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Mitochondrial function decline in a mouse model of Marfan syndrome. A through D, RNA-sequencing analysis of aortas from 4 Fbn1 C1039G/+ mice with 3 Fbn1 +/+ littermates (24-week-old male mice). B, Top 10 significantly changed canonical pathways predicted by ingenuity pathway analysis based on differentially regulated genes. Metabolism-related pathways are highlighted in blue lettering; P<0.01. C, Activation or inhibition of upstream regulators predicted by ingenuity pathway analysis (-2>bias-corrected z-score>4; P<0.05). The predicted inhibition of Tfam is highlighted. D, Expression of genes encoding mitochondrial complexes (Co) and fatty acid oxidation enzymes, and genes related to mitochondrial function and glycolysis; P < 0.05. E, Quantitative reverse transcription polymerase chain reaction analysis of Tfam mRNA expression and quantitative polymerase chain reaction analysis of relative mtDNA content in aortic extracts from 20-week-old Fbn1 C1039G/+ and Fbn1 +/+ male mice. F through I, Primary murine vascular smooth muscle cells transduced with shFbn1 or shControl for 5 days. F, Quantitative reverse transcription polymerase chain reaction of Hif1a, Pdk1, and representative immunoblots analysis, and relative quantification of Hif1a and Pdk1 protein levels. G, Quantitative reverse transcription polymerase chain reaction of Tfam and Ppargc1a and representative immunoblot analysis and quantification of Pgc1α, Tfam, Mt-Nd1, and Mt-Co1. H, Quantitative polymerase chain reaction analysis of relative mtDNA content in shFbn1-and shControl-transduced vascular smooth muscle cells. I, OCR in shFbn1 and shControl vascular smooth muscle cells at basal respiration and after addition of the complex V inhibitor oligomycin (I) and fluoro carbonyl cyanide phenylhydrazone (II) to measure maximal respiration, followed by a combination of rotenone and antimycin A (III). J, Levels of extracellular lactate in the supernatant from shFbn1 and shControl vascular smooth muscle cells. Actin was used as total protein loading control. Data are mean±SEM Statistical significance was assessed by Student t test. *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001 vs Fbn1 +/+ mice (E), shControl (F through J). Acaa1b indicates 3-ketoacyl-CoA thiolase B, peroxisomal; Acsl5, Acyl-CoA Synthetase Long Chain Family Member 5; Akt, serine/threonine kinase 1; Atpaf2, ATP synthase mitochondrial F1 complex assembly factor 2; Ccn2, cellular communication network factor 2; CoI-V, mitochondrial complexes I-V; Cox8b, cytochrome c oxidase subunit 8B; Cycs, cytochrome c, somatic; Echs1, enoyl-CoA hydratase, short chain 1; Erk, extracellular signal regulated kinases; Fbn1, fibrillin-1; Hadh, hydroxyacyl-CoA dehydrogenase; Hif1a, hypoxia-inducible factor 1 α; Idh3g, isocitrate dehydrogenase (NAD(+)) 3 non-catalytic subunit gamma; Ivd, isovaleryl-CoA dehydrogenase; Mrtfa, b, myocardin related transcription factor A, B; Mt-Atp6, mitochondrially-encoded ATP synthase membrane subunit 6; Mt-Co1, 2, mitochondrially encoded cytochrome c oxidase I /II; Mt-Nd1-4I, mitochondrially encoded NADH dehydrogenase 1-4; Myc, Myc protoncogen, myelocytomatosis oncogene; Ndufa9, 10, NADH:ubiquinone oxidoreductase subunit A9-10; Ndufb8, NADH:ubiquinone oxidoreductase subunit B8; Ndufs4, 8, NADH:ubiquinone oxidoreductase core subunit S4,8; Ndufv1-3, NADH:ubiquinone oxidoreductase core subunit V1-3; Nos2, nitric oxide synthase 2; (Continued)
Source publication
Background: Marfan syndrome (MFS) is an autosomal dominant disorder of the connective tissue caused by mutations in the FBN1 gene encoding a large glycoprotein in the extracellular matrix called fibrillin-1. The major complication of this connective disorder is the risk to develop thoracic aortic aneurysm (TAA). To date, no effective pharmacologica...
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... C1039G/+ mice reproduce the aortic dilation, aneurysms, and histologic features of aortic medial degeneration found in MFS patients. 28 To identify novel molecular mechanisms underlying TAA formation, we performed transcriptional analysis in aortas from 24-week-old Fbn1 C1039G/+ mice, showing an intermediate stage of the aortic disease ( Figure 1A). 34,35 Ingenuity pathway analysis revealed that 6 of the 10 most altered canonical pathways were related to metabolism, including oxidative phosphorylation, mitochondrial dysfunction, fatty acid β-oxidation, and the tricarboxylic acid cycle ( Figure 1B). ...
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... To identify novel molecular mechanisms underlying TAA formation, we performed transcriptional analysis in aortas from 24-week-old Fbn1 C1039G/+ mice, showing an intermediate stage of the aortic disease ( Figure 1A). 34,35 Ingenuity pathway analysis revealed that 6 of the 10 most altered canonical pathways were related to metabolism, including oxidative phosphorylation, mitochondrial dysfunction, fatty acid β-oxidation, and the tricarboxylic acid cycle ( Figure 1B). Ingenuity pathway analysis prediction of activity of upstream regulators identified canonical MFS regulators such as inducible Nos2 (nitric oxide synthase) and Tgfb1 (transforming growth factor β1). 28,32 This analysis pointed to increased activity of the glycolytic regulator Hif1α (hypoxia-inducible factor α) and reduced activity of several mitochondrial biogenesis and function regulators, including Tfam ( Figure 1C). ...
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... Ingenuity pathway analysis revealed that 6 of the 10 most altered canonical pathways were related to metabolism, including oxidative phosphorylation, mitochondrial dysfunction, fatty acid β-oxidation, and the tricarboxylic acid cycle ( Figure 1B). Ingenuity pathway analysis prediction of activity of upstream regulators identified canonical MFS regulators such as inducible Nos2 (nitric oxide synthase) and Tgfb1 (transforming growth factor β1). 28,32 This analysis pointed to increased activity of the glycolytic regulator Hif1α (hypoxia-inducible factor α) and reduced activity of several mitochondrial biogenesis and function regulators, including Tfam ( Figure 1C). Fbn1 C1039G/+ aortas showed reduced A through D, RNA-sequencing analysis of aortas from 4 Fbn1 C1039G/+ mice with 3 Fbn1 +/+ littermates (24-week-old male mice). ...
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... Fbn1 +/+ mice (E), shControl (F through J). Acaa1b indicates 3-ketoacyl-CoA thiolase B, peroxisomal; Acsl5, Acyl-CoA Synthetase Long Chain Family Member 5; Akt, serine/threonine kinase 1; Atpaf2, ATP synthase mitochondrial F1 complex assembly factor 2; Ccn2, cellular communication network factor 2; CoI-V, mitochondrial complexes I-V; Cox8b, cytochrome c oxidase subunit 8B; Cycs, cytochrome c, somatic; Echs1, enoyl-CoA hydratase, short chain 1; Erk, extracellular signal regulated kinases; Fbn1, fibrillin-1; Hadh, hydroxyacyl-CoA dehydrogenase; Hif1a, hypoxia-inducible factor 1 α; Idh3g, isocitrate dehydrogenase (NAD(+)) 3 non-catalytic subunit gamma; Ivd, isovaleryl-CoA dehydrogenase; Mrtfa, b, myocardin related transcription factor A, B; Mt-Atp6, mitochondrially-encoded ATP synthase membrane subunit 6; Mt-Co1, 2, mitochondrially encoded cytochrome c oxidase I /II; Mt-Nd1-4I, mitochondrially encoded NADH dehydrogenase 1-4; Myc, Myc protoncogen, myelocytomatosis oncogene; Ndufa9, 10, NADH:ubiquinone oxidoreductase subunit A9-10; Ndufb8, NADH:ubiquinone oxidoreductase subunit B8; Ndufs4, 8, NADH:ubiquinone oxidoreductase core subunit S4,8; Ndufv1-3, NADH:ubiquinone oxidoreductase core subunit V1-3; Nos2, nitric oxide synthase 2; (Continued) Figure 1E). Tfam is a nuclear-encoded mitochondrial transcription factor that controls the transcription, replication, and stability of mtDNA. ...
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... is a nuclear-encoded mitochondrial transcription factor that controls the transcription, replication, and stability of mtDNA. 23 Analysis of relative mtDNA content in Fbn1 C1039G/+ aortas revealed below-normal mtDNA content ( Figure 1E). To model MFS in vitro, we silenced Fbn1 with lentiviral vectors in primary murine VSMCs ( Figure IA in the Data Supplement). ...
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... model MFS in vitro, we silenced Fbn1 with lentiviral vectors in primary murine VSMCs ( Figure IA in the Data Supplement). Confirming the transcriptomic data from MFS mice, shFbn1 VSMCs displayed increased levels of Hif1α and its targets Pdk1 (pyruvate dehydrogenase kinase-1) and Slc2a1 (glucose-transporter 1; Fig- ure 1F), and significantly reduced expression of Pgc1α (Ppargc1a), as well as Tfam and its targets, MT-Nd1 (mitochondrially-encoded NADH-ubiquinone oxidoreductase chain 1) and MT-Co1 ( Figure 1G), correlating with a reduction in mtDNA content ( Figure 1H). Flux analysis of the OCR, an index of mitochondrial oxidative phosphorylation, revealed reduced mitochondrial respiration in Fbn1-silenced cells ( Figure 1I). ...
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... model MFS in vitro, we silenced Fbn1 with lentiviral vectors in primary murine VSMCs ( Figure IA in the Data Supplement). Confirming the transcriptomic data from MFS mice, shFbn1 VSMCs displayed increased levels of Hif1α and its targets Pdk1 (pyruvate dehydrogenase kinase-1) and Slc2a1 (glucose-transporter 1; Fig- ure 1F), and significantly reduced expression of Pgc1α (Ppargc1a), as well as Tfam and its targets, MT-Nd1 (mitochondrially-encoded NADH-ubiquinone oxidoreductase chain 1) and MT-Co1 ( Figure 1G), correlating with a reduction in mtDNA content ( Figure 1H). Flux analysis of the OCR, an index of mitochondrial oxidative phosphorylation, revealed reduced mitochondrial respiration in Fbn1-silenced cells ( Figure 1I). ...
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... model MFS in vitro, we silenced Fbn1 with lentiviral vectors in primary murine VSMCs ( Figure IA in the Data Supplement). Confirming the transcriptomic data from MFS mice, shFbn1 VSMCs displayed increased levels of Hif1α and its targets Pdk1 (pyruvate dehydrogenase kinase-1) and Slc2a1 (glucose-transporter 1; Fig- ure 1F), and significantly reduced expression of Pgc1α (Ppargc1a), as well as Tfam and its targets, MT-Nd1 (mitochondrially-encoded NADH-ubiquinone oxidoreductase chain 1) and MT-Co1 ( Figure 1G), correlating with a reduction in mtDNA content ( Figure 1H). Flux analysis of the OCR, an index of mitochondrial oxidative phosphorylation, revealed reduced mitochondrial respiration in Fbn1-silenced cells ( Figure 1I). ...
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... the transcriptomic data from MFS mice, shFbn1 VSMCs displayed increased levels of Hif1α and its targets Pdk1 (pyruvate dehydrogenase kinase-1) and Slc2a1 (glucose-transporter 1; Fig- ure 1F), and significantly reduced expression of Pgc1α (Ppargc1a), as well as Tfam and its targets, MT-Nd1 (mitochondrially-encoded NADH-ubiquinone oxidoreductase chain 1) and MT-Co1 ( Figure 1G), correlating with a reduction in mtDNA content ( Figure 1H). Flux analysis of the OCR, an index of mitochondrial oxidative phosphorylation, revealed reduced mitochondrial respiration in Fbn1-silenced cells ( Figure 1I). This was accompanied by increased production of extracellular lactate, an indicator of glycolysis ( Figure 1J). ...
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... analysis of the OCR, an index of mitochondrial oxidative phosphorylation, revealed reduced mitochondrial respiration in Fbn1-silenced cells ( Figure 1I). This was accompanied by increased production of extracellular lactate, an indicator of glycolysis ( Figure 1J). As mitochondrial decline induces cellular senescence through p53, 36 and our ingenuity pathway analysis predicts p53 (Tp53) as an active upstream regulator ( Figure 1C), we analyzed senescence features in shFbn1 VSMCs. ...
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... was accompanied by increased production of extracellular lactate, an indicator of glycolysis ( Figure 1J). As mitochondrial decline induces cellular senescence through p53, 36 and our ingenuity pathway analysis predicts p53 (Tp53) as an active upstream regulator ( Figure 1C), we analyzed senescence features in shFbn1 VSMCs. Both protein and mRNA p53 levels were upregulated in shFbn1 VSMCs ( Figure IB in the Data Supplement) together with increased SABG (senescence-associated β-galactosidase) activity ( Figure IC in the Data Supplement) and increased expression of proinflammatory cytokines related to SASPs (senescence-associated secretory phenotype) such as Tnfa, Il1b (interleukin 1β), and Il6 (interleukin 6; Figure ID in the Data Supplement). ...
Citations
... These findings reinforce the idea that disrupted mitochondrial biogenesis and function could contribute to aneurysmal diseases [33,37]. Additionally, transcriptomic and metabolomic analyses of aortic samples from a murine model of MFS identified mitochondrial dysfunction as a significant contributor to the pathogenesis of aortic disease [40]. In accordance with this evidence, our proteomic results further support the view that perturbed mitochondrial metabolism might play a role in the pathogenesis of vascular connective tissue disorders. ...
Background: Dominant mutations in COL3A1 are known to cause vascular Ehlers–Danlos syndrome (vEDS) by impairing extracellular matrix (ECM) homeostasis. This disruption leads to the fragility of soft connective tissues and a significantly increased risk of life-threatening arterial and organ ruptures. Currently, treatments for vEDS are primarily symptomatic, largely due to a limited understanding of its underlying pathobiology and molecular mechanisms. Methods: In this study, we conducted a comprehensive analysis of the intracellular proteome of vEDS fibroblasts, integrating these findings with our previous transcriptome results to identify key molecular pathways that drive the disease. Additionally, we explored the therapeutic potential of inhibiting miR-29b-3p as a proof of concept. Results: Our integrative multi-omics analysis revealed complex pathological networks, emphasizing the critical role of miRNAs, particularly miR-29b-3p, in impairing ECM organization, autophagy, and cellular stress responses, all of which contribute to the pathogenesis of vEDS. Notably, the inhibition of miR-29b-3p in vEDS fibroblasts resulted in the upregulation of several differentially expressed target genes involved in these critical processes, as well as increased protein expression of essential ECM components, such as collagen types V and I. These changes suggest potential therapeutic benefits aimed at improving ECM integrity and restoring intracellular homeostasis. Conclusions: Overall, our findings advance our understanding of the complex biological mechanisms driving vEDS and lay a solid foundation for future research focused on developing targeted and effective treatment strategies for this life-threatening disorder.
... These findings reinforce the idea that disrupted mitochondrial biogenesis and function could contribute to aneurysmal diseases [22,26]. Additionally, transcriptomic and metabolomic analyses of aortic samples from a murine model of MFS identified mitochondrial dysfunction as a significant contributor to the pathogenesis of aortic disease [29]. In accordance with this evidence, our proteomic results further support the view that perturbed mitochondrial metabolism might play a role in the pathogenesis of vascular connective tissue disorders. ...
Dominant mutations in COL3A1 are known to cause vascular Ehlers-Danlos syndrome (vEDS) by impairing extracellular matrix (ECM) homeostasis. This disruption leads to the fragility of soft connective tissues and a significantly increased risk of life-threatening arterial and organ ruptures. Currently, treatments for vEDS are primarily symptomatic, largely due to a limited understanding of its underlying pathobiology and molecular mechanisms. In this study, we conducted a com-prehensive analysis of the intracellular proteome of vEDS fibroblasts, integrating these findings with our previous transcriptome results to identify key molecular pathways that drive the disease. Additionally, we explored the therapeutic potential of inhibiting miR-29b-3p as a proof of concept. Our integrative multi-omics analysis revealed complex pathological networks, emphasizing the critical role of miRNAs, particularly miR-29b-3p, in impairing ECM organization, autophagy, and cellular stress responses, all of which contribute to the pathogenesis of vEDS. Notably. the inhi-bition of miR-29b-3p in vEDS fibroblasts resulted in the upregulation of several differentially expressed target genes involved in these critical processes, as well as increased protein expression of essential ECM components, such as collagen types V and I. These changes suggest potential therapeutic benefits aimed at improving ECM integrity and restoring intracellular homeostasis. Overall, these insights not only enhance our understanding of the complex biological mechanisms underlying vEDS but also provide a solid foundation for future research focused on developing targeted treatment strategies to address this life-threatening disorder effectively.
... This reduction in aortic growth rate after resveratrol treatment may involve reduced redox stress 10 and/or normalised TGF-β signalling, 12 promoting aortic repair. Recently, mitochondrial dysfunction has been shown in MFS mice 13 and in MFS aortic smooth muscle cells, 14 which could be reversed by nicotinamide riboside treatment in MFS mice, preventing aneurysm formation. This may be a key downstream pathological pathway impairing aortic repair, which is beneficially affected by resveratrol. ...
Background
Resveratrol, a dietary supplement that intervenes in cellular metabolism, has been shown to reduce aortic growth rate in a mouse model of Marfan syndrome (MFS), a condition associated in humans with life-threatening aortic complications, often preceded by aortic dilatation. The primary objective of this study was to investigate the effects of resveratrol on aortic growth rate in patients with MFS .
Methods
In this investigator-initiated, single-arm open-label multicentre trial, we analysed resveratrol treatment in adults aged 18–50 years with MFS. The primary endpoint was the change in estimated annual aortic growth at five predefined levels in the thoracic aorta after 1 year of resveratrol treatment, evaluated using a linear mixed model. Aortic diameters were measured by cardiac MRI at three time points to analyse the annual aortic expansion rate before and after initiation of treatment. Additionally, annual aortic growth was compared with growth in a previously conducted losartan randomised clinical trial.
Results
898 patients were screened of which 19% (168/898) patients met the inclusion criteria.
36% (61/168) patients signed informed consent and 93% (57/61) aged 37±9 years, of which 28 males (49%) were included in the final analysis of the study. 46% (26/57) had undergone aortic root replacement prior to the study. Aortic root diameters remained stable after 1.2±0.3 years of resveratrol administration. A trend towards a decrease in estimated growth rate (mm/year) was observed in the aortic root (from 0.39±0.06 to −0.13±0.23, p=0.072), ascending aorta (from 0.40±0.05 to −0.01±0.18, p=0.072) and distal descending aorta (from 0.32±0.04 to 0.01±0.14, p=0.072).
Conclusion
Resveratrol treatment for 1 year may stabilise the aortic growth rate in adult patients with MFS. However, a subsequent randomised clinical trial with a longer follow-up duration and a larger study cohort is needed to establish an actual long-term beneficial effect of this dietary supplement in patients with MFS.
Trial registration number
NL66127.018.18.
... The mitochondrial function of VSMCs is regulated by the extracellular matrix and it drives the development of aortic aneurysms in MFS. Restoring mitochondrial metabolism with the NAD precursor nicotinamide riboside rapidly reverses aortic aneurysms in Marfan mice [22]. In our previous study, we identified a new subpopulation of fibroblasts with greater SPP1 expression in the aortas of Marfan mice using bulk RNA-seq and scRNA-seq. ...
Mutations in fibrillin 1 (FBN1) is the main cause of Marfan syndrome (MFS) with thoracic aortic aneurysm (TAA) as the main complication. Activation of the complement system plays a key role in the formation of thoracic and abdominal aortic aneurysms. However, the role of the complement system in MFS-associated aortic aneurysms remains unclear. In this study, we observed increased levels of complement C3a and C5a in the plasma of MFS patients and mouse, and the increased deposition of the activated complement system product C3b/iC3b was also observed in the elastic fiber rupture zone of 3-month-old MFS mice. The expression of C3a receptor (C3aR) was increased in MFS aortas, and recombinant C3a promoted the expression of cytokines in macrophages. The administration of a C3aR antagonist (C3aRA) attenuated the development of thoracic aortic aneurysms in MFS mice. The increased inflammation response and matrix metalloproteinases activities were also attenuated by C3aRA treatment in MFS mice. Therefore, these findings indicate that the complement C3a/C3aR inhibition alleviates the formation of aortic aneurysm in Marfan syndrome mice.
... Consequently, this transition leads to the production of large amounts of the glycolytic metabolite lactate. 10 Lactate, integral to numerous physiological processes, serves as a key regulator of signalling transduction and energy metabolism. 11 However, excessively elevated lactate levels can exacerbate various diseases, including heart failure, pulmonary hypertension, and cancer. ...
Background and Aims
Vascular smooth muscle cell (VSMC) senescence is crucial for the development of atherosclerosis, characterized by metabolic abnormalities. Tumour necrosis factor receptor-associated protein 1 (TRAP1), a metabolic regulator associated with ageing, might be implicated in atherosclerosis. As the role of TRAP1 in atherosclerosis remains elusive, this study aimed to examine the function of TRAP1 in VSMC senescence and atherosclerosis.
Methods
TRAP1 expression was measured in the aortic tissues of patients and mice with atherosclerosis using western blot and RT–qPCR. Senescent VSMC models were established by oncogenic Ras, and cellular senescence was evaluated by measuring senescence-associated β-galactosidase expression and other senescence markers. Chromatin immunoprecipitation (ChIP) analysis was performed to explore the potential role of TRAP1 in atherosclerosis.
Results
VSMC-specific TRAP1 deficiency mitigated VSMC senescence and atherosclerosis via metabolic reprogramming. Mechanistically, TRAP1 significantly increased aerobic glycolysis, leading to elevated lactate production. Accumulated lactate promoted histone H4 lysine 12 lactylation (H4K12la) by down-regulating the unique histone lysine delactylase HDAC3. H4K12la was enriched in the senescence-associated secretory phenotype (SASP) promoter, activating SASP transcription and exacerbating VSMC senescence. In VSMC-specific Trap1 knockout ApoeKO mice (ApoeKOTrap1SMCKO), the plaque area, senescence markers, H4K12la, and SASP were reduced. Additionally, pharmacological inhibition and proteolysis-targeting chimera (PROTAC)-mediated TRAP1 degradation effectively attenuated atherosclerosis in vivo.
Conclusions
This study reveals a novel mechanism by which mitonuclear communication orchestrates gene expression in VSMC senescence and atherosclerosis. TRAP1-mediated metabolic reprogramming increases lactate-dependent H4K12la via HDAC3, promoting SASP expression and offering a new therapeutic direction for VSMC senescence and atherosclerosis.
... A subsequent comprehensive study combining transcriptomics and metabolic analysis in the aortas of Fbn1 C1039G/+ mice aimed to discover novel molecular mechanisms underlying TAA formation [28]. This mouse model is heterozygous for the most common class of mutation causing MFS, resulting in progressive aortic root dilatation [29]. ...
... This might be due to the advanced state of the pathology, considering the suggested dual role of TGF-β signaling in aneurysm progression [34][35][36]. The altered mitochondrial function was observed in MFS mice and patients, also by Oller et al. [28], corroborating the results. Collectively, the findings of these two studies emphasize the potential of mitochondrial pathway members to function as markers for TAA progression or as therapeutic targets for MFS treatment. ...
Marfan syndrome (MFS) is a rare congenital disorder of the connective tissue, leading to thoracic aortic aneurysms (TAA) and dissection, among other complications. Currently, the most efficient strategy to prevent life-threatening dissection is preventive surgery. Periodic imaging applying complex techniques is required to monitor TAA progression and to guide the timing of surgical intervention. Thus, there is an acute demand for non-invasive biomarkers for diagnosis and prognosis, as well as for innovative therapeutic targets of MFS. Unraveling the intricate pathomolecular mechanisms underlying the syndrome is vital to address these needs. High-throughput platforms are particularly well-suited for this purpose, as they enable the integration of different datasets, such as transcriptomic and epigenetic profiles. In this narrative review, we summarize relevant studies investigating changes in both the coding and non-coding transcriptome and epigenome in MFS-induced TAA. The collective findings highlight the implicated pathways, such as TGF-β signaling, extracellular matrix structure, inflammation, and mitochondrial dysfunction. Potential candidates as biomarkers, such as miR-200c, as well as therapeutic targets emerged, like Tfam, associated with mitochondrial respiration, or miR-632, stimulating endothelial-to-mesenchymal transition. While these discoveries are promising, rigorous and extensive validation in large patient cohorts is indispensable to confirm their clinical relevance and therapeutic potential.
... However, inhibition of mitochondrial metabolism leads to a maladaptive switch to glycolysis, adversely affecting cell function and phenotype [81]. The pathophysiological role of the glycolytic switch in vascular smooth muscle cells and adventitial fibroblasts [85] promotes aortic aneurysms and vascular fibrosis [86]. In endothelial cells, the glycolytic switch promotes phagocytosis of gap junctions, increasing endothelial barrier permeability and inducing the endothelial-mesenchymal transition [81]. ...
There is a “popular” belief that a fat-free diet is beneficial, supported by the scientific dogma indicating that high levels of fatty acids promote many pathological metabolic, cardiovascular, and neurodegenerative conditions. This dogma pressured scientists not to recognize the essential role of fatty acids in cellular metabolism and focus on the detrimental effects of fatty acids. In this work, we critically review several decades of studies and recent publications supporting the critical role of mitochondrial fatty acid metabolism in cellular homeostasis and many pathological conditions. Fatty acids are the primary fuel source and essential cell membrane building blocks from the origin of life. The essential cell membranes phospholipids were evolutionarily preserved from the earlier bacteria in human subjects. In the past century, the discovery of fatty acid metabolism was superseded by the epidemic growth of metabolic conditions and cardiovascular diseases. The association of fatty acids and pathological conditions is not due to their “harmful” effects but rather the result of impaired fatty acid metabolism and abnormal lifestyle. Mitochondrial dysfunction is linked to impaired metabolism and drives multiple pathological conditions. Despite metabolic flexibility, the loss of mitochondrial fatty acid oxidation cannot be fully compensated for by other sources of mitochondrial substrates, such as carbohydrates and amino acids, resulting in a pathogenic accumulation of long-chain fatty acids and a deficiency of medium-chain fatty acids. Despite popular belief, mitochondrial fatty acid oxidation is essential not only for energy-demanding organs such as the heart, skeletal muscle, and kidneys but also for metabolically “inactive” organs such as endothelial and epithelial cells. Recent studies indicate that the accumulation of long-chain fatty acids in specific organs and tissues support the impaired fatty acid oxidation in cell- and tissue-specific fashion. This work, therefore, provides a basis to challenge these established dogmas and articulate the need for a paradigm shift from the “pathogenic” role of fatty acids to the critical role of fatty acid oxidation. This is important to define the causative role of impaired mitochondrial fatty acid oxidation in specific pathological conditions and develop novel therapeutic approaches targeting mitochondrial fatty acid metabolism.
... Mitochondrial transcription factor A (TFAM) plays a crucial role in regulating the biogenesis of the mitochondrial respiratory chain by triggering transcription and replication of mitochondrial DNA (mtDNA), which encodes 13 core ETC subunits [39,40]. To explore how irisin improved mitochondrial energy metabolism, we examined TFAM protein levels. ...
... The biogenesis of the respiratory chain is a complex process that requires the coordinated expression of the nuclear and mitochondrial genome [53]. TFAM, a member of the high mobility group box protein family, plays a crucial role in this process by binding upstream of two major promoters of the mitochondrial genome (known as the light-and the heavy-strand promoter) to promote the transcription and replication of mtDNA, which in turn encodes 13 crucial ETC subunits [39,40]. Reduced expression of TFAM has been observed in the hippocampus of APPswe/PS1dE9 transgenic mice and AD patient brains [54][55][56]. ...
Background
The accumulation of senescent microglia has been highlighted as a critical contributor to the progression of tauopathies. Irisin, a muscle-derived hormone produced by the proteolytic cleavage of Fibronectin-domain III containing 5 (FNDC5), mediates the pleiotropic effects of exercise on the physical body. Herein, we investigate the potential role of irisin in microglial senescence in tauopathies.
Methods
To model tauopathies both in vivo and in vitro, we utilized P301S tau transgenic mice and tau K18 fibril-treated microglia BV2 cells, respectively. We first examined the expression of the irisin expression and senescence phenotypes of microglia in tauopathies. Subsequently, we investigated the impact of irisin on microglial senescence and its underlying molecular mechanisms.
Result
We observed a reduction in irisin levels and an onset of premature microglial senescence both in vivo and in vitro. Irisin administration was found to counteract microglial senescence and ameliorate cognitive decline in P301S mice. Mechanistically, irisin effectively inhibited microglial senescence by stimulating the expression of mitochondrial transcription factor A (TFAM), a master regulator of mitochondrial respiratory chain biogenesis, thereby enhancing mitochondrial oxidative phosphorylation (OXPHOS). Silencing TFAM eliminated the inhibitory effect of irisin on microglial senescence as well as the restorative effect of irisin on mitochondrial OXPHOS. Furthermore, the SIRT1/PGC1α signaling pathway appeared to be implicated in irisin-mediated upregulation of TFAM.
Conclusion
Taken together, our study revealed that irisin mitigated microglial senescence via TFAM-driven mitochondrial biogenesis, suggesting a promising new avenue for therapeutic strategies targeting tauopathies.
... This does not negate the pathophysiological role of glycolytic switch in vascular smooth muscle cells and adventitial fibroblasts, 49 which promotes aortic aneurysms and vascular fibrosis. 50 Targeting of vascular metabolism was proposed to reduce the aneurysmal formation and diminish mortality due to reduced aortic ruptures. 51,52 Meanwhile, the current dogma is that endothelial cells rely on glycolysis instead of mitochondrial respiration, implying that mitochondria are not critical for endothelial metabolism. ...
BACKGROUND
Nearly half of adults have hypertension, a major risk factor for cardiovascular disease. Mitochondrial hyperacetylation is linked to hypertension, but the role of acetylation of specific proteins is not clear. We hypothesized that acetylation of mitochondrial CypD (cyclophilin D) at K166 contributes to endothelial dysfunction and hypertension.
METHODS
To test this hypothesis, we studied CypD acetylation in patients with essential hypertension, defined a pathogenic role of CypD acetylation in deacetylation mimetic CypD-K166R mutant mice and endothelial-specific GCN5L1 (general control of amino acid synthesis 5 like 1)–deficient mice using an Ang II (angiotensin II) model of hypertension.
RESULTS
Arterioles from hypertensive patients had 280% higher CypD acetylation coupled with reduced Sirt3 (sirtuin 3) and increased GCN5L1 levels. GCN5L1 regulates mitochondrial protein acetylation and promotes CypD acetylation, which is counteracted by mitochondrial deacetylase Sirt3. In human aortic endothelial cells, GCN5L1 depletion prevents superoxide overproduction. Deacetylation mimetic CypD-K166R mice were protected from vascular oxidative stress, endothelial dysfunction, and Ang II-induced hypertension. Ang II-induced hypertension increased mitochondrial GCN5L1 and reduced Sirt3 levels resulting in a 250% increase in GCN5L1/Sirt3 ratio promoting CypD acetylation. Treatment with mitochondria-targeted scavenger of cytotoxic isolevuglandins normalized GCN5L1/Sirt3 ratio, reduced CypD acetylation, and attenuated hypertension. The role of mitochondrial acetyltransferase GCN5L1 in the endothelial function was tested in endothelial-specific GCN5L1 knockout mice. Depletion of endothelial GCN5L1 prevented Ang II-induced mitochondrial oxidative stress, reduced the maladaptive switch of vascular metabolism to glycolysis, prevented inactivation of endothelial nitric oxide, preserved endothelial-dependent relaxation, and attenuated hypertension.
CONCLUSIONS
These data support the pathogenic role of CypD acetylation in endothelial dysfunction and hypertension. We suggest that targeting cytotoxic mitochondrial isolevuglandins and GCN5L1 reduces CypD acetylation, which may be beneficial in cardiovascular disease.
... evaluated, and found that utilizing nicotinamide riboside to enhance mitochondrial metabolism reverted the development of aortic aneurysm and restored histological features of medial degeneration. Though our report does not investigate molecular mechanisms contributing to these in vivo alterations, it is important to recognize that multiple mechanisms may be independently or collectively contributing to these changes 40 . ...
... Previous studies have shown a potential link between aortic root pathology and increased TGF-β signaling, mitochondrial respiration decline, inflammation, redox stress, increased iNOS expression, and endothelial dysfunction. One recent study has shown a significant reduction in mitochondrial transcription factor A (TFAM) and oxygen consumption in aortic smooth muscle cells, where intervention with nicotinamide riboside (NR), a precursor of NAD + , could restore TFAM levels and normalize mitochondrial respiration 40 . Another study has shown that resveratrol can inhibit aortic root dilatation in MFS mice by promoting elastin integrity and smooth muscle cell survival through downregulation of the aneurysm-related micro-RNA-29b in the aorta 73 . ...
In individuals with Marfan Syndrome (MFS), fibrillin-1 gene (FBN1) mutations can lead to vascular wall weakening and dysfunction. The experimental mouse model of MFS (Fbn1C1041G/+) has been advantageous in investigating MFS-associated life-threatening aortic aneurysms. It is well established that the MFS mouse model exhibits an accelerated-aging phenotype in elastic organs like the aorta, lung, and skin. However, the impact of Fbn1 mutations on the in vivo function and structure of various artery types with the consideration of sex and age, has not been adequately explored in real-time and a clinically relevant context. In this study, we investigate if Fbn1 mutation contributes to sex-dependent alterations in central and cerebral vascular function similar to phenotypic changes associated with normal aging in healthy control mice. In vivo ultrasound imaging of central and cerebral vasculature was performed in 6-month-old male and female MFS and C57BL/6 mice and sex-matched 12-month-old (middle-aged) healthy control mice. Our findings confirm aortic enlargement (aneurysm) and wall stiffness in MFS mice, but with exacerbation in male diameters. Coronary artery blood flow velocity (BFV) in diastole was not different but left pulmonary artery BFV was decreased in MFS and 12-month-old control mice regardless of sex. At 6 months of age, MFS male mice show decreased posterior cerebral artery BFV as compared to age-matched control males, with no difference observed between female cohorts. Reduced mitral valve early-filling velocities were indicated in MFS mice regardless of sex. Male MFS mice also demonstrated left ventricular hypertrophy. Overall, these results underscore the significance of biological sex in vascular function and structure in MFS mice, while highlighting a trend of pre-mature vascular aging phenotype in MFS mice that is comparable to phenotypes observed in older healthy controls. Furthermore, this research is a vital step in understanding MFS's broader implications and sets the stage for more in-depth future analyses, while providing data-driven preclinical justification for re-evaluating diagnostic approaches and therapeutic efficacy.
