Mitochondrial complex II and reactive oxygen species in disease and therapy

Vanova, Katerina Hadrava; Kraus, Michal; Neužil, Jiřı́; Rohlena, Jakub

doi:10.1080/13510002.2020.1752002

Cited by 107 publications

(78 citation statements)

References 112 publications

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“…However, decreased SDH activity (Fig. 1J), which may increase succinate levels (48,49), and NAD 1 hydrolysis by the tuberculosis necrotizing toxin (28,50) could also contribute. We found no role for ROS generated by NADPH oxidase in M. tuberculosis-induced macrophage cytolysis.…”

Section: Discussionmentioning

confidence: 99%

Sirtuin 3 Downregulation in Mycobacterium tuberculosis -Infected Macrophages Reprograms Mitochondrial Metabolism and Promotes Cell Death

Smulan

Martínez

Kiritsy

et al. 2021

mBio

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Mycobacterium tuberculosis induces metabolic reprogramming in macrophages like the Warburg effect. This enhances antimicrobial performance at the expense of increased inflammation, which may promote a pathogen-permissive host environment. Since the NAD+-dependent protein deacetylase Sirtuin 3 (SIRT3) is an important regulator of mitochondrial metabolism and cellular redox homeostasis, we hypothesized that SIRT3 modulation mediates M. tuberculosis-induced metabolic reprogramming. Infection of immortalized and primary murine macrophages resulted in reduced levels of SIRT3 mRNA and protein and perturbation of SIRT3-regulated enzymes in the tricarboxylic acid cycle, electron transport chain, and glycolytic pathway. These changes were associated with increased reactive oxygen species and reduced antioxidant scavenging, thereby triggering mitochondrial stress and macrophage cell death. Relevance to tuberculosis disease in vivo was indicated by greater bacterial burden and immune pathology in M. tuberculosis-infected Sirt3−/− mice. CD11b+ lung leukocytes isolated from infected Sirt3−/− mice showed decreased levels of enzymes involved in central mitochondrial metabolic pathways, along with increased reactive oxygen species. Bacterial burden was also greater in lungs of LysMcreSirt3L2/L2 mice, demonstrating the importance of macrophage-specific SIRT3 after infection. These results support the model of SIRT3 as a major upstream regulatory factor, leading to metabolic reprogramming in macrophages by M. tuberculosis. IMPORTANCE Tuberculosis, the disease caused by the bacterium M. tuberculosis, remains one of the top 10 causes of death worldwide. Macrophages, the first cells to encounter M. tuberculosis and critical for defense against infection, are hijacked by M. tuberculosis as a protected growth niche. M. tuberculosis-infected macrophages undergo metabolic reprogramming where key mitochondrial pathways are modulated, but the mechanisms driving this metabolic shift is unknown. Our study demonstrates that M. tuberculosis downregulates Sirtuin 3 (SIRT3), an important regulator of mitochondrial metabolism, leading to SIRT3-dependent transcriptional downregulation of mitochondrial metabolic proteins, which is followed by oxidative stress and macrophage necrosis. This study identifies SIRT3 modulation as a key event in M. tuberculosis-induced metabolic reprograming in macrophages that defend against tuberculosis.

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Section: Discussionmentioning

confidence: 99%

Sirtuin 3 Downregulation in Mycobacterium tuberculosis -Infected Macrophages Reprograms Mitochondrial Metabolism and Promotes Cell Death

Smulan

Martínez

Kiritsy

et al. 2021

mBio

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“…As discussed above, complex II plays a role in reverse flow-induced ROS generation. The complex II may also directly generate ROS within complex II [ 93 , 94 ]. ROS generation by complex II is dependent on the succinate concentration [ 79 ].…”

Section: Oxidant Stress and Cardiovascular Diseasementioning

confidence: 99%

“…High concentration of succinate (>5 mM used in most in vitro analysis) inhibits ROS generation from complex II. ROS generation is increased in complex II when a relatively low concentration of succinate (0.5 mM) is used in the presence of complex II inhibitor (thenoyltrifluoroacetone (TTFA)) or a complex III Qo center inhibitor [ 93 ]. TTFA blocks electron transport at the terminal part of complex II, which increases electron accumulation within complex II and subsequent ROS generation [ 93 ].…”

Section: Oxidant Stress and Cardiovascular Diseasementioning

confidence: 99%

“…ROS generation is increased in complex II when a relatively low concentration of succinate (0.5 mM) is used in the presence of complex II inhibitor (thenoyltrifluoroacetone (TTFA)) or a complex III Qo center inhibitor [ 93 ]. TTFA blocks electron transport at the terminal part of complex II, which increases electron accumulation within complex II and subsequent ROS generation [ 93 ]. In contrast, inhibition of complex II at the succinate-binding site with malonate decreases ROS generation from complex II due to decreased electron flowing into complex II [ 65 ].…”

Section: Oxidant Stress and Cardiovascular Diseasementioning

confidence: 99%

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Preventing Myocardial Injury Following Non-Cardiac Surgery: A Potential Role for Preoperative Antioxidant Therapy with Ubiquinone

Chen

Hocum-Stone

et al. 2021

Antioxidants

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Over 240 million non-cardiac operations occur each year and are associated with a 15–20% incidence of adverse perioperative cardiovascular events. Unfortunately, preoperative therapies that have been useful for chronic ischemic heart diseases, such as coronary artery revascularization, antiplatelet agents, and beta-blockers have failed to improve outcomes. In a pre-clinical swine model of ischemic heart disease, we showed that daily administration of ubiquinone (coenzyme Q10, CoQ10) enhances the antioxidant status of mitochondria within chronically ischemic heart tissue, potentially via a PGC1α-dependent mechanism. In a randomized controlled trial, among high-risk patients undergoing elective vascular surgery, we showed that NT Pro-BNP levels are an important means of risk-stratification during the perioperative period and can be lowered with administration of CoQ10 (400 mg/day) for 3 days prior to surgery. The review provides background information for the role of oxidant stress and inflammation during high-risk operations and the potential novel application of ubiquinone as a preoperative antioxidant therapy that might reduce perioperative adverse cardiovascular outcomes.

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“…Unlike the other complexes, succinate dehydrogenase is not involved in the transfer of protons from the matrix to the intermembrane space, and therefore does not directly contribute to the creation of the mitochondrial membrane potential. However, recent studies have highlighted the connection of this complex with the apoptotic pathway mediated by death receptors [ 37 , 38 ]. Complex II inhibitors, such as α-tocopheryl succinate (α-TOS) [ 39 ], gracillin [ 40 ], and atpenins [ 41 , 42 , 43 ], were found to increase ROS production, triggering apoptotic death in vitro and in vivo.…”

Section: Targeting Mitochondrial Metabolism In Cancermentioning

confidence: 99%

Targeting the Mitochondrial Metabolic Network: A Promising Strategy in Cancer Treatment

Frattaruolo

Brindisi

Curcio

et al. 2020

IJMS

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Metabolic reprogramming is a hallmark of cancer, which implements a profound metabolic rewiring in order to support a high proliferation rate and to ensure cell survival in its complex microenvironment. Although initial studies considered glycolysis as a crucial metabolic pathway in tumor metabolism reprogramming (i.e., the Warburg effect), recently, the critical role of mitochondria in oncogenesis, tumor progression, and neoplastic dissemination has emerged. In this report, we examined the main mitochondrial metabolic pathways that are altered in cancer, which play key roles in the different stages of tumor progression. Furthermore, we reviewed the function of important molecules inhibiting the main mitochondrial metabolic processes, which have been proven to be promising anticancer candidates in recent years. In particular, inhibitors of oxidative phosphorylation (OXPHOS), heme flux, the tricarboxylic acid cycle (TCA), glutaminolysis, mitochondrial dynamics, and biogenesis are discussed. The examined mitochondrial metabolic network inhibitors have produced interesting results in both preclinical and clinical studies, advancing cancer research and emphasizing that mitochondrial targeting may represent an effective anticancer strategy.

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Mitochondrial complex II and reactive oxygen species in disease and therapy

Cited by 107 publications

References 112 publications

Sirtuin 3 Downregulation in Mycobacterium tuberculosis -Infected Macrophages Reprograms Mitochondrial Metabolism and Promotes Cell Death

Sirtuin 3 Downregulation in Mycobacterium tuberculosis -Infected Macrophages Reprograms Mitochondrial Metabolism and Promotes Cell Death

Preventing Myocardial Injury Following Non-Cardiac Surgery: A Potential Role for Preoperative Antioxidant Therapy with Ubiquinone

Targeting the Mitochondrial Metabolic Network: A Promising Strategy in Cancer Treatment

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