scholarly journals The Role of Adenine Nucleotide Translocase in the Assembly of Respiratory Supercomplexes in Cardiac Cells

Cells ◽  
2019 ◽  
Vol 8 (10) ◽  
pp. 1247 ◽  
Author(s):  
Rebecca M. Parodi-Rullán ◽  
Xavier Chapa-Dubocq ◽  
Roberto Guzmán-Hernández ◽  
Sehwan Jang ◽  
Carlos A. Torres-Ramos ◽  
...  
Keyword(s):  
Structural Integrity ◽  
Adenine Nucleotide ◽  
Physiological Role ◽  
Cardiac Cells ◽  
Adenine Nucleotide Translocase ◽  
Inner Mitochondrial Membrane ◽  
Chain Complexes ◽  
Transport Chain ◽  
H9c2 Cardiomyoblasts

Individual electron transport chain complexes have been shown to assemble into the supramolecular structures known as the respiratory chain supercomplexes (RCS). Several studies reported an associative link between RCS disintegration and human diseases, although the physiological role, structural integrity, and mechanisms of RCS formation remain unknown. Our previous studies suggested that the adenine nucleotide translocase (ANT), the most abundant protein of the inner mitochondrial membrane, can be involved in RCS assembly. In this study, we sought to elucidate whether ANT knockdown (KD) affects RCS formation in H9c2 cardiomyoblasts. Results showed that genetic silencing of ANT1, the main ANT isoform in cardiac cells, stimulated proliferation of H9c2 cardiomyoblasts with no effect on cell viability. ANT1 KD reduced the ΔΨm but increased total cellular ATP levels and stimulated the production of total, but not mitochondrial, reactive oxygen species. Importantly, downregulation of ANT1 had no significant effects on the enzymatic activity of individual ETC complexes I–IV; however, RCS disintegration was stimulated in ANT1 KD cells as evidenced by reduced levels of respirasome, the main RCS. The effects of ANT1 KD to induce RCS disassembly was not associated with acetylation of the exchanger. In conclusion, our study demonstrates that ANT is involved in RCS assembly.

scholarly journals The Role of Adenine Nucleotide Translocase in the Mitochondrial Permeability Transition

Cells ◽  
2020 ◽  
Vol 9 (12) ◽  
pp. 2686
Author(s):  
Nickolay Brustovetsky
Keyword(s):  
Atp Synthase ◽  
Mitochondrial Membrane ◽  
Mitochondrial Permeability Transition ◽  
Adenine Nucleotide ◽  
Permeability Transition ◽  
Adenine Nucleotide Translocase ◽  
Inner Mitochondrial Membrane ◽  
Mitochondrial Permeability ◽  
F0f1 Atp Synthase

The mitochondrial permeability transition, a Ca2+-induced significant increase in permeability of the inner mitochondrial membrane, plays an important role in various pathologies. The mitochondrial permeability transition is caused by induction of the permeability transition pore (PTP). Despite significant effort, the molecular composition of the PTP is not completely clear and remains an area of hot debate. The Ca2+-modified adenine nucleotide translocase (ANT) and F0F1 ATP synthase are the major contenders for the role of pore in the PTP. This paper briefly overviews experimental results focusing on the role of ANT in the mitochondrial permeability transition and proposes that multiple molecular entities might be responsible for the conductance pathway of the PTP. Consequently, the term PTP cannot be applied to a single specific protein such as ANT or a protein complex such as F0F1 ATP synthase, but rather should comprise a variety of potential contributors to increased permeability of the inner mitochondrial membrane.

Cardiac expression of adenine nucleotide translocase-1 in transgenic mice overexpressing bovine GH

2007 ◽  
Vol 194 (3) ◽  
pp. 521-527 ◽  
Author(s):  
Fausto Bogazzi ◽  
Francesco Raggi ◽  
Federica Ultimieri ◽  
Dania Russo ◽  
Antonella Manariti ◽  
...  
Keyword(s):  
Lactic Acid ◽  
Transgenic Mice ◽  
Adenine Nucleotide ◽  
Adenine Nucleotide Translocase ◽  
Common Finding ◽  
Atp Production ◽  
Tissue Levels ◽  
Atp Generation ◽  
Gh Excess

Heart hypertrophy is a common finding of acromegaly, a syndrome due to GH excess. Impairment of adenine nucleotide translocase-1 (ANT-1) gene, the main mitochondrial ADP/ATP exchanger, leads to cardiac hypertrophy. The aim of the study was to evaluate cardiac expression and the functional role of ANT-1 in 1- to 12-month-old transgenic mice overexpressing bovine GH (acromegalic mice, Acro) and littermate controls (wild-type mice, Wt). GH specificity of protein degree variation was assessed treating Acro with pegvisomant, a GH receptor competitor. Tissue levels of ANT-1, NF-κB, ATP, and lactic acid were evaluated by western blot, bioluminescence, and Fourier transform infrared spectroscopy respectively. The degree of ANT-1 expression was higher in 1-month-old Acro than in Wt (47±5% OD vs 33±4% OD, P<0 01). On the contrary, ANT-1 expression was lower in 3- to 12-month-old Acro than in Wt (P<0 03). Changes in ANT-1 expression were associated with consistent changes of cellular ATP content, increasing at 1 month (P<0 05) and reducing thereafter in Acro when compared with Wt (P<0 04). Treatment with pegvisomant abolished ANT-1 and ATP changes observed in 1- and 3-month-old Acro, thus supporting a GH-dependent mechanism. Reduced ATP generation in hypertrophied hearts of older Acro was associated with increased lactic acid levels suggesting that part of energy was due to glycolysis. Variations in ANT-1 expression were linked to GH through changes in NF-κB, the levels of which changed accordingly. In conclusion, 1-month-old acromegalic mice had increased ANT-1 expression and higher degree of ATP production. Long-standing disease was associated with a consistent reduction of ANT-1 and ATP tissue levels, which became GH-independent in older animals. This study demonstrated a direct effect of GH on key proteins involved in energy metabolism of acromegalic hearts.

scholarly journals Functional role of respiratory supercomplexes in mice: segmentation of the Qpool and SCAF1

2019 ◽  
Author(s):  
Enrique Calvo ◽  
Sara Cogliati ◽  
Pablo Hernansanz-Agustín ◽  
Marta Loureiro-López ◽  
Adela Guarás ◽  
...  
Keyword(s):  
Quantitative Data ◽  
Functional Role ◽  
Physiological Role ◽  
Oxidative Capacity ◽  
Wild Type ◽  
Knock Out ◽  
Transport Chain ◽  
Native Gel ◽  
Blue Native

SummaryMitochondrial respiratory complexes assemble into different forms of supercomplexes (SC). In particular, SC III2+IV require the SCAF1 protein. However, the structural role of this factor in the formation of the respirasome (I+III2+IV) and the physiological role of SCs are controversial. Here, we study C57BL/6J mice harbouring either non-functional SCAF1, the full knock-out for SCAF1 or the wild-type version of the protein and found a growth and exercise phenotype due to the lack of functional SCAF1. By combining quantitative data-independent proteomics, high resolution 2D Blue Native Gel Electrophoresis and functional analysis of enriched respirasome fractions, we show that SCAF1 confers structural attachment between III2 and IV within the respirasome, increases NADH-dependent respiration and reduces ROS production. Furthermore, through the expression of AOX in cells and mice we confirm that CI-CIII superassembly segments the CoQ in two pools and modulates CI-NADH oxidative capacity. These data demonstrate that SC assembly, regulated by SCAF1, modulates the functionality of the electron transport chain.

scholarly journals Role of Calcium and Mitochondria in MeHg-Mediated Cytotoxicity

2012 ◽  
Vol 2012 ◽  
pp. 1-15 ◽  
Author(s):  
Daniel Roos ◽  
Rodrigo Seeger ◽  
Robson Puntel ◽  
Nilda Vargas Barbosa
Keyword(s):  
Mitochondrial Permeability Transition ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Mitochondrial Dysfunctions ◽  
Mptp Opening ◽  
Molecular Events ◽  
Chain Complexes ◽  
Transport Chain ◽  
Intracellular Ca

Methylmercury (MeHg) mediated cytotoxicity is associated with loss of intracellular calcium (Ca2+) homeostasis. The imbalance in Ca2+physiology is believed to be associated with dysregulation of Ca2+intracellular stores and/or increased permeability of the biomembranes to this ion. In this paper we summarize the contribution of glutamate dyshomeostasis in intracellular Ca2+overload and highlight the mitochondrial dysfunctions induced by MeHg via Ca2+overload. Mitochondrial disturbances elicited by Ca2+may involve several molecular events (i.e., alterations in the activity of the mitochondrial electron transport chain complexes, mitochondrial proton gradient dissipation, mitochondrial permeability transition pore (MPTP) opening, thiol depletion, failure of energy metabolism, reactive oxygen species overproduction) that could culminate in cell death. Here we will focus on the role of oxidative stress in these phenomena. Additionally, possible antioxidant therapies that could be effective in the treatment of MeHg intoxication are briefly discussed.

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