Selective mitochondrial antioxidant MitoTEMPO reduces renal dysfunction and systemic inflammation in experimental sepsis in rats

Arulkumaran, Nishkantha; Pollen, Sean; Tidswell, Robert; Gaupp, Charlotte; Peters, Vera B. M.; Stanzani, Giacomo; Snow, Timothy Arthur Chandos; Duchen, Michael R.; Singer, Mervyn

doi:10.1016/j.bja.2021.05.036

Cited by 15 publications

(11 citation statements)

References 37 publications

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“…The treatment with mitoTEMPO decreased the mean values of iNOS and IL-6 (Figure 3a,c), whereas the treatment with TPP even further increased the gene expression levels, with that of IL-6 being significant. These data are in line with the previously reported data on beneficial effects of mtAOX such as mitoTEMPO [2][3][4][5][6]. Interestingly, we found that the LPS-mediated increase in the expression levels of TNFR1, NFkBialpha, and CHOP was not affected by mitoTEMPO, indicating that mainly the pathogen-associated molecules drive these targets.…”

Section: Resultssupporting

confidence: 93%

“…We observed that markers of organ damage as well as markers of the inflammatory response, particularly those associated with NO metabolism that increase in circulating blood, can be significantly lowered by mitoTEMPO, but not by TPP, pointing towards the role of ROS in the upregulation of theses markers in response to LPS. The effect of mitoTEMPO is in line with previous reports published by us and others in similar models of acute inflammation [2][3][4][5][6]. In contrast, both TPP and mitoTEMPO reduced the W/D ratio of the lung 24 h after LPS treatment to a similar extent.…”

Section: Discussionsupporting

confidence: 92%

“…The effects of mtAOX, as described in the literature, are predominantly beneficial, mitigating pathological changes in the body [ 2 , 3 , 4 , 5 , 6 ]. However, there are also reports showing that the effect of mtAOX can be harmful [ 7 ].…”

Section: Introductionmentioning

confidence: 99%

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Systemic Effects of mitoTEMPO upon Lipopolysaccharide Challenge Are Due to Its Antioxidant Part, While Local Effects in the Lung Are Due to Triphenylphosphonium

et al. 2022

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Mitochondria-targeted antioxidants (mtAOX) are a promising treatment strategy against reactive oxygen species-induced damage. Reports about harmful effects of mtAOX lead to the question of whether these could be caused by the carrier molecule triphenylphosphonium (TPP). The aim of this study was to investigate the biological effects of the mtAOX mitoTEMPO, and TPP in a rat model of systemic inflammatory response. The inflammatory response was induced by lipopolysaccharide (LPS) injection. We show that mitoTEMPO reduced expression of inducible nitric oxide synthase in the liver, lowered blood levels of tissue damage markers such as liver damage markers (aspartate aminotransferase and alanine aminotransferase), kidney damage markers (urea and creatinine), and the general organ damage marker, lactate dehydrogenase. In contrast, TPP slightly, but not significantly, increased the LPS-induced effects. Surprisingly, both mitoTEMPO and TPP reduced the wet/dry ratio in the lung after 24 h. In the isolated lung, both substances enhanced the increase in pulmonary arterial pressure induced by LPS observed within 3 h after LPS treatments but did not affect edema formation at this time. Our data suggest that beneficial effects of mitoTEMPO in organs are due to its antioxidant moiety (TEMPO), except for the lung where its effects are mediated by TPP.

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Section: Resultssupporting

confidence: 93%

Section: Discussionsupporting

confidence: 92%

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Systemic Effects of mitoTEMPO upon Lipopolysaccharide Challenge Are Due to Its Antioxidant Part, While Local Effects in the Lung Are Due to Triphenylphosphonium

et al. 2022

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“…The cells of the innate immune system, including macrophages and antigen-presenting cells, play a vital role in providing host resistance to infection and promoting inflammatory response [ 41 ], which were also corroborated by various studies that the mitochondrial morphological changes were involved in the regulation of cellular metabolism, which may indirectly affect the activation and response of immune cells [ 42 , 43 ] along with the presence of mtROS, produced by electron transport chain (ETC) can trigger innate immune signals or cause immune cell damage in accordance with the measure and timing of their production [ 44 ]. Chronic inflammation results in the release of a substantial number of cellular mtROS into the blood, thereby interfering with their functions and disrupting intercellular communication [ 45 ].…”

Section: Discussionmentioning

confidence: 75%

The Imbalance of Mitochondrial Homeostasis of Peripheral Blood-Derived Macrophages Mediated by MAFLD May Impair the Walking Ability of Elderly Patients with Osteopenia

Wang

Liu

et al. 2022

Oxidative Medicine and Cellular Longevity

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Introduction. Many Asian cohort studies have shown that nonalcoholic fatty liver disease (NAFLD), now renamed as metabolic dysfunction-associated fatty liver disease (MAFLD), increases the risk of osteoporosis, yet the effect of MAFLD on elderly patients with osteopenia (OPe) has not been reported. Objective. This study aimed to explore the influence of MAFLD on the function of macrophages in patients with OPe. Methods. A total of 107 elderly OPe patients with or without MAFLD who visited the Huadong Hospital Affiliated to Fudan University (Shanghai, China) between January 1st, 2021, and September 30th, 2021, were evaluated for an interviewer-assisted questionnaire, as well as clinical and biological assessments. Results. Comparing two groups of elderly patients with the same bone mass level, we found that the six-minute walking distance ( P = 0.012 ) and short physical performance battery (SPPB) score ( P = 0.0029 ) of the elderly OPe patients with MAFLD are worse than those in OPe patients without MAFLD. Our results confirmed that the mitochondrial reactive oxygen species (mtROS) in peripheral blood of OPe patients with MAFLD was significantly higher than those without. We also observed the mitochondrial metabolism level of peripheral blood-derived macrophages in the included patients and peripheral blood macrophages in patients with MAFLD with more unbalanced mitochondrial dynamics of macrophages, more weakened mitochondrial respiratory capacity, and greater mitochondrial microstructure damage, when compared with the elderly patients without MAFLD. Conclusions. To conclude, our data revealed that MAFLD itself may aggravate the inflammatory state in elderly OPe people due to mitochondrial homeostasis imbalance of peripheral blood macrophages. Damaged monocyte-macrophages might trigger attenuation of the walking ability of OPe patients.

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“…Increased production of mtROS is a common feature of AKI and CKD (64,65). Enhanced mitochondrial antioxidant defenses by supplementation with mitochondria-targeted antioxidants have been shown to attenuate mitochondrial dysfunction and reduce kidney injury in animal models of IR-induced renal fibrosis, diabetic nephropathy, and unilateral ureteral obstruction (UUO)-induced CKD (66)(67)(68). Notably, a moderate increase in mtROS may regulate signaling pathways involved in renal injury and incomplete renal repair (69).…”

Section: Role In Kidney Injurymentioning

confidence: 99%

Mitochondrial Dysfunction: An Emerging Link in the Pathophysiology of Cardiorenal Syndrome

Shi

Zhang

et al. 2022

Front. Cardiovasc. Med.

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The crosstalk between the heart and kidney is carried out through various bidirectional pathways. Cardiorenal syndrome (CRS) is a pathological condition in which acute or chronic dysfunction in the heart or kidneys induces acute or chronic dysfunction of the other organ. Complex hemodynamic factors and biochemical and hormonal pathways contribute to the development of CRS. In addition to playing a critical role in generating metabolic energy in eukaryotic cells and serving as signaling hubs during several vital processes, mitochondria rapidly sense and respond to a wide range of stress stimuli in the external environment. Impaired adaptive responses ultimately lead to mitochondrial dysfunction, inducing cell death and tissue damage. Subsequently, these changes result in organ failure and trigger a vicious cycle. In vitro and animal studies have identified an important role of mitochondrial dysfunction in heart failure (HF) and chronic kidney disease (CKD). Maintaining mitochondrial homeostasis may be a promising therapeutic strategy to interrupt the vicious cycle between HF and acute kidney injury (AKI)/CKD. In this review, we hypothesize that mitochondrial dysfunction may also play a central role in the development and progression of CRS. We first focus on the role of mitochondrial dysfunction in the pathophysiology of HF and AKI/CKD, then discuss the current research evidence supporting that mitochondrial dysfunction is involved in various types of CRS.

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Selective mitochondrial antioxidant MitoTEMPO reduces renal dysfunction and systemic inflammation in experimental sepsis in rats

Cited by 15 publications

References 37 publications

Systemic Effects of mitoTEMPO upon Lipopolysaccharide Challenge Are Due to Its Antioxidant Part, While Local Effects in the Lung Are Due to Triphenylphosphonium

Systemic Effects of mitoTEMPO upon Lipopolysaccharide Challenge Are Due to Its Antioxidant Part, While Local Effects in the Lung Are Due to Triphenylphosphonium

The Imbalance of Mitochondrial Homeostasis of Peripheral Blood-Derived Macrophages Mediated by MAFLD May Impair the Walking Ability of Elderly Patients with Osteopenia

Mitochondrial Dysfunction: An Emerging Link in the Pathophysiology of Cardiorenal Syndrome

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