Protective effects of farnesyltransferase inhibitor on sepsis-induced morphological aberrations of mitochondria in muscle and increased circulating mitochondrial DNA levels in mice

Tsuji, Daisuke; Nakazawa, Harumasa; Yorozu, Tomoko; Kaneki, Masao

doi:10.1016/j.bbrc.2021.03.141

Cited by 5 publications

(3 citation statements)

References 26 publications

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“…CoQ10 deficiency causes mitochondrial dysfunction. Increased circulating mtDNA levels are considered to be associated with mitochondrial disintegrity [ 60 , 61 ] as well as with cellular damage. Therefore, we measured plasma mtDNA levels as a biomarker that reflects mitochondrial dysfunction/disintegrity as well as systemic inflammation.…”

Section: Discussionmentioning

confidence: 99%

Bioavailability of Reduced Coenzyme Q10 (Ubiquinol-10) in Burn Patients

Kuriyama

Nakamura²,

Nakazawa³

et al. 2022

Metabolites

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Mitochondrial dysfunction has been implicated in the pathogenesis of inflammation and multi-organ dysfunction in major trauma, including burn injury. Coenzyme Q10 (CoQ10) is a metabolite of the mevalonate pathway and an essential cofactor for the electron transport in the mitochondria. In addition, its reduced form (ubiquinol) functions as an antioxidant. Little is known as to whether oral CoQ10 supplementation effectively increases intracellular CoQ10 levels in humans. To study the bioavailability of CoQ10 supplementation, we conducted a randomized, double-blind, placebo-controlled study of reduced CoQ10 (ubiquinol-10) (1800 mg/day, t.i.d.) in burn patients at a single, tertiary-care hospital. Baseline plasma CoQ10 levels were significantly lower in burn patients than in healthy volunteers, although plasma CoQ10/cholesterol ratio did not differ between the groups. CoQ10 supplementation increased plasma concentrations of total and reduced CoQ10 and total CoQ10 content in peripheral blood mononuclear cells (PBMCs) in burn patients compared with the placebo group. CoQ10 supplementation did not significantly change circulating levels of mitochondrial DNA, inflammatory markers (e.g., interleukins, TNF-α, IFN-γ), or Sequential Organ Failure Assessment (SOFA) scores compared with the placebo group. This study showed that a relatively high dose of reduced CoQ10 supplementation increased the intracellular CoQ10 content in PBMCs as well as plasma concentrations in burn patients.

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Section: Discussionmentioning

confidence: 99%

Bioavailability of Reduced Coenzyme Q10 (Ubiquinol-10) in Burn Patients

Kuriyama

Nakamura²,

Nakazawa³

et al. 2022

Metabolites

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“…Furthermore, not only a diminished number of mitochondria, but also ultrastructural changes in the remaining organelles point to severe alterations in mitochondrial integrity during critical illness. Mitochondrial swelling, a fragmented or nearly absent cristae structure, matrix space enlargement and vacuolization are the most frequent morphological pathologies that have been reported in animal [ 79 , 80 , 103 ] and human [ 13 , 104 ] skeletal muscle biopsies associated with critical illness-induced muscle wasting. In accordance with the rapid development of muscle weakness and the degradation of muscle mass due to critical illness, the decrease in mitochondrial content can be observed within several days after ICU admission [ 83 ].…”

Section: Structural and Functional Impairments Of Mitochondria In Icu...mentioning

confidence: 99%

Mitochondrial Dysfunction in Intensive Care Unit-Acquired Weakness and Critical Illness Myopathy: A Narrative Review

Klawitter

Ehler

Bajorat

et al. 2023

IJMS

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Mitochondria are key structures providing most of the energy needed to maintain homeostasis. They are the main source of adenosine triphosphate (ATP), participate in glucose, lipid and amino acid metabolism, store calcium and are integral components in various intracellular signaling cascades. However, due to their crucial role in cellular integrity, mitochondrial damage and dysregulation in the context of critical illness can severely impair organ function, leading to energetic crisis and organ failure. Skeletal muscle tissue is rich in mitochondria and, therefore, particularly vulnerable to mitochondrial dysfunction. Intensive care unit-acquired weakness (ICUAW) and critical illness myopathy (CIM) are phenomena of generalized weakness and atrophying skeletal muscle wasting, including preferential myosin breakdown in critical illness, which has also been linked to mitochondrial failure. Hence, imbalanced mitochondrial dynamics, dysregulation of the respiratory chain complexes, alterations in gene expression, disturbed signal transduction as well as impaired nutrient utilization have been proposed as underlying mechanisms. This narrative review aims to highlight the current known molecular mechanisms immanent in mitochondrial dysfunction of patients suffering from ICUAW and CIM, as well as to discuss possible implications for muscle phenotype, function and therapeutic approaches.

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“…So far, studies have demonstrated that mitochondrial dysfunction plays an important role in the pathogenesis of sepsis [ 3 , 4 , 5 , 6 ]. Mitochondria, the organelles that produce the energy required by human body, play a key role in the whole life activities of human body.…”

Section: Introductionmentioning

confidence: 99%

High Concentration Hydrogen Mitigates Sepsis-Induced Acute Lung Injury in Mice by Alleviating Mitochondrial Fission and Dysfunction

Zhao

Sun

Cui

et al. 2023

JPM

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Background: Multiple organ failure (MOF) is the main cause of early death in septic shock. Lungs are among the organs that are affected in MOF, resulting in acute lung injury. A large number of inflammatory factors and stress injury in sepsis can lead to alterations in mitochondrial dynamics. Numerous studies have confirmed that hydrogen can alleviate sepsis in the animal model. The purpose of this experiment was to explore the therapeutic effect of high concentration (67%) hydrogen on acute lung injury in septic mice and its mechanism. Methods: The moderate and severe septic models were prepared by cecal ligation and puncture. Hydrogen with different concentrations was inhaled for one hour at 1 h and 6 h after the corresponding surgery. The arterial blood gas of mice during hydrogen inhalation was monitored in real time, and the 7-day survival rate of mice with sepsis was recorded. The pathological changes of lung tissues and functions of livers and kidneys were measured. The changes of oxidation products, antioxidant enzymes and pro-inflammatory cytokines in lungs and serums were detected. Mitochondrial function was measured. Results: The inhalation of 2% or 67% hydrogen improves the 7-day survival rate and reduces acute lung injury as well as liver and kidney injury in sepsis. The therapeutic effect of 67% hydrogen inhalation on sepsis was related to increasing antioxidant enzyme activity, reducing oxidation products and pro-inflammatory cytokines in lungs and serums. Compared with the Sham group, mitochondrial dysfunction was alleviated in hydrogen groups. Conclusions: Hydrogen inhalation by high or low concentration can both significantly improve sepsis; however, a high concentration demonstrates a better protective effect. High concentration hydrogen inhalation can significantly improve the mitochondrial dynamic balance and reduce the lung injury in septic mice.

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Protective effects of farnesyltransferase inhibitor on sepsis-induced morphological aberrations of mitochondria in muscle and increased circulating mitochondrial DNA levels in mice

Cited by 5 publications

References 26 publications

Bioavailability of Reduced Coenzyme Q10 (Ubiquinol-10) in Burn Patients

Bioavailability of Reduced Coenzyme Q10 (Ubiquinol-10) in Burn Patients

Mitochondrial Dysfunction in Intensive Care Unit-Acquired Weakness and Critical Illness Myopathy: A Narrative Review

High Concentration Hydrogen Mitigates Sepsis-Induced Acute Lung Injury in Mice by Alleviating Mitochondrial Fission and Dysfunction

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