The Role of Mitochondrial Mutations in Chronification of Inflammation: Hypothesis and Overview of Own Data

Orekhov, Alexander N.; Nikiforov, Nikita G.; Omelchenko, A. V.; Sinyov, Vasily V.; Sobenin, Igor A.; Vinokurov, Andrey Y.; Orekhova, Varvara A.

doi:10.3390/life12081153

Cited by 8 publications

(3 citation statements)

References 47 publications

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“…The violation of immune tolerance in terms of CCL2 may be an important factor in the pathogenesis of chronic in ammation in SSc since impaired tolerance of the immune response indicates persistent over-secretion of the chemokine CCL2 promoting the in ammatory cells recruitment to the sites of in ammation and differentiation of broblasts that leads to tissue brosis and damage. These ndings match the hypothesis that the violation of immune response of macrophages on the in ammatory stimulation is an important mechanism of chroni cation of in ammation, that was demonstrated previously in cybrid lines carrying atherosclerosis-associated mitochondrial DNA mutations [20]. In this regard, CCL2 should be considered as therapeutic target for the development of immunomodulatory strategies for SSc treatment.…”

Section: Discussionsupporting

confidence: 88%

Pro-inflammatory response of monocytes in systemic sclerosis

Kirichenko

Markin

Gerasimova³

et al. 2023

Preprint

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Objective. The investigation of inflammatory response of immune cells is one of the most actual trends in research of autoimmune disorders including SSc. This study was aimed to investigate the inflammatory cytokines secretion and to evaluate the pro-inflammatory status of blood-derived monocytes in SSc. Methods. The study included 35 SSc and 25 heathy participants. Secretion of inflammatory cytokines TNF-α a, IL1β, CCL2 and IL8 was measured by ELISA in primary culture of monocytes/macrophages after stimulation with LPS on day 1 and 6 of incubation to assess the pro-inflammatory activation and immune tolerance of monocytes. Impaired tolerance of immune response is characterized by increased secretion of inflammatory mediators in response to re-stimulation. Results. Basal secretion of TNF-α, IL1β, CCL2 and IL8 was significantly higher in SSc patients than in healthy subjects. After the first LPS-stimulation secretion of TNF-α and IL1β, but not CCL2 and IL8 was also higher in SSc group. In 24 hours after re-stimulation, the secretion of IL1β, CCL2 and IL8, but not TNF-α increased significantly in SSc group compared to healthy control. CCL2 secretion by re-stimulated monocytes was 1.8-fold higher than in cells without re-stimulation in SSc group, that was significantly different from healthy subjects. Conclusion. The study results demonstrate pro-inflammatory activation and impaired immune tolerance of monocytes in SSc. The violation of immune response in terms of CCL2 may be an important factor of the chronification of inflammation in SSc. Thus, CCL2 should be considered as therapeutic target for the development of immunomodulatory strategies for SSc treatment.

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Section: Discussionsupporting

confidence: 88%

Pro-inflammatory response of monocytes in systemic sclerosis

Kirichenko

Markin

Gerasimova³

et al. 2023

Preprint

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“…119 A direct relationship between the presence of some mtDNA mutations and defective mitophagy was also established in chronic inflammation-associated atherosclerotic disease. 147 Therefore, it is possible to suggest that mitochondrial mutations can be the cause of defective mitophagy (Fig. 3), which, in turn, can disrupt the immune response, leading to the development of local chronic inflammation and the formation of an atherosclerotic lesion in the arterial wall, as observed in atherosclerosis.…”

Section: Defective Mitophagy and Mtdna Mutationsmentioning

confidence: 99%

Role of Mitochondria in the Chronification of Inflammation: Focus on Dysfunctional Mitophagy and Mitochondrial DNA Mutations

Orekhov,

Summerhill,

Khotina

et al. 2023

Gene Expr

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Inflammation is a natural reaction of the innate immune system that evolved primarily to protect the human body from invading pathogens and to heal injuries. There are two different types of inflammation, acute and chronic inflammation, differing in duration, underlying causes, and characteristics. The acute-to-chronic transition can be determined by several pathomechanisms, including dysregulation of immune response and failure to eliminate the underlying cause. Moreover, epigenetic changes that refer to modifications in gene expression that are heritable but do not involve changes to the underlying DNA sequence can also contribute to prolonged inflammation. Emerging evidence suggests that dysfunctional mitochondria can promote the development of chronic inflammation. In this respect, the mechanisms triggering defective mitophagy, a selective form of autophagy that exterminates dysfunctional mitochondria to maintain cellular homeostasis, attracted special attention. The hypothesis on the pivotal role of mutations in mitochondrial DNA causing defective mitophagy stimulated the area of the research that applies editing of the mitochondrial genome. The mitoCAS9 vector and two single guide RNAs to the G15059A mutation were used to eliminate the mutation from the macrophage-like cells. The normal activity of the initially defective mitophagy was restored in intact macrophage-like cells, confirming the causal role of the G15059A mutation in the disruption of the mitophagy process. The unraveling of the underlying mechanisms of chronic inflammation will help to develop targeted therapeutic approaches aimed at restoring mitochondrial health and alleviating chronic inflammation that can be used for the treatment of a wide range of chronic inflammatory diseases.

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“…The presence of heteroplasmic mutations in mitochondrial DNA (mtDNA) can result in the appearance of dysfunctional mitochondria in intimal cells 3 . The primary mechanism for the removal of damaged mitochondria in cells is through mitophagy, a process in which mitochondria fuse with lysosomes and undergo subsequent degradation 4 .…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial genome editing: a possible interplay of atherosclerosis-associated mutation m.15059G>A with defective mitophagy

Khotina

Kalmykov

Zhuravlev

et al. 2023

Preprint

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Objective: It was assumed that the cause of chronic inflammation in atherosclerosis is a disturbance of the innate immunity response, caused, among other factors, by mitochondrial dysfunctions. It was also suggested that mitochondrial dysfunction may be caused by heteroplasmic mutations in mitochondrial DNA. The aim of this study was to evaluate the effect of the mitochondrial nonsense mutation m.15059G>A on cellular functions in atherosclerosis: lipoidosis, pro-inflammatory response, and mitophagy. Approach and Results: The human monocytic cell line THP-1 and cytoplasmic hybrid cell line TC-HSMAM1 were used. An original approach based on the CRISPR/Cas9 system was developed and used for the elimination of mtDNA copies carrying the m.15059G>A mutation in the MT-CYB gene. Using this approach, the Cas9-TC-HSMAM1 cells with an eliminated m.15059G>A mutation was obtained. The gene expression levels of genes encoding enzymes related to cholesterol metabolism were analyzed by quantitative RT-PCR. The evaluation of pro-inflammatory cytokine secretion was assessed using ELISA. Mitophagy in cells was detected using confocal microscopy. In contrast to intact TC-HSMAM1 cybrids, in Cas9-TC-HSMAM1 cells, incubation with atherogenic LDL led to a decrease in the expression of the gene encoding fatty acid synthase (FASN). It was found that TC-HSMAM1 cybrids are characterized by defective mitophagy and are also unable to reduce the production of pro-inflammatory cytokines (to form immune tolerance) in response to repeated LPS stimulation. Elimination of mtDNA carrying the m.15059G>A mutation led to the restoration of immune tolerance and activation of mitophagy in the studied cells. Conclusion: The m.15059G>A mutation was found to be associated with defective mitophagy, immune tolerance, and impaired metabolism of intracellular lipids due to upregulation of the FASN. Thus, this mutation may play an important role in atherogenesis due to its contribution to the chronification of inflammation, which aggravates the progression of atherosclerosis.

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The Role of Mitochondrial Mutations in Chronification of Inflammation: Hypothesis and Overview of Own Data

Cited by 8 publications

References 47 publications

Pro-inflammatory response of monocytes in systemic sclerosis

Pro-inflammatory response of monocytes in systemic sclerosis

Role of Mitochondria in the Chronification of Inflammation: Focus on Dysfunctional Mitophagy and Mitochondrial DNA Mutations

Mitochondrial genome editing: a possible interplay of atherosclerosis-associated mutation m.15059G>A with defective mitophagy

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