have tested the hypothesis that inhibition of mitochondrial fission attenuates the development of hypertension and associated vascular remodeling. In C57BL6 mice infused with angiotensin II for 2 weeks, co-treatment of mitochondrial fission inhibitor, mdivi1, significantly inhibited angiotensin II-induced development of hypertension assessed by radiotelemetry. Histological assessment of hearts and aortas showed that mdivi1 inhibited vessel fibrosis and hypertrophy induced by angiotensin II. This was associated with attenuation of angiotensin II-induced decline in mitochondrial aspect ratio seen in both the endothelial and medial layers of aortas. Mdivi1 also mitigated angiotensin II-induced cardiac hypertrophy assessed by heart weight-to-body weight ratio as well as by echocardiography. In ex vivo experiments, mdivi1 inhibited vasoconstriction and abolished the enhanced vascular reactivity by angiotensin II in small mesenteric arteries. Proteomic analysis on endothelial cell culture media with angiotensin II and/or mdivi1 treatment revealed that mdivi1 inhibited endothelial cell hypersecretory phenotype induced by angiotensin II. In addition, mdivi1 attenuated angiotensin II-induced protein induction of periostin, a myofibroblast marker in cultured vascular fibroblasts. In conclusion, these data suggest that mdivi1 prevented angiotensin II-induced hypertension and cardiovascular remodeling via multicellular mechanisms in the vasculature.

Keywords:  Angiotensin II; Fibrosis; Hypertension; Mitochondria; Proteomics

DOI:  https://doi.org/10.1038/s41440-024-01610-0
Rev Neurosci. 2024 Feb 19.

Mitochondria and MICOS - function and modeling.

Haym Benaroya.

  An extensive review is presented on mitochondrial structure and function, mitochondrial proteins, the outer and inner membranes, cristae, the role of F1FO-ATP synthase, the mitochondrial contact site and cristae organizing system (MICOS), the sorting and assembly machinery morphology and function, and phospholipids, in particular cardiolipin. Aspects of mitochondrial regulation under physiological and pathological conditions are outlined, in particular the role of dysregulated MICOS protein subunit Mic60 in Parkinson's disease, the relations between mitochondrial quality control and proteins, and mitochondria as signaling organelles. A mathematical modeling approach of cristae and MICOS using mechanical beam theory is introduced and outlined. The proposed modeling is based on the premise that an optimization framework can be used for a better understanding of critical mitochondrial function and also to better map certain experiments and clinical interventions.

Keywords:  MICOS; Mic60; cristae; metabolism; mitochondria; physiology

DOI:  https://doi.org/10.1515/revneuro-2024-0004
Cells. 2024 Feb 08. pii: 316. [Epub ahead of print]13(4):

GOLPH3 Participates in Mitochondrial Fission and Is Necessary to Sustain Bioenergetic Function in MDA-MB-231 Breast Cancer Cells.

Catalina M Polanco, Viviana A Cavieres, Abigail J Galarza, Claudia Jara, Angie K Torres, Jorge Cancino, Manuel Varas-Godoy, Patricia V Burgos, Cheril Tapia-Rojas, Gonzalo A Mardones.

  In this study, we investigated the inter-organelle communication between the Golgi apparatus (GA) and mitochondria. Previous observations suggest that GA-derived vesicles containing phosphatidylinositol 4-phosphate (PI(4)P) play a role in mitochondrial fission, colocalizing with DRP1, a key protein in this process. However, the functions of these vesicles and potentially associated proteins remain unknown. GOLPH3, a PI(4)P-interacting GA protein, is elevated in various types of solid tumors, including breast cancer, yet its precise role is unclear. Interestingly, GOLPH3 levels influence mitochondrial mass by affecting cardiolipin synthesis, an exclusive mitochondrial lipid. However, the mechanism by which GOLPH3 influences mitochondria is not fully understood. Our live-cell imaging analysis showed GFP-GOLPH3 associating with PI(4)P vesicles colocalizing with YFP-DRP1 at mitochondrial fission sites. We tested the functional significance of these observations with GOLPH3 knockout in MDA-MB-231 cells of breast cancer, resulting in a fragmented mitochondrial network and reduced bioenergetic function, including decreased mitochondrial ATP production, mitochondrial membrane potential, and oxygen consumption. Our findings suggest a potential negative regulatory role for GOLPH3 in mitochondrial fission, impacting mitochondrial function and providing insights into GA-mitochondria communication.

Keywords:  DRP1; GOLPH3; Golgi apparatus; Golgi–mitochondria communication; PI(4)P; mitochondrial bioenergetics; mitochondrial fission and fusion; mitochondrial fragmentation

DOI:  https://doi.org/10.3390/cells13040316
Front Pharmacol. 2024 ;15 1344075

Mitophagy regulates mitochondrial number following pharmacological induction of mitochondrial biogenesis in renal proximal tubule cells.

Kevin A Hurtado, Rick G Schnellmann.

  Background: Mitochondrial biogenesis (MB) induction through the activation of the 5-Hydroxytriptamine (5-HT) 1F receptor (HTR1F) is a promising mechanism for the treatment of diseases characterized by mitochondrial dysfunction, such as acute kidney injury (AKI). While several studies report pharmacological activation of MB in the proximal tubule, it is unclear how the proximal tubule regulates itself once the pharmacological activation is removed. Mitophagy is the process of selective mitochondria degradation. We hypothesize that mitophagy decreases mitochondrial number after pharmacological stimulation and restore mitochondrial homeostasis. Methods: Renal proximal tubules were treated at time 0hr with LY344864 or vehicle for 24 h and then removed. LY344864, a selective HTR1F agonist, induces MB in renal proximal tubules as previously reported (Gibbs et al., Am J Physiol Renal Physiol, 2018, 314(2), F260-F268). Vehicle and pharmacological reagents were added at the 24 h time point. Electron microscopy was used to assess mitochondrial morphology, number, and autolysosomes. Seahorse Bioscience XF-96 extracellular flux analyzer was used to measure maximal mitochondrial oxygen consumption rates (FCCP-OCR), a functional marker of MB. Results: LY344864 treatment increased FCCP-OCR, phosphorylation of protein kinase B (AKT), peroxisome proliferator-activated receptor γ coactivator-1alpha (PGC-1α), and mitochondrial number after 24 h. These endpoints decreased to baseline 24 h after LY344864 removal. Treatment with ROC-325, an autophagy inhibitor, increased Sequestosome-1 (SQSTM1/P62) and microtubule-associated protein-1 light chain 3 (LC3B) after 24 h of treatment. Also, ROC-325 treatment sustained the elevated mitochondrial number after LY344864 pre-treatment and removal. Conclusion: These data revealed that inhibition of autophagy extends elevated mitochondrial number and function by preventing the lysosomal degradation of mitochondria after the removal of LY344864.

Keywords:  HTR1F; autophagy; mitochondrial biogenesis; mitophagy; proximal tubule

DOI:  https://doi.org/10.3389/fphar.2024.1344075
Cell Rep. 2024 Feb 19. pii: S2211-1247(24)00133-5. [Epub ahead of print]43(3): 113805

Role of the small protein Mco6 in the mitochondrial sorting and assembly machinery.

Jon V Busto, Iniyan Ganesan, Hannah Mathar, Conny Steiert, Eva F Schneider, Sebastian P Straub, Lars Ellenrieder, Jiyao Song, Sebastian B Stiller, Philipp Lübbert, Ritwika Chatterjee, Jana Elsaesser, Laura Melchionda, Christina Schug, Fabian den Brave, Uwe Schulte, Till Klecker, Claudine Kraft, Bernd Fakler, Thomas Becker, Nils Wiedemann.

  The majority of mitochondrial precursor proteins are imported through the Tom40 β-barrel channel of the translocase of the outer membrane (TOM). The sorting and assembly machinery (SAM) is essential for β-barrel membrane protein insertion into the outer membrane and thus required for the assembly of the TOM complex. Here, we demonstrate that the α-helical outer membrane protein Mco6 co-assembles with the mitochondrial distribution and morphology protein Mdm10 as part of the SAM machinery. MCO6 and MDM10 display a negative genetic interaction, and a mco6-mdm10 yeast double mutant displays reduced levels of the TOM complex. Cells lacking Mco6 affect the levels of Mdm10 and show assembly defects of the TOM complex. Thus, this work uncovers a role of the SAMMco6 complex for the biogenesis of the mitochondrial outer membrane.

Keywords:  CP: Cell biology; ERMES complex; Mdm10; SAM complex; TOM complex; mitochondria; outer membrane; protein import; protein translocation; β-barrel protein

DOI:  https://doi.org/10.1016/j.celrep.2024.113805
Front Physiol. 2024 ;15 1344951

Mitochondrial quality control alterations and placenta-related disorders.

Yamei Wu, Meng Li, Hao Ying, Ying Gu, Yunlong Zhu, Yanfang Gu, Lu Huang.

  Mitochondria are ubiquitous in eukaryotic cells. Normal maintenance of function is the premise and basis for various physiological activities. Mitochondrial dysfunction is commonly observed in a wide range of pathological conditions, such as neurodegenerative, metabolic, cardiovascular, and various diseases related to foetal growth and development. The placenta is a highly energy-dependent organ that acts as an intermediary between the mother and foetus and functions to maintain foetal growth and development. Recent studies have demonstrated that mitochondrial dysfunction is associated with placental disorders. Defects in mitochondrial quality control mechanisms may lead to preeclampsia and foetal growth restriction. In this review, we address the quality control mechanisms of mitochondria and the relevant pathologies of mitochondrial dysfunction in placenta-related diseases, such as preeclampsia and foetal growth restriction. This review also investigates the relation between mitochondrial dysfunction and placental disorders.

Keywords:  foetal growth restriction; mitochondria; mitochondrial dysfunction; placenta; preeclampsia

DOI:  https://doi.org/10.3389/fphys.2024.1344951
Diabetes. 2024 Mar 01. 73(3): 357-358

A New Mitochondrial Uncoupler Improves Metabolic Homeostasis in Mice.

Gautham Ramshankar, Rachel J Perry.

DOI: https://doi.org/10.2337/dbi23-0033
Nat Commun. 2024 Feb 19. 15(1): 1504

Author Correction: Mitophagy curtails cytosolic mtDNA-dependent activation of cGAS/STING inflammation during aging.

Juan Ignacio Jiménez-Loygorri, Beatriz Villarejo-Zori, Álvaro Viedma-Poyatos, Juan Zapata-Muñoz, Rocío Benítez-Fernández, María Dolores Frutos-Lisón, Francisco A Tomás-Barberán, Juan Carlos Espín, Estela Area-Gómez, Aurora Gomez-Duran, Patricia Boya.

DOI: https://doi.org/10.1038/s41467-024-46010-7
Br Poult Sci. 2024 Feb 21. 1-11

Disturbance of mitochondrial dynamics in myocardium of broilers with pulmonary hypertension syndrome.

W Zhang, M Li, X Ye, M Jiang, X Wu, Z Tang, L Hu, H Zhang, Y Li, J Pan.

  1. The following study investigated the relationship between pulmonary hypertension syndrome (PHS) and mitochondrial dynamics in broiler cardiomyocytes.2. An animal model for PHS was established by injecting broiler chickens with CM-32 cellulose particles. Broiler myocardial cells were cultured under hypoxic conditions to establish an in vitro model. The ascites heart index, histomorphology, mitochondrial ultrastructure, and mitochondrial dynamic-related gene and protein expression were evaluated.3. The myocardial fibres from PHS broilers had wider spaces and were wavy and twisted and the number of mitochondria increased. Compared with the control group, the gene and protein expression levels were decreased for Opa1, Mfn1, and Mfn2 in the myocardium of PHS broilers. The gene and protein expression was significantly increased for Drp1 and Mff.4. This study showed that PHS in broilers may cause myocardial mitochondrial dysfunction, specifically by diminishing mitochondrial fusion and enhancing fission, causing disturbances in the mitochondrial dynamics of the heart.

Keywords:  Broilers; heart; hypoxia; mitochondrial dynamics; pulmonary hypertension syndrome

DOI:  https://doi.org/10.1080/00071668.2024.2308277
Int J Mol Sci. 2024 Feb 08. pii: 2052. [Epub ahead of print]25(4):

Mitochondrial Quantity and Quality in Age-Related Sarcopenia.

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

  Sarcopenia, the age-associated decline in skeletal muscle mass and strength, is a condition with a complex pathophysiology. Among the factors underlying the development of sarcopenia are the progressive demise of motor neurons, the transition from fast to slow myosin isoform (type II to type I fiber switch), and the decrease in satellite cell number and function. Mitochondrial dysfunction has been indicated as a key contributor to skeletal myocyte decline and loss of physical performance with aging. Several systems have been implicated in the regulation of muscle plasticity and trophism such as the fine-tuned and complex regulation between the stimulator of protein synthesis, mechanistic target of rapamycin (mTOR), and the inhibitor of mTOR, AMP-activated protein kinase (AMPK), that promotes muscle catabolism. Here, we provide an overview of the molecular mechanisms linking mitochondrial signaling and quality with muscle homeostasis and performance and discuss the main pathways elicited by their imbalance during age-related muscle wasting. We also discuss lifestyle interventions (i.e., physical exercise and nutrition) that may be exploited to preserve mitochondrial function in the aged muscle. Finally, we illustrate the emerging possibility of rescuing muscle tissue homeostasis through mitochondrial transplantation.

Keywords:  DAMPs; extracellular vesicles; inflammaging; metabolism; mitochondrial DNA; mitochondrial biogenesis; mitochondrial transplantation; mitophagy; muscle aging; muscle plasticity

DOI:  https://doi.org/10.3390/ijms25042052
Int J Mol Sci. 2024 Feb 18. pii: 2394. [Epub ahead of print]25(4):

Pulsed Hyperoxia Acts on Plasmatic Advanced Glycation End Products and Advanced Oxidation Protein Products and Modulates Mitochondrial Biogenesis in Human Peripheral Blood Mononuclear Cells: A Pilot Study on the "Normobaric Oxygen Paradox".

Costantino Balestra, Sara Baldelli, Fabio Virgili, Michele Salvagno, Simona Mrakic-Sposta, Deborah Fratantonio.

  The "normobaric oxygen paradox" (NOP) describes the response to the return to normoxia after a hyperoxic event, sensed by tissues as an oxygen shortage, up-regulating redox-sensitive transcription factors. We have previously characterized the time trend of oxygen-sensitive transcription factors in human PBMCs, in which the return to normoxia after 30% oxygen is sensed as a hypoxic trigger, characterized by hypoxia-induced factor (HIF-1) activation. On the contrary, 100% and 140% oxygen induce a shift toward an oxidative stress response, characterized by NRF2 and NF-kB activation in the first 24 h post exposure. Herein, we investigate whether this paradigm triggers Advanced Glycation End products (AGEs) and Advanced Oxidation Protein Products (AOPPs) as circulating biomarkers of oxidative stress. Secondly, we studied if mitochondrial biogenesis was involved to link the cellular response to oxidative stress in human PBMCs. Our results show that AGEs and AOPPs increase in a different manner according to oxygen dose. Mitochondrial levels of peroxiredoxin (PRX3) supported the cellular response to oxidative stress and increased at 24 h after mild hyperoxia, MH (30% O2), and high hyperoxia, HH (100% O2), while during very high hyperoxia, VHH (140% O2), the activation was significantly high only at 3 h after oxygen exposure. Mitochondrial biogenesis was activated through nuclear translocation of PGC-1α in all the experimental conditions. However, the consequent release of nuclear Mitochondrial Transcription Factor A (TFAM) was observed only after MH exposure. Conversely, HH and VHH are associated with a progressive loss of NOP response in the ability to induce TFAM expression despite a nuclear translocation of PGC-1α also occurring in these conditions. This study confirms that pulsed high oxygen treatment elicits specific cellular responses, according to its partial pressure and time of administration, and further emphasizes the importance of targeting the use of oxygen to activate specific effects on the whole organism.

Keywords:  Nrf2; PGC-1α; Prx3; human; mitochondrial biogenesis; oxidative stress; peripheral blood mononuclear cells (PBMCs); reactive oxygen species (ROS); targeted use of oxygen

DOI:  https://doi.org/10.3390/ijms25042394
ACS Infect Dis. 2024 Feb 22.

Ubiquitin Ligase Parkin Regulates the Stability of SARS-CoV-2 Main Protease and Suppresses Viral Replication.

Li Zhou, Ruochuan Liu, Heather Pathak, Xiaoyu Wang, Geon H Jeong, Pratima Kumari, Mukesh Kumar, Jun Yin.

  The highly infectious coronavirus SARS-CoV-2 relies on the viral main protease (Mpro, also known as 3CLpro or Nsp5) to proteolytically process the polyproteins encoded by the viral genome for the release of functional units in the host cells to initiate viral replication. Mpro also interacts with host proteins of the innate immune pathways, such as IRF3 and STAT1, to suppress their activities and facilitate virus survival and proliferation. To identify the host mechanism for regulating Mpro, we screened various classes of E3 ubiquitin ligases and found that Parkin of the RING-between-RING family can induce the ubiquitination and degradation of Mpro in the cell. Furthermore, when the cells undergo mitophagy, the PINK1 kinase activates Parkin and enhances the ubiquitination of Mpro. We also found that elevated expression of Parkin in the cells significantly decreased the replication of SARS-CoV-2 virus. Interestingly, SARS-CoV-2 infection downregulates Parkin expression in the mouse lung tissues compared to healthy controls. These results suggest an antiviral role of Parkin as a ubiquitin ligase targeting Mpro and the potential for exploiting the virus-host interaction mediated by Parkin to treat SARS-CoV-2 infection.

Keywords:  E3 ubiquitin ligase; Parkin; SARS-CoV-2; main protease; mitophagy

DOI:  https://doi.org/10.1021/acsinfecdis.3c00418
Phytomedicine. 2024 Feb 07. pii: S0944-7113(24)00099-0. [Epub ahead of print]126 155434

Regulatory mechanism of perinatal nonylphenol exposure on cardiac mitochondrial autophagy and the PINK1/Parkin signaling pathway in male offspring rats.

Xiaolian Yang, Jie Xu, Yuzhu Xu, Chengxing Wang, Fangmei Lin, Jie Yu.

  OBJECTIVE: This study investigated whether perinatal exposure to nonylphenol (NP) induces mitochondrial autophagy (i.e., mitophagy) damage in neonatal rat cardiomyocytes (NRCMs) and whether the PINK1/Parkin signaling pathway is involved in NP-induced primary cardiomyocyte injury.METHODS AND RESULTS: In vivo: Perinatal NP exposure increased apoptosis and mitochondrial damage in NRCMs. Mitochondrial swelling and autophagosome-like structures with multiple concentric membranes were observed in the 100 mg/kg NP group, with an increase in the number of autophagosomes. Disorganized fiber arrangement and elevated serum myocardial enzyme levels were observed with increasing NP dosage. Additionally, NP exposure led to increased MDA levels and decreased SOD activity and ATP levels in myocardial tissue. The mRNA expression levels of autophagy-related genes, including Beclin-1, p62, and LC3B, as well as the expression of mitochondrial autophagy-related proteins (PINK1, p-Parkin, Parkin, Beclin-1, p62, LC3-I, LC3-II, and LC3-II/I) and apoptosis-related proteins (Bax and caspase-3), increased, whereas the expression levels of the mitochondrial membrane protein TOMM20 and the anti-apoptotic protein Bcl-2 decreased. In vitro: NP increased ROS levels, LDH release, and decreased ATP levels in NRCMs. CsA treatment significantly inhibited the expression of autophagy-related proteins (Beclin-1, LC3-II/I, and p62) and apoptosis-related proteins (caspase-3 and Bax), increased the expression levels of TOMM20 and Bcl-2 proteins, increased cellular ATP levels, and inhibited LDH release. The inhibition of the PINK1/Parkin signaling pathway suppressed the expression of mitochondrial autophagy-related proteins (PINK1, p-Parkin, Parkin, Beclin-1, LC3-II/I, and p62) and apoptosis-related proteins (caspase-3 and Bax), increased TOMM20 and Bcl-2 protein expression, increased ATP levels, and decreased LDH levels in NRCMs.
CONCLUSIONS: This study is novel in reporting that perinatal NP exposure induced myocardial injury in male neonatal rats, thereby inducing mitophagy. The PINK1/Parkin signaling pathway was involved in this injury by regulating mitophagy.

Keywords:  Cardiac damage; Mitochondrial autophagy; Nonylphenol; PINK1/Parkin signaling pathway

DOI:  https://doi.org/10.1016/j.phymed.2024.155434
Cell Death Dis. 2024 Feb 23. 15(2): 168

Targeting SIRT3 sensitizes glioblastoma to ferroptosis by promoting mitophagy and inhibiting SLC7A11.

Xiaohe Li, Wenlong Zhang, Zhengcao Xing, Shuming Hu, Geqiang Zhang, Tiange Wang, Tianshi Wang, Qiuju Fan, Guoqiang Chen, Jinke Cheng, Xianguo Jiang, Rong Cai.

Glioblastoma (GBM) cells require large amounts of iron for tumor growth and progression, which makes these cells vulnerable to destruction via ferroptosis induction. Mitochondria are critical for iron metabolism and ferroptosis. Sirtuin-3 (SIRT3) is a deacetylase found in mitochondria that regulates mitochondrial quality and function. This study aimed to characterize SIRT3 expression and activity in GBM and investigate the potential therapeutic effects of targeting SIRT3 while also inducing ferroptosis in these cells. We first found that SIRT3 expression was higher in GBM tissues than in normal brain tissues and that SIRT3 protein expression was upregulated during RAS-selective lethal 3 (RSL3)-induced GBM cell ferroptosis. We then observed that inhibition of SIRT3 expression and activity in GBM cells sensitized GBM cells to RSL3-induced ferroptosis both in vitro and in vivo. Mechanistically, SIRT3 inhibition led to ferrous iron and ROS accumulation in the mitochondria, which triggered mitophagy. RNA-Sequencing analysis revealed that upon SIRT3 knockdown in GBM cells, the mitophagy pathway was upregulated and SLC7A11, a critical antagonist of ferroptosis via cellular import of cystine for glutathione (GSH) synthesis, was downregulated. Forced expression of SLC7A11 in GBM cells with SIRT3 knockdown restored cellular cystine uptake and consequently the cellular GSH level, thereby partially rescuing cell viability upon RSL3 treatment. Furthermore, in GBM cells, SIRT3 regulated SLC7A11 transcription through ATF4. Overall, our study results elucidated novel mechanisms underlying the ability of SIRT3 to protect GBM from ferroptosis and provided insight into a potential combinatorial approach of targeting SIRT3 and inducing ferroptosis for GBM treatment.

DOI: https://doi.org/10.1038/s41419-024-06558-0
Mol Neurobiol. 2024 Feb 21.

Transcription Factor TFAP2B Exerts Neuroprotective Effects Targeting BNIP3-Mediated Mitophagy in Ischemia/Reperfusion Injury.

Yong Peng, Jiaoying Jia, Mingming Zhang, Wenjia Ma, Yan Cui, Mengqiang Yu.

  Cerebral ischemia-reperfusion injury (CIRI) leads to malignant brain edema, blood-brain barrier destruction, and neuronal apoptosis. N6-methyladenosine (m6A) RNA modification in CIRI was still limited explored. In this study, MeRIP- and RNA-sequencing were performed of middle cerebral artery occlusion and reperfusion (MCAO/R) rats to find novel potential molecular targets. Transcription factor TFAP2B stood out of which its m6A abundance decreased associated with a marked reduction of its mRNA based on cojoint interactive bioinformatics analysis of the MeRIP- and RNA-sequencing data. It was suggested TFAP2B could have a role in CIRI. Functionally, overexpression of TFAP2B in cultured primary neurons could effectively improve the cell survival and pro-survival autophagy in parallel with reduced cell apoptosis during OGD/R in vitro. Through the RNA-sequencing of TFAP2B overexpressed primary neurons and subsequent validation experiments, it was found that mitophagy receptor BNIP3 was one of the important targets of TFAP2B in OGD/R neurons through which TFAP2B could bind to its promoter region for transcriptional activation of BNIP3, thereby enhancing BNIP3-mediated mitophagy to protect against OGD/R injury of neurons. Lastly, TFAP2B was demonstrated to alleviate the MCAO/R damage to a certain extent in vivo. Although it failed to confirm TFAP2B dysregulation was m6A dependent in current research, this is the first research of TFAP2B in CIRI field with important guiding significance.

Keywords:  BNIP3; Cerebral ischemia–reperfusion injury; MeRIP-sequencing; Mitophagy; Primary neurons; RNA-sequencing; TFAP2B

DOI:  https://doi.org/10.1007/s12035-024-04004-y
Biochem Biophys Rep. 2024 Jul;38 101654

Identification of mitophagy-related hub genes during the progression of spinal cord injury by integrated multinomial bioinformatics analysis.

Zhihao Guo, Zihui Zhao, Xiaoge Wang, Jie Zhou, Jie Liu, Ward Plunet, Wenjie Ren, Linqiang Tian.

  Spinal cord injury (SCI) is a disturbance of peripheral and central nerve conduction that causes disability in sensory and motor function. Currently, there is no effective treatment for SCI. Mitophagy plays a vital role in mitochondrial quality control during various physiological and pathological processes. The study aimed to elucidate the role of mitophagy and identify potential mitophagy-related hub genes in SCI pathophysiology. Two datasets (GSE15878 and GSE138637) were analyzed. Firstly, the differentially expressed genes (DEGs) were identified and mitophagy-related genes were obtained from GeneCards, then the intersection between SCI and mitophagy-related genes was determined. Next, we performed gene set enrichment analysis (GSEA), weighted gene co-expression network analysis (WGCNA), protein-protein interaction network (PPI network), least absolute shrinkage and selection operator (LASSO), and cluster analysis to identify and define the hub genes in SCI. Finally, the link between hub genes and infiltrating immune cells was investigated and the potential transcriptional regulation/small molecular compounds to target hub genes were predicted. In total, SKP1 and BAP1 were identified as hub genes of mitophagy-related DEGs during SCI development and regulatory T cells (Tregs)/resting NK cells/activated mast cells may play an essential role in the progression of SCI. LINC00324 and SNHG16 may regulate SKP1 and BAP1, respectively, through miRNAs. Eleven and eight transcriptional factors (TFs) regulate SKP1 and BAP1, respectively, and six small molecular compounds target BAP1. Then, the mRNA expression levels of BAP1 and SKP1 were detected in the injured sites of spinal cord of SD rats at 6 h and 72 h after injury using RT-qPCR, and found that the level were decreased. Therefore, the pathways of mitophagy are downregulated during the pathophysiology of SCI, and SKP1 and BAP1 could be accessible targets for diagnosing and treating SCI.

Keywords:  Bioinformatics analysis; Hub genes; Immune cells; Mitophagy; Spinal cord injury

DOI:  https://doi.org/10.1016/j.bbrep.2024.101654