Mitochondrial fidelity and metabolic agility control immune cell fate and function

Sack, Michael N.

doi:10.1172/jci120845

Cited by 39 publications

(29 citation statements)

References 168 publications

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“…In addition, in this study, we modeled sterile inflammation in HF using mitochondrial extracts to mimic MitoDAMP. This mixture contains mitochondrial DNA, RNA, proteins, and phospholipids, many of which have been shown to be proinflammatory (11). The specific component(s) in MitoDAMP responsible for triggering PBMC proinflammatory activation are yet to be identified, and quantitative changes of MitoDAMP in peripheral blood of patients with HF warrant further investigation.…”

Section: Discussionmentioning

confidence: 99%

Boosting NAD level suppresses inflammatory activation of PBMCs in heart failure

Zhou¹,

Wang

Qiu³

et al. 2020

Journal of Clinical Investigation

150

100

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BACKGROUND. While mitochondria play an important role in innate immunity, the relationship between mitochondrial dysfunction and inflammation in heart failure (HF) is poorly understood. In this study we aimed to investigate the mechanistic link between mitochondrial dysfunction and inflammatory activation in peripheral blood mononuclear cells (PBMCs), and the potential antiinflammatory effect of boosting the NAD level. METHODS. We compared the PBMC mitochondrial respiration of 19 hospitalized patients with stage D HF with that of 19 healthy participants. We then created an in vitro model of sterile inflammation by treating healthy PBMCs with mitochondrial damage-associated molecular patterns (MitoDAMPs) isolated from human heart tissue. Last, we enrolled patients with stage D HF and sampled their blood before and after taking 5 to 9 days of oral nicotinamide riboside (NR), a NAD precursor. RESULTS. We demonstrated that HF is associated with both reduced respiratory capacity and elevated proinflammatory cytokine gene expressions. In our in vitro model, MitoDAMP-treated PBMCs secreted IL-6 that impaired mitochondrial respiration by reducing complex I activity. Last, oral NR administration enhanced PBMC respiration and reduced proinflammatory cytokine gene expression in 4 subjects with HF. CONCLUSION. These findings suggest that systemic inflammation in patients with HF is causally linked to mitochondrial function of the PBMCs. Increasing NAD levels may have the potential to improve mitochondrial respiration and attenuate proinflammatory activation of PBMCs in HF. TRIAL REGISTRATION. ClinicalTrials.gov NCT03727646.

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Section: Discussionmentioning

confidence: 99%

Boosting NAD level suppresses inflammatory activation of PBMCs in heart failure

Zhou¹,

Wang

Qiu³

et al. 2020

Journal of Clinical Investigation

150

100

View full text Add to dashboard Cite

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“…Overall, mitochondria are dynamic organelles whose function, morphology, distribution, and contacts with other organelles (49,109,148) undergo changes in response to intracellular energy requirements, as well as other physiological and pathological stimuli (109).…”

Section: Er-mitochondria Contact Sites (Ermcs)mentioning

confidence: 99%

Mitochondrial Bioenergetics and Dynamics in Secretion Processes

et al. 2020

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Secretion is an energy consuming process that plays a relevant role in cell communication and adaptation to the environment. Among others, endocrine cells producing hormones, immune cells producing cytokines or antibodies, neurons releasing neurotransmitters at synapsis, and more recently acknowledged, senescent cells synthesizing and secreting multiple cytokines, growth factors and proteases, require energy to successfully accomplish the different stages of the secretion process. Calcium ions (Ca 2+ ) act as second messengers regulating secretion in many of these cases. In this setting, mitochondria appear as key players providing ATP by oxidative phosphorylation, buffering Ca 2+ concentrations and acting as structural platforms. These tasks also require the concerted actions of the mitochondrial dynamics machinery. These proteins mediate mitochondrial fusion and fission, and are also required for transport and tethering of mitochondria to cellular organelles where the different steps of the secretion process take place. Herein we present a brief overview of mitochondrial energy metabolism, mitochondrial dynamics, and the different steps of the secretion processes, along with evidence of the interaction between these pathways. We also analyze the role of mitochondria in secretion by different cell types in physiological and pathological settings.

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“…The lung microenvironment will likely be proven consequential to immune metabolism and function, especially regarding metabolite concentrations in this oxygen‐rich environment. Numerous pathogens, including IAV, induce hyperglycolysis in respiratory epithelial cells, which is now an accepted hallmark of activated MØ, DCs, B cells, and both migratory and effector T cells 16 . Nevertheless, competing interests may collide as parasitized epithelial cell metabolism fuels virion production and the host response relies on the same key metabolites for immediate immune functions with long‐term consequences.…”

Section: The Immune Response To Influenza Infectionmentioning

confidence: 99%

Fueling influenza and the immune response: Implications for metabolic reprogramming during influenza infection and immunometabolism

Bahadoran

Bezavada

Smallwood

2020

Immunological Reviews

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The metabolic impact of influenza A virus (IAV) infections on immune cells remains largely uncharacterized. However, much is known about the metabolism of IAV infection and immunometabolism. Thus, we will consider four main factors: the metabolic requirements of influenza virus, metabolic reprogramming of immune cells that are mobilized to fight IAV infection, the impact of systemic or local metabolism on the infection and immune response, and vice versa. We will also address the interplay of metabolism and cytokines with a focus on those relevant to IAV infections. Finally, we will limit information on immunometabolism to key cell types critical to fighting IAV infection. We will relate this information to the unique metabolic demands on immune cells and discuss how their translocation through nutrient diverse and changing environments may affect their functions in IAV infection. | ME TABOLIS M AND THE LUNG MICROENVIRONMENT | Steady-state metabolismUnder aerobic conditions, cells sustain themselves catabolically using glycolytic carbons to fuel the tricarboxylic acid (TCA) cycle. AbstractRecent studies support the notion that glycolysis and oxidative phosphorylation are rheostats in immune cells whose bioenergetics have functional outputs in terms of their biology. Specific intrinsic and extrinsic molecular factors function as molecular potentiometers to adjust and control glycolytic to respiratory power output. In many cases, these potentiometers are used by influenza viruses and immune cells to support pathogenesis and the host immune response, respectively. Influenza virus infects the respiratory tract, providing a specific environmental niche, while immune cells encounter variable nutrient concentrations as they migrate in response to infection. Immune cell subsets have distinct metabolic programs that adjust to meet energetic and biosynthetic requirements to support effector functions, differentiation, and longevity in their ever-changing microenvironments. This review details how influenza coopts the host cell for metabolic reprogramming and describes the overlap of these regulatory controls in immune cells whose function and fate are dictated by metabolism. These details are contextualized with emerging evidence of the consequences of influenzainduced changes in metabolic homeostasis on disease progression. K E Y W O R D Shost pathogen, immune response, Immunometabolism, Influenza, metabolism, viral infection, virus | 141 BAHADORAN et Al.

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Mitochondrial fidelity and metabolic agility control immune cell fate and function

Cited by 39 publications

References 168 publications

Boosting NAD level suppresses inflammatory activation of PBMCs in heart failure

Boosting NAD level suppresses inflammatory activation of PBMCs in heart failure

Mitochondrial Bioenergetics and Dynamics in Secretion Processes

Fueling influenza and the immune response: Implications for metabolic reprogramming during influenza infection and immunometabolism

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