Mitochondrial OXPHOS influences immune cell fate: lessons from hematopoietic AIF-deficient and NDUFS4-deficient mouse models

Mitochondria are small cellular constituents that generate cellular energy (ATP) by oxidative phosphorylation (OXPHOS). Dysfunction of these organelles is linked to a heterogeneous group of multisystemic disorders, including diabetes, cancer, ageing-related pathologies and rare mitochondrial diseases (MDs). With respect to the latter, mutations in subunit-encoding genes and assembly factors of the first OXPHOS complex (CI) induce isolated CI deficiency and Leigh syndrome (LS). This syndrome is an early-onset, often fatal, encephalopathy with a variable clinical presentation and poor prognosis due to the lack of effective intervention strategies. Mutations in the nuclear DNA (nDNA)-encoded NDUFS4 gene, encoding the NADH: Ubiquinone oxidoreductase subunit S4 (NDUFS4) of CI induce “mitochondrial complex I deficiency, nuclear type 1” (MC1DN1) and LS in pediatric patients. A variety of (tissue-specific) Ndufs4 knockout mouse models were developed to study the LS pathomechanism and intervention testing. Here, we review and discuss the role of CI and NDUFS4 mutations in human MD, and review how the analysis of Ndufs4 knockout mouse models has generated new insights into the MC1ND1/LS pathomechanism and its therapeutic targeting.

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“…Mouse models focusing on the impact of Ndufs4 deletion on inflammation, bone resorption and immune cell fate are presented elsewhere. 73 , 74 …”

Section: The Ndufs4 Whole-body Knockout Mouse Modelmentioning

confidence: 99%

Ndufs4 knockout mouse models of Leigh syndrome: pathophysiology and intervention

Wal

Adjobo‐Hermans

Keijer

et al. 2021

Brain

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“…Besides its expression in ECs, Tie2 is also expressed in around 80-90% of hematopoietic cells including lymphocytes and macrophages 15,16 . However, genetic disruption of mitochondrial respiration in lymphocytes did not result in embryonic lethality [17][18][19] . Similarly, we did not observe embryonic lethality upon specific ablation of cox10 in myeloid cells using LysM-Cre transgenic mice 20 ( Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

Mitochondrial respiration controls neoangiogenesis during wound healing and tumour growth

et al. 2020

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The vasculature represents a highly plastic compartment, capable of switching from a quiescent to an active proliferative state during angiogenesis. Metabolic reprogramming in endothelial cells (ECs) thereby is crucial to cover the increasing cellular energy demand under growth conditions. Here we assess the impact of mitochondrial bioenergetics on neovascularisation, by deleting cox10 gene encoding an assembly factor of cytochrome c oxidase (COX) specifically in mouse ECs, providing a model for vasculature-restricted respiratory deficiency. We show that EC-specific cox10 ablation results in deficient vascular development causing embryonic lethality. In adult mice induction of EC-specific cox10 gene deletion produces no overt phenotype. However, the angiogenic capacity of COX-deficient ECs is severely compromised under energetically demanding conditions, as revealed by significantly delayed wound-healing and impaired tumour growth. We provide genetic evidence for a requirement of mitochondrial respiration in vascular endothelial cells for neoangiogenesis during development, tissue repair and cancer.

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“…It is reported that these differential genes play an important role in the process of mitochondrial damage. [34][35][36][37][38][39] For example, the expression of ndufb6 and ndufs3 increased after AF-HF001 treatment, which increased myocardial contractility and improved oxidative damage. 38 Overexpression of Uqcrh can improve mitochondrial function.…”

Section: Discussionmentioning

confidence: 98%

Protective effects of agrimonolide on hypoxia‐induced H9c2 cell injury by maintaining mitochondrial homeostasis

Wang

Liu

et al. 2021

J of Cellular Biochemistry

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Cardiomyocyte death caused by hypoxia is one of the main causes of myocardial infarction or heart failure, and mitochondria play an important role in this process. Agrimonolide (AM) is a monomeric component extracted from Agrimonia pilosa L. and has antioxidant, antitumor, and anti-inflammatory effects. This study aimed to investigate the role and mechanism of AM in improving hypoxia-induced H9c2 cell damage. The results showed that low AM concentrations promote H9c2 cell proliferation and increase cellular ATP content. Transcriptome sequencing showed that AM induces differential expression of genes in H9c2 cells. Gene ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses revealed that these genes were concentrated in mitochondrial function. Subsequent experiments confirmed that AM regulates hypoxia-induced cell cycle arrest. AM inhibited the rate of apoptosis by regulating the expression of apoptosis-related proteins, reducing the level of cleaved Caspase 3 and Bax, and increasing the level of Bcl2, thereby protecting H9c2 cells from hypoxiainduced apoptosis. AM restored the mitochondrial membrane potential, inhibited the generation of ROS, maintained the normal shape of the mitochondria, improved the level of the mitochondrial functional proteins OPA1, MFN1, MFN2, Tom20, and increased the level of ATP. In conclusion, AM protects H9c2 cells from hypoxia-induced cell damage.

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Mitochondrial OXPHOS influences immune cell fate: lessons from hematopoietic AIF-deficient and NDUFS4-deficient mouse models

Cited by 7 publications

References 16 publications

Ndufs4 knockout mouse models of Leigh syndrome: pathophysiology and intervention

Ndufs4 knockout mouse models of Leigh syndrome: pathophysiology and intervention

Mitochondrial respiration controls neoangiogenesis during wound healing and tumour growth

Protective effects of agrimonolide on hypoxia‐induced H9c2 cell injury by maintaining mitochondrial homeostasis

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