Differential requirements for mitochondrial electron transport chain components in the adult murine liver

Lesner, Nicholas P.; Wang, Xun; Chen, Zhenkang; Frank, Anderson R.; Menezes, Cameron J; House, Sara; Shelton, Spencer D.; Lemoff, Andrew; McFadden, David G.; Wanaspura, Janaka; DeBerardinis, Ralph J.; Mishra, Prashant

doi:10.7554/elife.80919

Cited by 18 publications

(14 citation statements)

References 69 publications

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“…Accordingly, a recent paper (Lesner, Wang et al 2022) reports that CIV is essential to maintain metabolic balance in the adult mouse liver, but CI is dispensable, which agrees with our conclusions.…”

Section: Discussionsupporting

confidence: 92%

The Role of Respiratory Complex IV in Lifespan Length and Quality

Castejon-Vega,

Fernandez-Guerrero,

Myers

et al. 2023

Preprint

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Mitochondria play a pivotal role in lifespan regulation, though the underlying mechanisms remain elusive. As ageing progresses, damaged mitochondria with reduced ATP production and increased Reactive Oxygen Species (ROS) generation accumulate, yet mitochondrial depletion extends the lifespan of various animal models. Our previous research demonstrated that complex I (CI) activity during development but not adulthood is crucial for determining the lifespan of Drosophila melanogaster. Still, CI-deficient mitochondria do not generate excessive ROS, failing to recapitulate mitochondrial ageing. In this study, we focus on complex IV (CIV), whose depletion leads to the accumulation of "old-mitochondria", i.e. producing less ATP and more ROS. We reveal that CIV's role in longevity is more intricate than CI's, shaping lifespan through two "windows of opportunity". The first window, shared by CI and CIV, occurs during development. Small perturbations in CIV during development lead to the emergence of short-lived flies. These flies exhibit an adult phenotype reminiscent of mitochondrial associated diseases, primarily characterised by their inability to store fat efficiently. Accordingly, partial complementation of CIV function using an alternative oxidase (AOX) restores molecular and physiological phenotypes. The second window emerges during fly senescence, where CIV deficiency curtails lifespan without hastening ageing, i.e. flies die earlier but not more rapidly. Notably, only the developmental phenotype is associated with TOR dysregulation and altered autophagy, emphasising that developmental dysfunction uniquely interferes with nutrient sensing and the main cellular recycling pathway. This study sheds light on the multifaceted role of mitochondrial complex IV in modulating lifespan, providing potential targets for interventions to foster healthy ageing.

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Section: Discussionsupporting

confidence: 92%

The Role of Respiratory Complex IV in Lifespan Length and Quality

Castejon-Vega,

Fernandez-Guerrero,

Myers

et al. 2023

Preprint

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“…Supporting the validity of our results, expression of COX6A1 and COX4I1, subunits of complex IV, was down-regulated. In the liver, mitochondrial complex IV down-regulation has both biochemical and functional consequences because it is required for cellular redox status maintenance [77], which correlates with our data by which Complex II is also downregulated. Complex II is the only one that participates in both the TCA cycle and the electron transport chain [78].…”

Section: Discussionsupporting

confidence: 90%

Natural Antioxidant By-Product Mixture Counteracts the Effects of Aflatoxin B1 and Ochratoxin A Exposure of Piglets after Weaning: A Proteomic Survey on Liver Microsomal Fraction

Popescu

Marinescu²,

Radulescu

et al. 2023

Toxins

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Mycotoxins are toxic compounds produced by certain strains of fungi that can contaminate raw feed materials. Once ingested, even in small doses, they cause multiple health issues for animals and, downstream, for people consuming meat. It was proposed that inclusion of antioxidant-rich plant-derived feed might diminish the harmful effects of mycotoxins, maintaining the farm animals’ health and meat quality for human consumption. This work investigates the large scale proteomic effects on piglets’ liver of aflatoxin B1 and ochratoxin A mycotoxins and the potential compensatory effects of grapeseed and sea buckthorn meal administration as dietary byproduct antioxidants against mycotoxins’ damage. Forty cross-bred TOPIGS-40 hybrid piglets after weaning were assigned to three (n = 10) experimental groups (A, M, AM) and one control group (C) and fed with experimental diets for 30 days. After 4 weeks, liver samples were collected, and the microsomal fraction was isolated. Unbiased label-free, library-free, data-independent acquisition (DIA) mass spectrometry SWATH methods were able to relatively quantify 1878 proteins from piglets’ liver microsomes, confirming previously reported effects on metabolism of xenobiotics by cytochrome P450, TCA cycle, glutathione synthesis and use, and oxidative phosphorylation. Pathways enrichment revealed that fatty acid metabolism, steroid biosynthesis, regulation of actin cytoskeleton, regulation of gene expression by spliceosomes, membrane trafficking, peroxisome, thermogenesis, retinol, pyruvate, and amino acids metabolism pathways are also affected by the mycotoxins. Antioxidants restored expression level of proteins PRDX3, AGL, PYGL, fatty acids biosynthesis, endoplasmic reticulum, peroxisome, amino acid synthesis pathways, and, partially, OXPHOS mitochondrial subunits. However, excess of antioxidants might cause significant changes in CYP2C301, PPP4R4, COL18A1, UBASH3A, and other proteins expression levels. Future analysis of proteomics data corelated to animals growing performance and meat quality studies are necessary.

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“…4 A) was also associated with impaired maximal complex IV oxidative capacity (Fig. 4 F), which has been shown to be the regulatory center for liver OXPHOS capacity and which is essential for liver function ( 26 , 27 ). However, reduced Mtr expression also led to decreased mtDNA content in the liver (Fig.…”

Section: Discussionmentioning

confidence: 95%

Reduced methionine synthase expression results in uracil accumulation in mitochondrial DNA and impaired oxidative capacity

et al. 2023

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Adequate thymidylate (dTMP or the “T” base in DNA) levels are essential for stability of mitochondrial DNA (mtDNA) and nuclear DNA (nDNA). Folate and vitamin B12 (B12) are essential cofactors in folate-mediated one carbon metabolism (FOCM), a metabolic network which supports synthesis of nucleotides (including dTMP) and methionine. Perturbations in FOCM impair dTMP synthesis, causing misincorporation of uracil (or a “U” base) into DNA. During B12 deficiency, cellular folate accumulates as 5-methyltetrahdryfolate (5-methyl-THF), limiting nucleotide synthesis. The purpose of this study was to determine how reduced levels of the B12-dpendent enzyme methionine synthase (MTR) and dietary folate interact to affect mtDNA integrity and mitochondrial function in mouse liver. Folate accumulation, uracil levels, mtDNA content, and oxidative phosphorylation capacity were measured in male Mtr+/+ and Mtr+/- mice weaned onto either a folate-sufficient control diet (2 mg/kg folic acid, C) or a folate-deficient diet (FD, lacking folic acid) for 7 weeks. Mtr heterozygosity led to increased liver 5-methyl-THF levels. Mtr+/- mice consuming the C diet also exhibited a 40-fold increase in uracil in liver mtDNA. Mtr+/- mice consuming the FD diet exhibited less uracil accumulation in liver mtDNA as compared to Mtr+/+ mice consuming the FD diet. Furthermore, Mtr+/- mice exhibited 25% lower liver mtDNA content and a 20% lower maximal oxygen consumption rates. Impairments in mitochondrial FOCM are known to lead to increased uracil in mtDNA. This study demonstrates that impaired cytosolic dTMP synthesis, induced by decreased Mtr expression, also leads to increased uracil in mtDNA.

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Differential requirements for mitochondrial electron transport chain components in the adult murine liver

Cited by 18 publications

References 69 publications

The Role of Respiratory Complex IV in Lifespan Length and Quality

The Role of Respiratory Complex IV in Lifespan Length and Quality

Natural Antioxidant By-Product Mixture Counteracts the Effects of Aflatoxin B1 and Ochratoxin A Exposure of Piglets after Weaning: A Proteomic Survey on Liver Microsomal Fraction

Reduced methionine synthase expression results in uracil accumulation in mitochondrial DNA and impaired oxidative capacity

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