Redox imbalance due to the loss of mitochondrial NAD(P)-transhydrogenase markedly aggravates high fat diet-induced fatty liver disease in mice

Navarro, Claudia D.C.; Figueira, Tiago Rezende; Francisco, Annelise; Dal'bó, G. A.; Ronchi, Juliana A.; Rovani, Juliana C.; Escanhoela, C.A.F.; Oliveira, Helena Coutinho Franco de; Castilho, Roger F.; Vercesi, Anı́bal E.

doi:10.1016/j.freeradbiomed.2017.09.026

Cited by 54 publications

(38 citation statements)

References 52 publications

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“…Indeed, Nnt ‐mutated mice on a HFD displayed histological markers of progression from simple steatosis to steatohepatitis. This is an important finding that comprises a proof of the concept that mitochondrial redox imbalance may potentiate the development of aggravated forms of HFD‐induced fatty liver disease (Navarro et al, ).…”

Section: Role Of Nnt Deficiency In Mpt and In High Fat Diet (Hfd)‐indmentioning

confidence: 79%

Facilitation of Ca²⁺‐induced opening of the mitochondrial permeability transition pore either by nicotinamide nucleotide transhydrogenase deficiency or statins treatment

Busanello

Figueira

Marques

et al. 2018

Cell Biology International

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Mitochondrial redox imbalance and high Ca uptake induce the opening of the permeability transition pore (PTP) that leads to disruption of energy-linked mitochondrial functions and triggers cell death in many disease states. In this review, we discuss the major results from our studies investigating the consequences of NAD(P)-transhydrogenase (NNT) deficiency, and of statins treatment for mitochondrial functions and susceptibility to Ca -induced PTP. We highlight the aggravation of high fat diet-induced fatty liver disease in the context of NNT deficiency and the role of antioxidants in the prevention of statins toxicity to mitochondria.

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Section: Role Of Nnt Deficiency In Mpt and In High Fat Diet (Hfd)‐indmentioning

confidence: 79%

Facilitation of Ca²⁺‐induced opening of the mitochondrial permeability transition pore either by nicotinamide nucleotide transhydrogenase deficiency or statins treatment

Busanello

Figueira

Marques

et al. 2018

Cell Biology International

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“…; Navarro et al . ). Mice were maintained on chow or HFD for 32 weeks prior to being sacrificed for forebrain and cerebellum removal.…”

Section: Methodsmentioning

confidence: 97%

“…Each group contained five to six animals. The HFD protocols were previously standardized in our laboratory using male mice to consistently induce a metabolic syndrome that includes glucose intolerance, hyperinsulinemia and nonalcoholic steatohepatitis (Pettersson et al 2012;Navarro et al 2017). Mice were maintained on chow or HFD for 32 weeks prior to being sacrificed for forebrain and cerebellum removal.…”

Section: Animalsmentioning

confidence: 99%

“…NNT is relevant to redox balance in HFD-fed mice We recently described that Nnt À/À mice chronically fed a HFD displayed liver mitochondrial redox imbalance and aggravation of nonalcoholic fatty liver disease from simple steatosis to nonalcoholic steatohepatitis (Navarro et al 2017). In view of this, it seems reasonable that the physiological stress caused by the ingestion of HFD could cause more oxidative stress in the central nervous system of mice without functional NNT than in mice with the functional protein.…”

Section: Nnt Deficiency Favors Higher Mitochondrial H 2 O 2 Releasementioning

confidence: 99%

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Nicotinamide nucleotide transhydrogenase is required for brain mitochondrial redox balance under hampered energy substrate metabolism and high‐fat diet

Francisco

Ronchi

Navarro

et al. 2018

Journal of Neurochemistry

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Among mitochondrial NADP‐reducing enzymes, nicotinamide nucleotide transhydrogenase (NNT) establishes an elevated matrix NADPH/NADP+ by catalyzing the reduction of NADP+ at the expense of NADH oxidation coupled to inward proton translocation across the inner mitochondrial membrane. Here, we characterize NNT activity and mitochondrial redox balance in the brain using a congenic mouse model carrying the mutated Nnt gene from the C57BL/6J strain. The absence of NNT activity resulted in lower total NADPH sources activity in the brain mitochondria of young mice, an effect that was partially compensated in aged mice. Nonsynaptic mitochondria showed higher NNT activity than synaptic mitochondria. In the absence of NNT, an increased release of H2O2 from mitochondria was observed when the metabolism of respiratory substrates occurred with restricted flux through relevant mitochondrial NADPH sources or when respiratory complex I was inhibited. In accordance, mitochondria from Nnt‐/‐ brains were unable to sustain NADP in its reduced state when energized in the absence of carbon substrates, an effect aggravated after H2O2 bolus metabolism. These data indicate that the lack of NNT in brain mitochondria impairs peroxide detoxification, but peroxide detoxification can be partially counterbalanced by concurrent NADPH sources depending on substrate availability. Notably, only brain mitochondria from Nnt−/− mice chronically fed a high‐fat diet exhibited lower activity of the redox‐sensitive aconitase, suggesting that brain mitochondrial redox balance requires NNT under the metabolic stress of a high‐fat diet. Overall, the role of NNT in the brain mitochondria redox balance especially comes into play under mitochondrial respiratory defects or high‐fat diet.

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“…and superoxide radical is one of the important mediators of free radical toxicity . Navarro et al recently demonstrated that H 2 O 2 release from mitochondria as well as the Ca ++ ‐induced mitochondrial permeability transition were very high in mitochondrial NAD(P)‐transhydrogenase null mice, which allow the progression of simple steatosis to steatohepatitis …”

Section: Mitochondria In Nafldmentioning

confidence: 99%

Role of mitochondria and mitochondria‐targeted agents in non‐alcoholic fatty liver disease

Ajith

2017

Clin Exp Pharma Physio

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Summary Mitochondria play a pivotal role in the fatty acid oxidation and have been found to be affected early during the macrovesicular fat accumulation in the hepatocytes. The fatty infiltration is the primary cause of oxidative stress and inflammation in the non‐alcoholic fatty liver disease (NAFLD), which can lead to the peroxidation of phospholipids, such as cardiolipin. Oxidative stress‐induced damage to mitochondrial DNA can result in the impairment of oxidative phosphorylation and further increases the generation of reactive oxygen species. The mitochondrial damage may eventually lead to apoptotic death of hepatocytes. The apoptosis along with the generated cytokines from the stellate and Kupffer cells further augment the fibrotic changes to advance the disease. Hence, alleviation of the mitochondrial impairment, particularly in the early stages of NAFLD, may prevent the progression of the disease. Among the various experimentally studied mitochondrial‐targeted agents, triphenylphosphonium cation ligated ubiquinone Q10 and vitamin E, Szeto‐Scheller peptides, and superoxide dismutase mimetic‐salen manganese complexes (EUK‐8 and EUK‐134) have been found to be most promising. In addition to these mitochondrial‐targeted agents, a novel area of therapy called mitotherapy have also emerged. However, clinical studies conducted so far are still fragmentary to validate their efficacy. This review article discusses the mitochondria‐targeted molecules and their potential role in the treatment of NAFLD.

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Redox imbalance due to the loss of mitochondrial NAD(P)-transhydrogenase markedly aggravates high fat diet-induced fatty liver disease in mice

Cited by 54 publications

References 52 publications

Facilitation of Ca²⁺‐induced opening of the mitochondrial permeability transition pore either by nicotinamide nucleotide transhydrogenase deficiency or statins treatment

Facilitation of Ca²⁺‐induced opening of the mitochondrial permeability transition pore either by nicotinamide nucleotide transhydrogenase deficiency or statins treatment

Nicotinamide nucleotide transhydrogenase is required for brain mitochondrial redox balance under hampered energy substrate metabolism and high‐fat diet

Role of mitochondria and mitochondria‐targeted agents in non‐alcoholic fatty liver disease

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Redox imbalance due to the loss of mitochondrial NAD(P)-transhydrogenase markedly aggravates high fat diet-induced fatty liver disease in mice

Cited by 54 publications

References 52 publications

Facilitation of Ca2+‐induced opening of the mitochondrial permeability transition pore either by nicotinamide nucleotide transhydrogenase deficiency or statins treatment

Facilitation of Ca2+‐induced opening of the mitochondrial permeability transition pore either by nicotinamide nucleotide transhydrogenase deficiency or statins treatment

Nicotinamide nucleotide transhydrogenase is required for brain mitochondrial redox balance under hampered energy substrate metabolism and high‐fat diet

Role of mitochondria and mitochondria‐targeted agents in non‐alcoholic fatty liver disease

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Facilitation of Ca²⁺‐induced opening of the mitochondrial permeability transition pore either by nicotinamide nucleotide transhydrogenase deficiency or statins treatment

Facilitation of Ca²⁺‐induced opening of the mitochondrial permeability transition pore either by nicotinamide nucleotide transhydrogenase deficiency or statins treatment