Browsing by Subject "Mitochondrial dysfunction"

Now showing 1 - 4 of 4
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    Chronic Inflammation in Chronic Kidney Disease Progression: Role of Nrf2
    (Elsevier, 2021-05-04) Stenvinkel, Peter; Chertow, Glenn M.; Devarajan, Prasad; Levin, Adeera; Andreoli, Sharon P.; Bangalore, Sripal; Warady, Bradley A.; Pediatrics, School of Medicine
    Despite recent advances in the management of chronic kidney disease (CKD), morbidity and mortality rates in these patients remain high. Although pressure-mediated injury is a well-recognized mechanism of disease progression in CKD, emerging data indicate that an intermediate phenotype involving chronic inflammation, oxidative stress, hypoxia, senescence, and mitochondrial dysfunction plays a key role in the etiology, progression, and pathophysiology of CKD. A variety of factors promote chronic inflammation in CKD, including oxidative stress and the adoption of a proinflammatory phenotype by resident kidney cells. Regulation of proinflammatory and anti-inflammatory factors through NF-κB– and nuclear factor, erythroid 2 like 2 (Nrf2)–mediated gene transcription, respectively, plays a critical role in the glomerular and tubular cell response to kidney injury. Chronic inflammation contributes to the decline in glomerular filtration rate (GFR) in CKD. Whereas the role of chronic inflammation in diabetic kidney disease (DKD) has been well-elucidated, there is now substantial evidence indicating unresolved inflammatory processes lead to fibrosis and eventual end-stage kidney disease (ESKD) in several other diseases, such as Alport syndrome, autosomal-dominant polycystic kidney disease (ADPKD), IgA nephropathy (IgAN), and focal segmental glomerulosclerosis (FSGS). In this review, we aim to clarify the mechanisms of chronic inflammation in the pathophysiology and disease progression across the spectrum of kidney diseases, with a focus on Nrf2.
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    Deciphering the Role of Mitochondrial Dysfunction in Pulmonary Arterial Hypertension
    (2024-06) Balachandar, Srimmitha; Aldred, Micheala A.; Graham, Brett H.; Zhang, Jie; Geraci, Mark W.; Machado, Roberto F.
    Pulmonary arterial hypertension (PAH) is a life-threatening vasculopathy caused by remodeling of pulmonary arterioles. It is unknown as to why some people are at more risk of developing PAH compared to others. Notably, while germline pathogenic variants in PAH genes are a strong driver of disease susceptibility, less than half of mutation carriers actually develop the disease, suggesting the need for additional triggers. Our previous studies have shown increased DNA damage and total reactive oxygen species (ROS) in cells from PAH patients and unaffected relatives, indicating a potential genetic component, leading to our hypothesis: Mitochondrial dysfunction is an independent genetically determined modifier of PAH susceptibility. Untargeted metabolomics (Metabolon) revealed abnormalities in the antioxidants, glutamate, urea, amino acid, galactose, and phospholipid metabolism pathways in the PAH Lymphoblastoid cells (LCLs) compared to controls. Intriguingly, the healthy relatives also had altered phospholipids, suggesting that it occurs independent of the disease. ROS analysis on LCLs from patients, their relatives and unrelated controls showed that the PAH LCLs had significantly higher levels of all ROS species compared to controls, with the highest in heritable PAH cells. LCLs from relatives clustered into two groups, one with increased mitochondrial (mt) ROS and hydrogen peroxide, the other comparable to controls. Seahorse assays showed that the LCLs with increased mtROS had reduced spare respiratory capacity indicative of dysfunctional electron transport chain (ETC); but no glycolytic switch. Cybrid models generated using the high and low ROS LCLs (H and L-donors) on a 143B nuclear background showed that the H-donors had mt respiration similar to L-donors, suggesting a functional ETC. However, these cells had significantly elevated mtROS, with reduced SOD2 protein (potentially a consequence of increased degradation), passed on from the parental LCLs to the recipient cybrids. PAH is a complex disease, and mutation status alone doesn’t determine disease susceptibility. LCLs from patients recapitulate some of the metabolomic abnormalities in lung vascular cells. Oxidative stress in LCLs extends to some unaffected relatives, suggesting this is an independent genetic trait that modifies PAH risk. Our study highlights the importance of identifying potential modifiers and the second hits in the pathogenesis of PAH.
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    Plasma and Fecal Metabolite Profiles in Autism Spectrum Disorder
    (Elsevier, 2021) Needham, Brittany D.; Adame, Mark D.; Serena, Gloria; Rose, Destanie R.; Preston, Gregory M.; Conrad, Mary C.; Campbell, A. Stewart; Donabedian, David H.; Fasano, Alessio; Ashwood, Paul; Mazmanian, Sarkis K.; Anatomy, Cell Biology and Physiology, School of Medicine
    Background: Autism spectrum disorder (ASD) is a neurodevelopmental condition with hallmark behavioral manifestations including impaired social communication and restricted repetitive behavior. In addition, many affected individuals display metabolic imbalances, immune dysregulation, gastrointestinal dysfunction, and altered gut microbiome compositions. Methods: We sought to better understand nonbehavioral features of ASD by determining molecular signatures in peripheral tissues through mass spectrometry methods (ultrahigh performance liquid chromatography-tandem mass spectrometry) with broad panels of identified metabolites. Herein, we compared the global metabolome of 231 plasma and 97 fecal samples from a large cohort of children with ASD and typically developing control children. Results: Differences in amino acid, lipid, and xenobiotic metabolism distinguished ASD and typically developing samples. Our results implicated oxidative stress and mitochondrial dysfunction, hormone level elevations, lipid profile changes, and altered levels of phenolic microbial metabolites. We also revealed correlations between specific metabolite profiles and clinical behavior scores. Furthermore, a summary of metabolites modestly associated with gastrointestinal dysfunction in ASD is provided, and a pilot study of metabolites that can be transferred via fecal microbial transplant into mice is identified. Conclusions: These findings support a connection between metabolism, gastrointestinal physiology, and complex behavioral traits and may advance discovery and development of molecular biomarkers for ASD.
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    S-Adenosylmethionine Negatively Regulates the Mitochondrial Respiratory Chain Repressor MCJ in the Liver
    (Ivyspring, 2024-01-27) Barbier-Torres, Lucía; Chhimwal, Jyoti; Kim, So Yeon; Ramani, Komal; Robinson, Aaron; Yang, Heping; Van Eyk, Jenny; Liangpunsakul, Suthat; Seki, Ekihiro; Mato, José M.; Lu, Shelly C.; Biochemistry and Molecular Biology, School of Medicine
    MCJ (Methylation-Controlled J protein), an endogenous repressor of the mitochondrial respiratory chain, is upregulated in multiple liver diseases but little is known about how it is regulated. S-adenosylmethionine (SAMe), the biological methyl donor, is frequently depleted in chronic liver diseases. Here, we show that SAMe negatively regulates MCJ in the liver. While deficiency in methionine adenosyltransferase alpha 1 (MATα1), enzyme that catalyzes SAMe biosynthesis, leads to hepatic MCJ upregulation, MAT1A overexpression and SAMe treatment reduced MCJ expression. We found that MCJ is methylated at lysine residues and that it interacts with MATα1 in liver mitochondria, likely to facilitate its methylation. Lastly, we observed that MCJ is upregulated in alcohol-associated liver disease, a condition characterized by reduced MAT1A expression and SAMe levels along with mitochondrial injury. MCJ silencing protected against alcohol-induced mitochondrial dysfunction and lipid accumulation. Our study demonstrates a new role of MATα1 and SAMe in reducing hepatic MCJ expression.