Interactions of Mitochondrial Transcription Factor A with DNA Damage: Mechanistic Insights and Functional Implications

Chew, Krystie; Zhao, Linlin

doi:10.3390/genes12081246

Cited by 22 publications

(14 citation statements)

References 83 publications

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“…Tfam, Nrf1, or PGC-1α and its gene regulatory network were increased in alb-SREBP-1c mice. Tfam acts as histone on mtDNA, regulating transcription and replication [ 18 , 19 ]. The transcriptional co-activator PGC-1α plays a multifaceted role to regulate mitochondrial metabolic functions and mitochondrial turnover [ 20 , 21 , 22 ].…”

Section: Discussionmentioning

confidence: 99%

Adaptation of Oxidative Phosphorylation Machinery Compensates for Hepatic Lipotoxicity in Early Stages of MAFLD

Fahlbusch

Nikolic

Hartwig

et al. 2022

IJMS

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Alterations in mitochondrial function are an important control variable in the progression of metabolic dysfunction-associated fatty liver disease (MAFLD), while also noted by increased de novo lipogenesis (DNL) and hepatic insulin resistance. We hypothesized that the organization and function of a mitochondrial electron transport chain (ETC) in this pathologic condition is a consequence of shifted substrate availability. We addressed this question using a transgenic mouse model with increased hepatic insulin resistance and DNL due to constitutively active human SREBP-1c. The abundance of ETC complex subunits and components of key metabolic pathways are regulated in the liver of these animals. Further omics approaches combined with functional assays in isolated liver mitochondria and primary hepatocytes revealed that the SREBP-1c-forced fatty liver induced a substrate limitation for oxidative phosphorylation, inducing enhanced complex II activity. The observed increased expression of mitochondrial genes may have indicated a counteraction. In conclusion, a shift of available substrates directed toward activated DNL results in increased electron flows, mainly through complex II, to compensate for the increased energy demand of the cell. The reorganization of key compounds in energy metabolism observed in the SREBP-1c animal model might explain the initial increase in mitochondrial function observed in the early stages of human MAFLD.

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Section: Discussionmentioning

confidence: 99%

Adaptation of Oxidative Phosphorylation Machinery Compensates for Hepatic Lipotoxicity in Early Stages of MAFLD

Fahlbusch

Nikolic

Hartwig

et al. 2022

IJMS

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“…As compared to wild type or OGG1 KO mice, mitochondria of OGG1 transgenic mice are elongated with increased expression of mitochondrial encoded genes, and upregulation of Tfam with reduced levels of NF-κB. Mitochondrial transcription factor A (TFAM) regulates mtDNA transcription, replication, packaging and maintenance and in so doing, encounters 8-oxoG lesions in mtDNA [55]. Although TFAM may interact with BER proteins during mtDNA repair [56], its downregulation decreases CN [57].…”

Section: Discussionmentioning

confidence: 99%

Small Molecule-Mediated Allosteric Activation of the Base Excision Repair Enzyme 8-Oxoguanine DNA Glycosylase: Impact on Mitochondrial Function

Tian¹,

Katchur²,

Jiang³

et al. 2022

Preprint

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8-Oxoguanine DNA glycosylase (OGG1) initiates base excision repair of the oxidative DNA damage product 8-oxoguanine. OGG1 is bifunctional; catalyzing glycosyl bond cleavage, followed by phosphodiester backbone incision via a β-elimination apurinic lyase reaction. The product from the glycosylase reaction, 8-oxoguanine, and its analogues, 8-bromoguanine and 8-aminoguanine, trigger the rate-limiting AP lyase reaction. The precise activation mechanism remains unclear. The product-assisted catalysis hypothesis suggests that 8-oxoguanine and analogues bind at the product recognition (PR) pocket to enhance strand cleavage as catalytic bases. Alternatively, they may allosterically activate OGG1 by binding outside of the PR pocket to induce an active-site conformational change to accelerate apurinic lyase. Herein, steady-state kinetic analyses demonstrated random binding of substrate and activator. 9-Deazaguanine, which can’t function as a substrate-competent base, activated OGG1, albeit with a lower Emax value than 8-bromoguanine and 8-aminoguanine. Random compound screening identified small molecules with Emax values similar to 8-bromoGua. Paraquat-induced mitochondrial dysfunction was attenuated by several small molecule OGG1 activators; benefits included enhanced mitochondrial membrane and DNA integrity, less cytochrome c translocation, ATP preservation, and mitochondrial membrane dynamics. Our results support an allosteric mechanism of OGG1 and not product-assisted catalysis. OGG1 small molecule activators may improve mitochondrial function in oxidative stress-related diseases.

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“…mtTFA is an mitochondrial DNA (mtDNA) packaging protein that dominates mtDNA replication and transcription ( 43 , 44 ). Derogation of mtTFA could bring out exhaustion of mtDNA and cause energy metabolism disorders ( 43 – 45 ). In addition to the protective role in mitochondrial DNA, mtTFA is also a regulator of calcium and ROS production ( 46 ).…”

Section: Discussionmentioning

confidence: 99%

Curcumin Improves Cardiopulmonary Resuscitation Outcomes by Modulating Mitochondrial Metabolism and Apoptosis in a Rat Model of Cardiac Arrest

Zhang

Liu

Jiang

et al. 2022

Front. Cardiovasc. Med.

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BackgroundCurcumin, a diarylheptanoid chemical compound extracted from curcuma longa, exerts a variety of biological and pharmacological effects in numerous pathological conditions, including ischemia/reperfusion (I/R) injury. In this study, we investigated its role in post-resuscitation myocardial dysfunction in a rat model of cardiac arrest (CA) and cardiopulmonary resuscitation (CPR) by targeting on mitochondrial metabolism and apoptosis.MethodsAnimals were randomized into three groups: sham, control and curcumin, with fifteen rats in each group. Ventricular fibrillation (VF) was induced in the rats of the control and curcumin groups. The rats in the two groups were untreated for 8 min, followed by CPR for 8 min. Placebo (saline) or curcumin was administered by intraperitoneal injection, respectively, 5 min after successful resuscitation. Myocardial function was measured at baseline and post-resuscitation for 6 h consecutively. Ten rats in each group were closely observed for an additional 66 h to analyze the survival status, and the remaining five were sacrificed for the measurement of mitochondrial parameters and cell apoptosis.ResultsCompared with the control group, myocardial function was significantly enhanced in the curcumin group, contributing to a better survival status. Curcumin treatment mitigated the depletion of superoxide dismutase (SOD) and the production of malondialdehyde (MDA). The structural damage of mitochondria was also alleviated, with improved conditions of mPTP and ΔΨm. Curcumin boosted the production of ATP and attenuated myocardial apoptosis. Cytochrome C, caspase-3 and its cleavage were suppressed by curcumin. Proteins closely related to the functional performance of mitochondria, including uncoupling protein 2 (UCP2) and uncoupling protein 3 (UCP3) were downregulated, while mitochondrial transcription factor A (mtTFA) was upregulated.ConclusionCurcumin improves the outcomes of CPR via alleviating myocardial dysfunction induced by I/R injury. It exhibits anti-oxidation properties. Moreover, it is capable of ameliorating mitochondrial structure and energy metabolism, as well as inhibiting the mitochondrial apoptosis pathway. UCP2, UCP3, and mtTFA might also be involved in curcumin mediated protective effects on mitochondria.

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Interactions of Mitochondrial Transcription Factor A with DNA Damage: Mechanistic Insights and Functional Implications

Cited by 22 publications

References 83 publications

Adaptation of Oxidative Phosphorylation Machinery Compensates for Hepatic Lipotoxicity in Early Stages of MAFLD

Adaptation of Oxidative Phosphorylation Machinery Compensates for Hepatic Lipotoxicity in Early Stages of MAFLD

Small Molecule-Mediated Allosteric Activation of the Base Excision Repair Enzyme 8-Oxoguanine DNA Glycosylase: Impact on Mitochondrial Function

Curcumin Improves Cardiopulmonary Resuscitation Outcomes by Modulating Mitochondrial Metabolism and Apoptosis in a Rat Model of Cardiac Arrest

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