bims-mikwok 2024-05-19 papers

bims-mikwok

Biomed News

on Mitochondrial quality control

Issue of 2024‒05‒19
twenty papers selected by
Gavin McStay, Liverpool John Moores University

Lack of compensatory mitophagy in skeletal muscles during sepsis.
F-actin/DRP1 axis-mediated mitochondrial fission promotes mitophagy in diabetic submandibular glands.
Mitophagy in health and disease. Molecular mechanisms, regulatory pathways, and therapeutic implications.
lncRNA Oip5-as1 inhibits excessive mitochondrial fission in myocardial ischemia/reperfusion injury by modulating DRP1 phosphorylation.
UVB radiation exposure modulates mitophagy in embryonic cells of freshwater prawn Macrobrachium olfersii: Exploring a protective organelle quality control mechanism.
Inflammatory lung injury is associated with endothelial cell mitochondrial fission and requires the nitration of RhoA and cytoskeletal remodeling.
Mitochondrial F0F1-ATP synthase governs the induction of mitochondrial fission.
Dynamin-related protein 1 mediates the therapeutic effect of isoliquiritigenin in diabetic intimal hyperplasia via regulation of mitochondrial fission.
Mitophagy in mammalian follicle development and health.
SIN-3 transcriptional coregulator maintains mitochondrial homeostasis and polyamine flux.
Driving Mitochondrial Fission Improves Cognitive, but not Motor Deficits in a Mouse Model of Ataxia of Charlevoix-Saguenay.
Aberrant expression of NEDD4L disrupts mitochondrial homeostasis by downregulating CaMKKβ in diabetic kidney disease.
Sirtuin 5 alleviates excessive mitochondrial fission via desuccinylation of ATPase inhibitory factor 1 in sepsis-induced acute kidney injury.
The Role of Protein S-Nitrosylation in Mitochondrial Quality Control in Central Nervous System Diseases.
Mitochondrial citrate transporters Ctp1-Yhm2 and respiratory chain: A coordinated functional connection in Saccharomyces cerevisiae metabolism.
PHLDA1 contributes to hypoxic ischemic brain injury in neonatal rats via inhibiting FUNDC1-mediated mitophagy.
Mitophagy Regulates the Circadian Rhythms by Degrading NR1D1 in Simulated Microgravity and Isolation Environments.
Serine synthesis controls mitochondrial biogenesis in macrophages.
Lactate regulates respiratory efficiency and mitochondrial dynamics in primary rat podocytes.
MitoTempo protects against nε-carboxymethyl lysine-induced mitochondrial dyshomeostasis and neuronal cells injury.

J Physiol. 2024 May 15.

Lack of compensatory mitophagy in skeletal muscles during sepsis.

Sami Sedraoui, Jean-Philippe Leduc-Gaudet, Dominique Mayaki, Alaa Moamer, Laurent Huck, Gilles Gouspillou, Basil J Petrof, Sabah Hussain.

  Skeletal muscle dysfunction is a major problem in critically ill patients suffering from sepsis. This condition is associated with mitochondrial dysfunction and increased autophagy in skeletal muscles. Autophagy is a proteolytic mechanism involved in eliminating dysfunctional cellular components, including mitochondria. The latter process, referred to as mitophagy, is essential for maintaining mitochondrial quality and skeletal muscle health. Recently, a fluorescent reporter system called mito-QC (i.e. mitochondrial quality control) was developed to specifically quantify mitophagy levels. In the present study, we used mito-QC transgenic mice and confocal microscopy to morphologically monitor mitophagy levels during sepsis. To induce sepsis, Mito-QC mice received Escherichia coli lipopolysaccharide (10 mg kg-1 i.p.) or phosphate-buffered saline and skeletal muscles (hindlimb and diaphragm) were excised 48 h later. In control groups, there was a negative correlation between the basal mitophagy level and overall muscle mitochondrial content. Sepsis increased general autophagy in both limb muscles and diaphragm but had no effect on mitophagy levels. Sepsis was associated with a downregulation of certain mitophagy receptors (Fundc1, Bcl2L13, Fkbp8 and Phbb2). The present study suggests that general autophagy and mitophagy can be dissociated from one another, and that the characteristic accumulation of damaged mitochondria in skeletal muscles under the condition of sepsis may reflect a failure of adequate compensatory mitophagy. KEY POINTS: There was a negative correlation between the basal level of skeletal muscle mitophagy and the mitochondrial content of individual muscles. Mitophagy levels in limb muscles and the diaphragm were unaffected by lipopolysaccharide (LPS)-induced sepsis. With the exception of BNIP3 in sepsis, LPS administration induced either no change or a downregulation of mitophagy receptors in skeletal muscles.

Keywords:  autophagy; mitochondria; mitophagy; mito‐QC; sepsis; skeletal muscles

DOI:  https://doi.org/10.1113/JP286216
Oral Dis. 2024 May 12.

F-actin/DRP1 axis-mediated mitochondrial fission promotes mitophagy in diabetic submandibular glands.

Hou-Wei Zhu, Yi-Ping Wang, Qiu-Fang Zhang, Kai-Di Wang, Yan Huang, Ruo-Lan Xiang.

  BACKGROUND: Diabetes is accompanied by a high prevalence of hyposalivation, causing severe damage to oral and systemic health. Mitochondrial dynamics play important roles in the pathogenesis of various diabetic complications; however, little is known about their roles in diabetic hyposalivation.MATERIALS AND METHODS: A diabetic mouse model and a high glucose (HG)-induced diabetic submandibular gland (SMG) cell model were employed.
RESULTS: More mitochondria surrounded by autophagosomes and higher expression of mitophagy-related proteins were detected in the SMGs of diabetic mice and HG-treated SMG cells. In diabetic SMGs, dynamin-related protein 1 (DRP1) was upregulated, whereas mitofusin-2 was downregulated both in vivo and in vitro. Shortened mitochondria and impaired mitochondrial functions were observed in the HG group. A DRP1-specific inhibitor, mdivi-1, suppressed mitochondrial fission and mitophagy, as well as restored mitochondrial functions in the HG condition. Moreover, the interaction of F-actin and DRP1 was enhanced in the diabetic group. Inhibiting F-actin with cytochalasin D repaired the injured effects of HG on mitochondrial dynamics and functions. Conversely, the F-actin-polymerization-inducer jasplakinolide aggravated mitochondrial fission and dysfunction.
CONCLUSIONS: F-actin contributes to HG-evoked mitochondrial fission by interacting with DRP1, which induces mitophagy and impairs mitochondrial function in SMG cells, ultimately damaging the SMG.

Keywords:  cytoskeleton; diabetes; mitochondrial dynamics; mitophagy; submandibular glands

DOI:  https://doi.org/10.1111/odi.14983
Apoptosis. 2024 May 17.

Mitophagy in health and disease. Molecular mechanisms, regulatory pathways, and therapeutic implications.

Mark S D'Arcy.

  Mitophagy, a specialised form of autophagy, selectively targeting damaged or dysfunctional mitochondria, and is crucial for maintaining cellular homeostasis and mitochondrial quality control. Dysregulation of mitophagy contributes to various pathological conditions, including cancer, neurodegenerative and cardiovascular diseases. This review presents a comprehensive analysis of the molecular mechanisms, regulatory pathways, and interplay with other cellular processes governing mitophagy, emphasizing its importance in physiological and pathological contexts. We explore the PINK1/Parkin-mediated and receptor-mediated mitophagy pathways, encompassing BNIP3/NIX, FUNDC1, and Bcl2-L-13. Additionally, we discuss post-translational modifications and cellular signalling pathways modulating mitophagy, as well as the connection between mitophagy and ageing, highlighting the decline in mitophagy efficiency and its impact on age-related pathologies. The review also investigates mitophagy's role in human diseases such as cancer, myocardial ischemia-reperfusion injury, Parkinson's, and Alzheimer's disease. We assess the potential of mitophagy-targeting therapeutic strategies, focusing on the development of dietary therapies, small molecules, drugs, and gene therapy approaches that modulate mitophagy levels and efficiency for treating these diseases and dysfunctions commonly observed in ageing individuals. In summary, this review offers an extensive overview of the molecular mechanisms and regulatory networks involved in mitophagy, its association with autophagy, and implications in human health and disease. By examining the potential of mitophagy-modulating therapies in disease and non-disease settings, we aim to inspire further research to develop innovative treatment strategies for various pathological conditions linked to mitochondrial dysfunction and to ageing.

Keywords:  Ageing; Autophagy; Mitophagy

DOI:  https://doi.org/10.1007/s10495-024-01977-y
Cell Mol Biol Lett. 2024 May 14. 29(1): 72

lncRNA Oip5-as1 inhibits excessive mitochondrial fission in myocardial ischemia/reperfusion injury by modulating DRP1 phosphorylation.

Xiaowei Niu, Jingjing Zhang, Shuwen Hu, Wenhui Dang, Kaiwen Wang, Ming Bai.

  BACKGROUND: Aberrant mitochondrial fission, a critical pathological event underlying myocardial ischemia/reperfusion (MI/R) injury, has emerged as a potential therapeutic target. The long non-coding RNA (lncRNA) Oip5-as1 is increasingly recognized for its regulatory roles, particularly in MI/R injury. However, its precise mechanistic role in modulating mitochondrial dynamics remains elusive. This study aims to elucidate the mechanistic role of Oip5-as1 in regulating mitochondrial fission and evaluate its therapeutic potential against MI/R injury.METHODS: To simulate in vitro MI/R injury, HL-1 cardiomyocytes were subjected to hypoxia/reoxygenation (H/R). Lentiviral vectors were employed to achieve overexpression or knockdown of Oip5-as1 in HL-1 cells by expressing Oip5-as1 or shRNA targeting Oip5-as1, respectively. The impact of Oip5-as1 on mitochondrial dynamics in HL-1 cells was assessed using CCK-8 assay, flow cytometry, immunofluorescence staining, and biochemical assays. MI/R injury was induced in mice by ligating the left anterior descending coronary artery. Conditional knockout mice for Oip5-as1 were generated using the CRISPR/Cas9 genome editing technology, while overexpression of Oip5-as1 in mice was achieved via intramyocardial administration of AAV9 vectors. In mice, the role of Oip5-as1 was evaluated through echocardiographic assessment, histopathological staining, and transmission electron microscopy. Furthermore, Western blotting, RNA pull-down, RNA immunoprecipitation, and co-immunoprecipitation assays were conducted to investigate Oip5-as1's underlying mechanisms.
RESULTS: The expression levels of Oip5-as1 are significantly decreased in MI/R-injured HL-1 cells and myocardium. In HL-1 cells undergoing H/R injury, overexpression of Oip5-as1 attenuated excessive mitochondrial fission, preserved mitochondrial functionality, and reduced cellular apoptosis, while knockdown of Oip5-as1 exhibited the opposite effects. Furthermore, in a mouse model of MI/R injury, overexpression of Oip5-as1 diminished mitochondrial fission, myocardial infarct size and improved cardiac function. However, knockout of Oip5-as1 exacerbated myocardial injury and cardiac dysfunction, which were significantly reversed by treatment with a mitochondrial division inhibitor-1 (Mdivi-1). Mechanistically, Oip5-as1 selectively interacts with AKAP1 and CaN proteins, inhibiting CaN activation and subsequent DRP1 dephosphorylation at Ser637, thereby constraining DRP1's translocation to the mitochondria and its involvement in mitochondrial fission.
CONCLUSIONS: Our study underscores the pivotal role of Oip5-as1 in mitigating excessive mitochondrial fission during MI/R injury. The findings not only enhance our comprehension of the molecular mechanisms underlying MI/R injury but also identify Oip5-as1 as a potential therapeutic target for ameliorating MI/R injury.

Keywords:  AKAP1; Calcineurin; DRP1; Long non-coding RNAs; Mitochondrial fission; Myocardial ischemia/reperfusion injury; Oip5-as1

DOI:  https://doi.org/10.1186/s11658-024-00588-4
Comp Biochem Physiol A Mol Integr Physiol. 2024 May 10. pii: S1095-6433(24)00091-6. [Epub ahead of print]295 111664

UVB radiation exposure modulates mitophagy in embryonic cells of freshwater prawn Macrobrachium olfersii: Exploring a protective organelle quality control mechanism.

Giuliam K Strücker, Michael L Jaramillo, Thaline de Quadros, Evelise M Nazari.

  Aquatic environments are subject to ultraviolet B (UVB) radiation incidence, and its effects on organisms are dose-dependent. Besides DNA, mitochondria are an important target of this radiation that causes structural damage and impairs its functional dynamics. Here, we hypothesize that mitophagy acts as an organelle quality control mechanism to mitigate UVB impacts in embryonic cells. Then, freshwater prawn Macrobrachium olfersii embryos was used as a model to investigate the effects of UVB on genes (Tomm20, Opa1, Pink, Prkn, Sqstm1, and Map1lc3) and proteins (TOM20, PINK1, p62 and LC3B) involved in mitophagy modulation. The choice of genes and proteins was based on the identification of mitochondrial membrane (Tomm20, Opa1 and TOM20), mediation of mitophagy (Pink1, Prkn and PINK1), and recognition of mitochondria by the autophagosome membrane (Sqstm1, Map1lc3, p62 and LC3B). First, the phylogeny of all genes presented bootstrap values >80 and conserved domains among crustacean species. Gene expression was inherently modulated during development, with transcripts (Tomm20, Opa1, Pink, Prkn, Sqstm1, and Map1lc3) overexpressed in the initial and final stages of development. Moreover, UVB radiation induced upregulation of Tomm20, Opa1, Pink, Prkn, Sqstm1, and Map1lc3 genes at 6 h after exposure. Interestingly, after 12 h, the protein content of PINK1, p62, and LC3B increased, while TOM20 was not responsive. Despite UVB radiation's harmful effects on embryonic cells, the chronology of gene expression and protein content indicates rapid activation of mitophagy, serving as an organelle quality control mechanism, given the analyzed cells' integrity.

Keywords:  Aquatic embryo; Autophagy; Development; Mitochondria; Ultraviolet radiation

DOI:  https://doi.org/10.1016/j.cbpa.2024.111664
Free Radic Biol Med. 2024 May 09. pii: S0891-5849(24)00454-4. [Epub ahead of print]

Inflammatory lung injury is associated with endothelial cell mitochondrial fission and requires the nitration of RhoA and cytoskeletal remodeling.

Marissa D Pokharel, Panfeng Fu, Alejandro Garcia-Flores, Manivannan Yegambaram, Qing Lu, Xutong Sun, Hoshang Unwalla, Saurabh Aggarwal, Jeffrey R Fineman, Ting Wang, Stephen M Black.

  Higher levels of extracellular nicotinamide phosphoribosyltransferase (eNAMPT), a TLR4 agonist, are associated with poor clinical outcomes in sepsis-induced acute lung injury (ALI). Little is known regarding the mechanisms by which eNAMPT is involved in ALI. Our recent work has identified a crucial role for mitochondrial dysfunction in ALI. Thus, this study aimed to determine if eNAMPT-mediated inflammatory injury is associated with the loss of mitochondrial function. Our data show that eNAMPT disrupted mitochondrial bioenergetics. This was associated with cytoskeleton remodeling and the loss of endothelial barrier integrity. These changes were associated with enhanced mitochondrial fission and blocked when Rho-kinase (ROCK) was inhibited. The increases in mitochondrial fission were also associated with the nitration-mediated activation of the small GTPase activator of ROCK, RhoA. Blocking RhoA nitration decreased eNAMPT-mediated mitochondrial fission and endothelial barrier dysfunction. The increase in fission was linked to a RhoA-ROCK mediated increase in Drp1 (dynamin-related protein 1) at serine(S)616. Another TLR4 agonist, lipopolysaccharide (LPS), also increased mitochondrial fission in a Drp1 and RhoA-ROCK-dependent manner. To validate our findings in vivo, we challenged C57BL/6 mice with eNAMPT in the presence and absence of the Drp1 inhibitor, Mdivi-1. Mdivi-1 treatment protected against eNAMPT-induced lung inflammation, edema, and lung injury. These studies demonstrate that mitochondrial fission-dependent disruption of mitochondrial function is essential in TLR4-mediated inflammatory lung injury and identify a key role for RhoA-ROCK signaling. Reducing mitochondrial fission could be a potential therapeutic strategy to improve ARDS outcomes.

Keywords:  ROS; acute lung injury; cytoskeleton; endothelial cell; mitochondrial bioenergetics; mitochondrial fission

DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.05.019
iScience. 2024 May 17. 27(5): 109808

Mitochondrial F0F1-ATP synthase governs the induction of mitochondrial fission.

Charlène Lhuissier, Valérie Desquiret-Dumas, Anaïs Girona, Jennifer Alban, Justine Faure, Julien Cassereau, Philippe Codron, Guy Lenaers, Olivier R Baris, Naïg Gueguen, Arnaud Chevrollier.

  Mitochondrial dynamics is a process that balances fusion and fission events, the latter providing a mechanism for segregating dysfunctional mitochondria. Fission is controlled by the mitochondrial membrane potential (ΔΨm), optic atrophy 1 (OPA1) cleavage, and DRP1 recruitment. It is thought that this process is closely linked to the activity of the mitochondrial respiratory chain (MRC). However, we report here that MRC inhibition does not decrease ΔΨm nor increase fission, as evidenced by hyperconnected mitochondria. Conversely, blocking F0F1-ATP synthase activity induces fragmentation. We show that the F0F1-ATP synthase is sensing the inhibition of MRC activity by immediately promoting its reverse mode of action to hydrolyze matrix ATP and restoring ΔΨm, thus preventing fission. While this reverse mode is expected to be inhibited by the ATPase inhibitor ATPIF1, we show that this sensing is independent of this factor. We have unraveled an unexpected role of F0F1-ATP synthase in controlling the induction of fission by sensing and maintaining ΔΨm.

Keywords:  Biochemistry; Cell biology; Functional aspects of cell biology

DOI:  https://doi.org/10.1016/j.isci.2024.109808
Hypertens Res. 2024 May 15.

Dynamin-related protein 1 mediates the therapeutic effect of isoliquiritigenin in diabetic intimal hyperplasia via regulation of mitochondrial fission.

Bao-Fu Zhang, Zi-Heng Wu, Kui Chen, Hao-Jie Jin, Jun Wu, Zi-Yi Huang, Xin-Wu Lu, Xiang-Tao Zheng.

  Phenotypic shift of vascular smooth muscle cells (VSMCs) plays a key role in intimal hyperplasia, especially in patients with diabetes mellitus (DM). This study aimed to investigate the role of dynamin-related protein 1 (DRP1) in mitochondrial fission-mediated VSMC phenotypic shift and to clarify whether DRP1 is the therapeutic target of isoliquiritigenin (ISL). Wire injury of carotid artery or platelet-derived growth factor treatment was performed in DM mice or high-glucose cultured human aortic smooth muscle cells (HASMCs), respectively. The effects of DRP1 silencing on DM-induced intimal hyperplasia were investigated both in vivo and in vitro. Phenotypic shift of HASMCs was evaluated by detection of reactive oxygen species (ROS) generation, cell viability, and related protein expressions. The effects of ISL on DM-induced intimal hyperplasia were evaluated both in vivo and in vitro. DRP1 silencing and ISL treatment attenuated DM-induced intimal hyperplasia with reduced ROS generation, cell viability, and VSMC dedifferentiation. The GTPase domain of DRP1 protein played a critical role in mitochondrial fission in DM-induced VSMC phenotypic shift. Cellular experiments showed that ISL inhibited mitochondrial fission and reduced the GTPase activity of DRP1, which was achieved by the directly binding to K216 of the DRP1 GTPase domain. ISL attenuated mouse intimal hyperplasia by reducing GTPase activity of DRP1 and inhibiting mitochondrial fission in vivo. In conclusion, increased GTPase activity of DRP1 aggregated DM-induced intimal hyperplasia by increasing mitochondrial fission-mediated VSMC phenotypic shift. ISL attenuated mouse intimal hyperplasia by reducing DRP1 GTPase activity and inhibiting mitochondrial fission of VSMCs.

Keywords:  Dynamin-related protein 1; GTPase; Intimal hyperplasia; Mitochondrial fission; Vascular smooth muscle cells

DOI:  https://doi.org/10.1038/s41440-024-01681-z
Reprod Biol. 2024 May 10. pii: S1642-431X(24)00035-4. [Epub ahead of print]24(2): 100889

Mitophagy in mammalian follicle development and health.

Zhengrong Zhou, Zhipeng Wu, Liufang Zhang, Yue Dai, Genbao Shao, Caifang Ren, Pan Huang.

  Mitophagy, the cellular process that removes damaged mitochondria, plays a crucial role in maintaining normal cell functions. It is deeply involved in the entire process of follicle development and is associated with various ovarian diseases. This review aims to provide a comprehensive overview of mitophagy regulation, emphasizing its role at different stages of follicular development. Additionally, the study illuminates the relationship between mitophagy and ovarian diseases, including ovary aging (OA), primary ovarian insufficiency (POI), and polycystic ovary syndrome (PCOS). A detailed understanding of mitophagy could reveal valuable insights and novel strategies for managing female ovarian reproductive health.

Keywords:  Follicle development; Mitophagy; Ovary aging; Polycystic ovary syndrome; Primary ovarian insufficiency

DOI:  https://doi.org/10.1016/j.repbio.2024.100889
iScience. 2024 May 17. 27(5): 109789

SIN-3 transcriptional coregulator maintains mitochondrial homeostasis and polyamine flux.

Giovannetti Marina, Rodríguez-Palero María-Jesús, Fabrizio Paola, Nicolle Ophélie, Bedet Cécile, Michaux Grégoire, Witting Michael, Artal-Sanz Marta, Palladino Francesca.

  Mitochondrial function relies on the coordinated transcription of mitochondrial and nuclear genomes to assemble respiratory chain complexes. Across species, the SIN3 coregulator influences mitochondrial functions, but how its loss impacts mitochondrial homeostasis and metabolism in the context of a whole organism is unknown. Exploring this link is important because SIN3 haploinsufficiency causes intellectual disability/autism syndromes and SIN3 plays a role in tumor biology. Here we show that loss of C. elegans SIN-3 results in transcriptional deregulation of mitochondrial- and nuclear-encoded mitochondrial genes, potentially leading to mito-nuclear imbalance. Consistent with impaired mitochondrial function, sin-3 mutants show extensive mitochondrial fragmentation by transmission electron microscopy (TEM) and in vivo imaging, and altered oxygen consumption. Metabolomic analysis of sin-3 mutant animals revealed a mitochondria stress signature and deregulation of methionine flux, resulting in decreased S-adenosyl methionine (SAM) and increased polyamine levels. Our results identify SIN3 as a key regulator of mitochondrial dynamics and metabolic flux, with important implications for human pathologies.

Keywords:  Cell biology; Omics; Systems biology

DOI:  https://doi.org/10.1016/j.isci.2024.109789
Cerebellum. 2024 May 13.

Driving Mitochondrial Fission Improves Cognitive, but not Motor Deficits in a Mouse Model of Ataxia of Charlevoix-Saguenay.

Chunling Chen, Ronald A Merrill, Chian Ju Jong, Stefan Strack.

  Autosomal-recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is caused by loss-of-function mutation in the SACS gene, which encodes sacsin, a putative HSP70-HSP90 co-chaperone. Previous studies with Sacs knock-out (KO) mice and patient-derived fibroblasts suggested that SACSIN mutations inhibit the function of the mitochondrial fission enzyme dynamin-related protein 1 (Drp1). This in turn resulted in mitochondrial hyperfusion and dysfunction. We experimentally tested this hypothesis by genetically manipulating the mitochondrial fission/fusion equilibrium, creating double KO (DKO) mice that also lack positive (PP2A/Bβ2) and negative (PKA/AKAP1) regulators of Drp1. Neither promoting mitochondrial fusion (Bβ2 KO) nor fission (Akap1 KO) influenced progression of motor symptoms in Sacs KO mice. However, our studies identified profound learning and memory deficits in aged Sacs KO mice. Moreover, this cognitive impairment was rescued in a gene dose-dependent manner by deletion of the Drp1 inhibitor PKA/Akap1. Our results are inconsistent with mitochondrial dysfunction as a primary pathogenic mechanism in ARSACS. Instead, they imply that promoting mitochondrial fission may be beneficial at later stages of the disease when pathology extends to brain regions subserving learning and memory.

Keywords:  A kinase anchoring protein; ARSACS; Ataxia; Dynamin-related protein 1; Mitochondrial dynamics; Protein phosphatase 2A

DOI:  https://doi.org/10.1007/s12311-024-01701-1
J Transl Med. 2024 May 16. 22(1): 465

Aberrant expression of NEDD4L disrupts mitochondrial homeostasis by downregulating CaMKKβ in diabetic kidney disease.

Fei Han, Shi Wu, Ya Dong, Yanjie Liu, Bei Sun, Liming Chen.

  Disturbance in mitochondrial homeostasis within proximal tubules is a critical characteristic associated with diabetic kidney disease (DKD). CaMKKβ/AMPK signaling plays an important role in regulating mitochondrial homeostasis. Despite the downregulation of CaMKKβ in DKD pathology, the underlying mechanism remains elusive. The expression of NEDD4L, which is primarily localized to renal proximal tubules, is significantly upregulated in the renal tubules of mice with DKD. Coimmunoprecipitation (Co-IP) assays revealed a physical interaction between NEDD4L and CaMKKβ. Moreover, deletion of NEDD4L under high glucose conditions prevented rapid CaMKKβ protein degradation. In vitro studies revealed that the aberrant expression of NEDD4L negatively influences the protein stability of CaMKKβ. This study also explored the role of NEDD4L in DKD by using AAV-shNedd4L in db/db mice. These findings confirmed that NEDD4L inhibition leads to a decrease in urine protein excretion, tubulointerstitial fibrosis, and oxidative stress, and mitochondrial dysfunction. Further in vitro studies demonstrated that si-Nedd4L suppressed mitochondrial fission and reactive oxygen species (ROS) production, effects antagonized by si-CaMKKβ. In summary, the findings provided herein provide strong evidence that dysregulated NEDD4L disturbs mitochondrial homeostasis by negatively modulating CaMKKβ in the context of DKD. This evidence underscores the potential of therapeutic interventions targeting NEDD4L and CaMKKβ to safeguard renal tubular function in the management of DKD.

Keywords:  CaMKKβ; Diabetic kidney disease; Mitochondrial homeostasis; NEDD4L

DOI:  https://doi.org/10.1186/s12967-024-05207-6
Shock. 2024 May 15.

Sirtuin 5 alleviates excessive mitochondrial fission via desuccinylation of ATPase inhibitory factor 1 in sepsis-induced acute kidney injury.

Jiaxin Li, Yi Yao, Xiaobao Lei, Jingna Bao, Sheng An, Hongbin Hu, Tong Sha, Qiaobing Huang, Tao Li, Zhenhua Zeng, Xiang Wang, Shumin Cai.

ABSTRACT: Sepsis-induced acute kidney injury (SAKI) poses a significant clinical challenge with high morbidity and mortality. Excessive mitochondrial fission has been identified as the central pathogenesis of sepsis-associated organ damage, which is also implicated in the early stages of SAKI. Sirtuin 5 (SIRT5) has emerged as a central regulator of cellular mitochondrial function; however, its role in the regulation of sepsis-induced excessive mitochondrial fission in kidney and the underlying mechanism remains unclear.In this study, SAKI was modeled in mice through cecal ligation and puncture (CLP), and in human renal tubular epithelial (HK-2) cells stimulated with lipopolysaccharide (LPS), to mimic the cell SAKI model. Our findings revealed that septic mice with a SIRT5 knockout (SIRT5 KO) exhibited shortened survival times and elevated levels of renal injury compared to wild-type (WT) mice, suggesting the significant involvement of SIRT5 in SAKI pathophysiology. Additionally, we observed that SIRT5 depletion led to increased renal mitochondrial fission, while the use of a mitochondrial fission inhibitor (Mdivi-1) reversed the detrimental effects caused by SIRT5 depletion, emphasizing the pivotal role of SIRT5 in preventing excessive mitochondrial fission. In vitro experiments demonstrated that the overexpression of SIRT5 effectively mitigated the adverse effects of LPS on HK-2 cells viability and mitochondrial fission. Conversely, downregulation of SIRT5 decreased HK-2 cells viability and exacerbated LPS-induced mitochondrial fission. Mechanistically, the protective function of SIRT5 may be in part, ascribed to its desuccinylating action on ATPase inhibitory factor 1 (ATPIF1).In conclusion, this study provides novel insights into the underlying mechanisms of SAKI, suggesting the possibility of identifying future drug targets in terms of improved mitochondrial dynamics by SIRT5.

DOI: https://doi.org/10.1097/SHK.0000000000002392
Aging Dis. 2024 Apr 25.

The Role of Protein S-Nitrosylation in Mitochondrial Quality Control in Central Nervous System Diseases.

Fang Qiu, Yuqiang Liu, Zhiheng Liu.

S-Nitrosylation is a reversible covalent post-translational modification. Under physiological conditions, S-nitrosylation plays a dynamic role in a wide range of biological processes by regulating the function of substrate proteins. Like other post-translational modifications, S-nitrosylation can affect protein conformation, activity, localization, aggregation, and protein interactions. Aberrant S-nitrosylation can lead to protein misfolding, mitochondrial fragmentation, synaptic damage, and autophagy. Mitochondria are essential organelles in energy production, metabolite biosynthesis, cell death, and immune responses, among other processes. Mitochondrial dysfunction can result in cell death and has been implicated in the development of many human diseases. Recent evidence suggests that S-nitrosylation and mitochondrial dysfunction are important modulators of the progression of several diseases. In this review, we highlight recent findings regarding the aberrant S- nitrosylation of mitochondrial proteins that regulate mitochondrial biosynthesis, fission and fusion, and autophagy. Specifically, we discuss the mechanisms by which S-nitrosylated mitochondrial proteins exercise mitochondrial quality control under pathological conditions, thereby influencing disease. A better understanding of these pathological events may provide novel therapeutic targets to mitigate the development of neurological diseases.

DOI: https://doi.org/10.14336/AD.2024.0099
Int J Biol Macromol. 2024 May 13. pii: S0141-8130(24)03169-6. [Epub ahead of print]270(Pt 1): 132364

Mitochondrial citrate transporters Ctp1-Yhm2 and respiratory chain: A coordinated functional connection in Saccharomyces cerevisiae metabolism.

Gabriella De Blasi, Paola Lunetti, Vincenzo Zara, Alessandra Ferramosca.

  The mitochondrial inner membrane contains some hydrophobic proteins that mediate the exchange of metabolites between the mitochondrial matrix and the cytosol. Ctp1 and Yhm2 are two carrier proteins in the yeast Saccharomyces cerevisiae responsible for the transport of citrate, a tricarboxylate involved in several metabolic pathways. Since these proteins also contribute to respiratory metabolism, in this study we investigated for the first time whether changes in citrate transport can affect the structural organization and functional properties of respiratory complexes. Through experiments in yeast mutant cells in which the gene encoding Ctp1 or Yhm2 was deleted, we found that in the absence of either mitochondrial citrate transporter, mitochondrial respiration was impaired. Structural analysis of the respiratory complexes III and IV revealed different expression levels of the catalytic and supernumerary subunits in the Δctp1 and Δyhm2 strains. In addition, Δyhm2 mitochondria appeared to be more sensitive than Δctp1 to the oxidative damage. Our results provide the first evidence for a coordinated modulation of mitochondrial citrate transport and respiratory chain activity in S. cerevisiae metabolism.

Keywords:  Carrier; Citrate; Mitochondria; Respiratory chain; Respiratory complexes

DOI:  https://doi.org/10.1016/j.ijbiomac.2024.132364
Acta Pharmacol Sin. 2024 May 15.

PHLDA1 contributes to hypoxic ischemic brain injury in neonatal rats via inhibiting FUNDC1-mediated mitophagy.

Xiao-Lu Jiang, Zu-Bin Zhang, Chen-Xi Feng, Chen-Jie Lin, Hui Yang, Lan-Lan Tan, Xin Ding, Li-Xiao Xu, Gen Li, Tao Pan, Zheng-Hong Qin, Bin Sun, Xing Feng, Mei Li.

  Hypoxia-ischemia (HI) is one of the main causes of neonatal brain injury. Mitophagy has been implicated in the degradation of damaged mitochondria and cell survival following neonatal brain HI injury. Pleckstrin homology-like domain family A member 1 (PHLDA1) plays vital roles in the progression of various disorders including the regulation of oxidative stress, the immune responses and apoptosis. In the present study we investigated the role of PHLDA1 in HI-induced neuronal injury and further explored the mechanisms underlying PHLDA1-regulated mitophagy in vivo and in vitro. HI model was established in newborn rats by ligation of the left common carotid artery plus exposure to an oxygen-deficient chamber with 8% O2 and 92% N2. In vitro studies were conducted in primary hippocampal neurons subjected to oxygen and glucose deprivation/-reoxygenation (OGD/R). We showed that the expression of PHLDA1 was significantly upregulated in the hippocampus of HI newborn rats and in OGD/R-treated primary neurons. Knockdown of PHLDA1 in neonatal rats via lentiviral vector not only significantly ameliorated HI-induced hippocampal neuronal injury but also markedly improved long-term cognitive function outcomes, whereas overexpression of PHLDA1 in neonatal rats via lentiviral vector aggravated these outcomes. PHLDA1 knockdown in primary neurons significantly reversed the reduction of cell viability and increase in intracellular reactive oxygen species (ROS) levels, and attenuated OGD-induced mitochondrial dysfunction, whereas overexpression of PHLDA1 decreased these parameters. In OGD/R-treated primary hippocampal neurons, we revealed that PHLDA1 knockdown enhanced mitophagy by activating FUNDC1, which was abolished by FUNDC1 knockdown or pretreatment with mitophagy inhibitor Mdivi-1 (25 μM). Notably, pretreatment with Mdivi-1 or the knockdown of FUNDC1 not only increased brain infarct volume, but also abolished the neuroprotective effect of PHLDA1 knockdown in HI newborn rats. Together, these results demonstrate that PHLDA1 contributes to neonatal HI-induced brain injury via inhibition of FUNDC1-mediated neuronal mitophagy.

Keywords:  FUNDC1; Mdivi-1; PHLDA1; hypoxia–ischemia; mitophagy; neonatal brain injury

DOI:  https://doi.org/10.1038/s41401-024-01292-x
Int J Mol Sci. 2024 Apr 29. pii: 4853. [Epub ahead of print]25(9):

Mitophagy Regulates the Circadian Rhythms by Degrading NR1D1 in Simulated Microgravity and Isolation Environments.

Sihai Zhou, Xiaopeng Li, Fengji Liang, Guohua Ji, Ke Lv, Yanhong Yuan, Yujie Zhao, Na Yan, Chuanjie Zhang, Shiou Cai, Shuhui Zhang, Xu Liu, Bo Song, Lina Qu.

  Long-term spaceflight is known to induce disruptions in circadian rhythms, which are driven by a central pacemaker located in the suprachiasmatic nucleus (SCN) of the hypothalamus, but the underlying molecular mechanisms remain unclear. Here, we developed a rat model that simulated microgravity and isolation environments through tail suspension and isolation (TSI). We found that the TSI environment imposed circadian disruptions to the core body temperature, heart rate, and locomotor-activity rhythms of rats, especially in the amplitude of these rhythms. In TSI model rats' SCNs, the core circadian gene NR1D1 showed higher protein but not mRNA levels along with decreased BMAL1 levels, which indicated that NR1D1 could be regulated through post-translational regulation. The autophagosome marker LC3 could directly bind to NR1D1 via the LC3-interacting region (LIR) motifs and induce the degradation of NR1D1 in a mitophagy-dependent manner. Defects in mitophagy led to the reversal of NR1D1 degradation, thereby suppressing the expression of BMAL1. Mitophagy deficiency and subsequent mitochondrial dysfunction were observed in the SCN of TSI models. Urolithin A (UA), a mitophagy activator, demonstrated an ability to enhance the amplitude of core body temperature, heart rate, and locomotor-activity rhythms by prompting mitophagy induction to degrade NR1D1. Cumulatively, our results demonstrate that mitophagy exerts circadian control by regulating NR1D1 degradation, revealing mitophagy as a potential target for long-term spaceflight as well as diseases with SCN circadian disruption.

Keywords:  NR1D1; circadian rhythms; mitophagy; suprachiasmatic nucleus; tail-suspension-and-isolation model; urolithin A

DOI:  https://doi.org/10.3390/ijms25094853
Sci Adv. 2024 May 17. 10(20): eadn2867

Serine synthesis controls mitochondrial biogenesis in macrophages.

Chuanlong Wang, Muyang Zhao, Peng Bin, Yuyi Ye, Qingyi Chen, Zhiru Tang, Wenkai Ren.

Mitochondrial dysfunction is the pivotal driving factor of multiple inflammatory diseases, and targeting mitochondrial biogenesis represents an efficacious approach to ameliorate such dysfunction in inflammatory diseases. Here, we demonstrated that phosphoglycerate dehydrogenase (PHGDH) deficiency promotes mitochondrial biogenesis in inflammatory macrophages. Mechanistically, PHGDH deficiency boosts mitochondrial reactive oxygen species (mtROS) by suppressing cytoplasmic glutathione synthesis. mtROS provokes hypoxia-inducible factor-1α signaling to direct nuclear specificity protein 1 and nuclear respiratory factor 1 transcription. Moreover, myeloid Phgdh deficiency reverses diet-induced obesity. Collectively, this study reveals that a mechanism involving de novo serine synthesis orchestrates mitochondrial biogenesis via mitochondrial-to-nuclear communication, and provides a potential therapeutic target for tackling inflammatory diseases and mitochondria-mediated diseases.

DOI: https://doi.org/10.1126/sciadv.adn2867
Free Radic Biol Med. 2024 May 11. pii: S0891-5849(24)00457-X. [Epub ahead of print]220 312-323

Lactate regulates respiratory efficiency and mitochondrial dynamics in primary rat podocytes.

Irena Audzeyenka, Maria Szrejder, Patrycja Rachubik, Klaudia Grochowalska, Tomasz Kulesza, Dorota Rogacka, Magdalena Narajczyk, Agnieszka Piwkowska.

  Podocytes are crucial for regulating glomerular permeability. They have foot processes that are integral to the renal filtration barrier. Understanding their energy metabolism could shed light on the pathogenesis of filtration barrier injury. Lactate has been increasingly recognized as more than a waste product and has emerged as a significant metabolic fuel and reserve. The recent identification of lactate transporters in podocytes, the expression of which is modulated by glucose levels and lactate, highlights lactate's relevance. The present study investigated the impact of lactate on podocyte respiratory efficiency and mitochondrial dynamics. We confirmed lactate oxidation in podocytes, suggesting its role in cellular energy production. Under conditions of glucose deprivation or lactate supplementation, a significant shift was seen toward oxidative phosphorylation, reflected by an increase in the oxygen consumption rate/extracellular acidification rate ratio. Notably, lactate dehydrogenase A (LDHA) and lactate dehydrogenase B (LDHB) isoforms, which are involved in lactate conversion to pyruvate, were detected in podocytes for the first time. The presence of lactate led to higher intracellular pyruvate levels, greater LDH activity, and higher LDHB expression. Furthermore, lactate exposure increased mitochondrial DNA-to-nuclear DNA ratios and resulted in upregulation of the mitochondrial biogenesis markers peroxisome proliferator-activated receptor coactivator-1α and transcription factor A mitochondrial, regardless of glucose availability. Changes in mitochondrial size and shape were observed in lactate-exposed podocytes. These findings suggest that lactate is a pivotal energy source for podocytes, especially during energy fluctuations. Understanding lactate's role in podocyte metabolism could offer insights into renal function and pathologies that involve podocyte injury.

Keywords:  LDHA; LDHB; Lactate dehydrogenase; Mitochondrial biogenesis; Oxidative phosphorylation

DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.05.022
Free Radic Biol Med. 2024 May 09. pii: S0891-5849(24)00446-5. [Epub ahead of print]220 192-206

MitoTempo protects against nε-carboxymethyl lysine-induced mitochondrial dyshomeostasis and neuronal cells injury.

Cristina Carvalho, Paula I Moreira.

  Enhanced formation of advanced glycation end products (AGEs) is a pivotal factor in diabetes pathophysiology, increasing the risk of diabetic complications. Nε-carboxy-methyl-lysine (CML) is one of the most relevant AGEs found in several tissues including the peripheral blood of diabetic subjects. Despite recognizing diabetes as a risk factor for neurodegenerative diseases and the documented role of mitochondrial abnormalities in this connection, the impact of CML on neuronal mitochondria and its contribution to diabetes-related neurodegeneration remain uncertain. Here, we evaluated the effects of CML in differentiated SH-SY5Y human neuroblastoma cells. Due to the association between mitochondrial dysfunction and increased production of reactive oxygen species (ROS), the possible protective effects of MitoTempo, a mitochondria-targeted antioxidant, were also evaluated. Several parameters were assessed namely cells viability, mitochondrial respiration and membrane potential, ATP and ROS production, Ca2+ levels, mitochondrial biogenesis and dynamics, mito/autophagy, endoplasmic reticulum (ER) stress and amyloidogenic and synaptic integrity markers. CML caused pronounced mitochondrial defects characterized by a significant decrease in mitochondrial respiration, membrane potential, and ATP production and an increase in ROS production. An accumulation of individual mitochondria associated with disrupted mitochondrial networks was also observed. Furthermore, CML caused mitochondrial fusion and a decrease in mitochondrial mass and induced ER stress associated with altered unfolded protein response and Ca2+ dyshomeostasis. Moreover, CML increased the protein levels of β-secretase-1 and amyloid precursor protein, key proteins involved in Alzheimer's Disease pathophysiology. All these effects contributed to the decline in neuronal cells viability. Notable, MitoTempo was able to counteract most of CML-mediated mitochondrial defects and neuronal cells injury and death. Overall, these findings suggest that CML induces pronounced defects in neuronal mitochondria and ER stress, predisposing to neurodegenerative events. More, our observations suggest that MitoTempo holds therapeutic promise in mitigating CML-induced mitochondrial imbalance and neuronal damage and death.

Keywords:  MitoTempo; Mitochondrial defects; Neurodegeneration; Neuroprotection; Nε-carboxymethyl lysine

DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.05.011