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New Insights into the Implication of Mitochondrial Dysfunction in Tissue, Peripheral Blood Mononuclear Cells, and Platelets during Lung Diseases.

ABSTRACT: Lung diseases such as chronic obstructive pulmonary disease, asthma, pulmonary arterial hypertension, or idiopathic pulmonary fibrosis are major causes of morbidity and mortality. Complex, their physiopathology is multifactorial and includes lung mitochondrial dysfunction and enhanced reactive oxygen species (ROS) release, which deserves increased attention. Further, and importantly, circulating blood cells (peripheral blood mononuclear cells-(PBMCs) and platelets) likely participate in these systemic diseases. This review presents the data published so far and shows that circulating blood cells mitochondrial oxidative capacity are likely to be reduced in chronic obstructive pulmonary disease (COPD), but enhanced in asthma and pulmonary arterial hypertension in a context of increased oxidative stress. Besides such PBMCs or platelets bioenergetics modifications, mitochondrial DNA (mtDNA) changes have also been observed in patients. These new insights open exciting challenges to determine their role as biomarkers or potential guide to a new therapeutic approach in lung diseases.

SUBMITTER: Riou M

PROVIDER: S-EPMC7287602 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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New Insights into the Implication of Mitochondrial Dysfunction in Tissue, Peripheral Blood Mononuclear Cells, and Platelets during Lung Diseases.

Riou Marianne M Alfatni Abrar A Charles Anne-Laure AL Andrès Emmanuel E Pistea Cristina C Charloux Anne A Geny Bernard B

Journal of clinical medicine 20200426 5

Lung diseases such as chronic obstructive pulmonary disease, asthma, pulmonary arterial hypertension, or idiopathic pulmonary fibrosis are major causes of morbidity and mortality. Complex, their physiopathology is multifactorial and includes lung mitochondrial dysfunction and enhanced reactive oxygen species (ROS) release, which deserves increased attention. Further, and importantly, circulating blood cells (peripheral blood mononuclear cells-(PBMCs) and platelets) likely participate in these sy ...[more]

PMID: 32357474

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Project description:BackgroundPatients with acute alcohol-associated hepatitis (AH) have immune dysfunction. Mitochondrial function is critical for immune cell responses and regulates senescence. Clinical translational studies using complementary bioinformatics-experimental validation of mitochondrial responses were performed in peripheral blood mononuclear cells (PBMC) from patients with AH, healthy controls (HC), and heavy drinkers without evidence of liver disease (HD).MethodsFeature extraction for differentially expressed genes (DEG) in mitochondrial components and telomere regulatory pathways from single-cell RNAseq (scRNAseq) and integrated 'pseudobulk' transcriptomics from PBMC from AH and HC (n = 4 each) were performed. After optimising isolation and processing protocols for functional studies in PBMC, mitochondrial oxidative responses to substrates, uncoupler, and inhibitors were quantified in independent discovery (AH n = 12; HD n = 6; HC n = 12) and validation cohorts (AH n = 10; HC n = 7). Intermediary metabolites (gas-chromatography/mass-spectrometry) and telomere length (real-time PCR) were quantified in subsets of subjects (PBMC/plasma AH n = 69/59; HD n = 8/8; HC n = 14/27 for metabolites; HC n = 13; HD n = 8; AH n = 72 for telomere length).ResultsMitochondrial, intermediary metabolite, and senescence-regulatory genes were differentially expressed in PBMC from AH and HC in a cell type-specific manner at baseline and with lipopolysaccharide (LPS). Fresh PBMC isolated using the cell preparation tube generated optimum mitochondrial responses. Intact cell and maximal respiration were lower (p ≤ .05) in AH than HC/HD in the discovery and validation cohorts. In permeabilised PBMC, maximum respiration, complex I and II function were lower in AH than HC. Most tricarboxylic acid (TCA) cycle intermediates in plasma were higher while those in PBMC were lower in patients with AH than those from HC. Lower telomere length, a measure of cellular senescence, was associated with higher mortality in AH.ConclusionPatients with AH have lower mitochondrial oxidative function, higher plasma TCA cycle intermediates, with telomere shortening in nonsurvivors.

Project description:OBJECTIVES:Metabolic derangements in sepsis stem from mitochondrial injury and contribute significantly to organ failure and mortality; however, little is known about mitochondrial recovery in human sepsis. We sought to test markers of mitochondrial injury and recovery (mitochondrial biogenesis) noninvasively in peripheral blood mononuclear cells from patients with sepsis and correlate serial measurements with clinical outcomes. DESIGN:Prospective case-control study. SETTING:Academic Medical Center and Veterans Affairs Hospital. PATIENTS:Uninfected control patients (n = 20) and septic ICU patients (n = 37). INTERVENTIONS:Blood samples were collected once from control patients and serially with clinical data on days 1, 3, and 5 from septic patients. Gene products for HMOX1, NRF1, PPARGC1A, and TFAM, and mitochondrial DNA ND1 and D-loop were measured by quantitative reverse transcriptase-polymerase chain reaction. Proinflammatory cytokines were measured in plasma and neutrophil lysates. MEASUREMENTS AND MAIN RESULTS:Median (interquartile range) Acute Physiology and Chronic Health Evaluation II and Sequential Organ Failure Assessment scores were 21 (8) and 10 (4), respectively, and 90-day mortality was 19%. Transcript levels of all four genes in peripheral blood mononuclear cells were significantly reduced in septic patients on day 1 (p < 0.05), whereas mitochondrial DNA copy number fell and plasma D-loop increased (both p < 0.05), indicative of mitochondrial damage. D-loop content was directly proportional to tumor necrosis factor-α and high-mobility group protein B1 cytokine expression. By day 5, we observed transcriptional activation of mitochondrial biogenesis and restoration of mitochondrial DNA copy number (p < 0.05). Patients with early activation of mitochondrial biogenesis were ICU-free by 1 week. CONCLUSIONS:Our findings support data that sepsis-induced mitochondrial damage is reversed by activation of mitochondrial biogenesis and that gene transcripts measured noninvasively in peripheral blood mononuclear cells can serve as novel biomarkers of sepsis recovery.

Project description:BackgroundMyalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a serious and complex physical illness that affects all body systems with a multiplicity of symptoms, but key hallmarks of the disease are pervasive fatigue and 'post-exertional malaise', exacerbation after physical and/or mental activity of the intrinsic fatigue and other symptoms that can be highly debilitating and last from days to months. Although the disease can vary widely between individuals, common symptoms also include pain, cognitive deficits, sleep dysfunction, as well as immune, neurological and autonomic symptoms. Typically, it is a very isolating illness socially, carrying a stigma because of the lack of understanding of the cause and pathophysiology.MethodsTo gain insight into the pathophysiology of ME/CFS, we examined the proteomes of peripheral blood mononuclear cells (PBMCs) by SWATH-MS analysis in a small well-characterised group of patients and matched controls. A principal component analysis (PCA) was used to stratify groups based on protein abundance patterns, which clearly segregated the majority of the ME/CFS patients (9/11) from the controls. This majority subgroup of ME/CFS patients was then further compared to the control group.ResultsA total of 60 proteins in the ME/CFS patients were differentially expressed (P < 0.01, Log10 (Fold Change) > 0.2 and < -0.2). Comparison of the PCA selected subgroup of ME/CFS patients (9/11) with controls increased the number of proteins differentially expressed to 99. Of particular relevance to the core symptoms of fatigue and post-exertional malaise experienced in ME/CFS, a proportion of the identified proteins in the ME/CFS groups were involved in mitochondrial function, oxidative phosphorylation, electron transport chain complexes, and redox regulation. A significant number were also involved in previously implicated disturbances in ME/CFS, such as the immune inflammatory response, DNA methylation, apoptosis and proteasome activation.ConclusionsThe results from this study support a model of deficient ATP production in ME/CFS, compensated for by upregulation of immediate pathways upstream of Complex V that would suggest an elevation of oxidative stress. This study and others have found evidence of a distinct pathology in ME/CFS that holds promise for developing diagnostic biomarkers.

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New Insights into the Implication of Mitochondrial Dysfunction in Tissue, Peripheral Blood Mononuclear Cells, and Platelets during Lung Diseases.

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New Insights into the Implication of Mitochondrial Dysfunction in Tissue, Peripheral Blood Mononuclear Cells, and Platelets during Lung Diseases.

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