Plasma level of ATPase inhibitory factor 1 (IF1) is associated with type 2 diabetes risk in humans: A prospective cohort study

Silva, Julie Pires Da; Wargny, Matthieu; Raffin, Jérémy; Croyal, Mikaël; Duparc, Thibaut; Combes, Guillaume; Genoux, Annelise; Perret, Bertrand; Vellas, Bruno; Guyonnet, Sophie; Thalamas, Claire; Langin, Dominique; Moro, Cédric; Viguerie, Nathalie; Rolland, Yves; Barreto, Philipe de Souto; Cariou, Bertrand; Martinez, Laurent O.

doi:10.1016/j.diabet.2022.101391

Cited by 8 publications

(4 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Recent findings emphasize the potential implication of IF1 in human pathophysiology, such as in cancer [ 7 , 21 ], diabetes [ 22 – 24 ], ischemia [ 25 ], cardiovascular [ 20 , 26 ] and neurodegenerative [ 18 , 27 ] diseases. In this regard, IF1 plays an anti-apoptotic role in protecting cells from death by different mechanisms [ 7 , 15 , 28 – 30 ].…”

Section: Introductionmentioning

confidence: 99%

IF1 ablation prevents ATP synthase oligomerization, enhances mitochondrial ATP turnover and promotes an adenosine-mediated pro-inflammatory phenotype

Domínguez-Zorita,

Romero-Carramiñana,

Santacatterina

et al. 2023

Cell Death Dis

View full text Add to dashboard Cite

ATPase Inhibitory Factor 1 (IF1) regulates the activity of mitochondrial ATP synthase. The expression of IF1 in differentiated human and mouse cells is highly variable. In intestinal cells, the overexpression of IF1 protects against colon inflammation. Herein, we have developed a conditional IF1-knockout mouse model in intestinal epithelium to investigate the role of IF1 in mitochondrial function and tissue homeostasis. The results show that IF1-ablated mice have increased ATP synthase/hydrolase activities, leading to profound mitochondrial dysfunction and a pro-inflammatory phenotype that impairs the permeability of the intestinal barrier compromising mouse survival upon inflammation. Deletion of IF1 prevents the formation of oligomeric assemblies of ATP synthase and alters cristae structure and the electron transport chain. Moreover, lack of IF1 promotes an intramitochondrial Ca2+ overload in vivo, minimizing the threshold to Ca2+-induced permeability transition (mPT). Removal of IF1 in cell lines also prevents the formation of oligomeric assemblies of ATP synthase, minimizing the threshold to Ca2+-induced mPT. Metabolomic analyses of mice serum and colon tissue highlight that IF1 ablation promotes the activation of de novo purine and salvage pathways. Mechanistically, lack of IF1 in cell lines increases ATP synthase/hydrolase activities and installs futile ATP hydrolysis in mitochondria, resulting in the activation of purine metabolism and in the accumulation of adenosine, both in culture medium and in mice serum. Adenosine, through ADORA2B receptors, promotes an autoimmune phenotype in mice, stressing the role of the IF1/ATP synthase axis in tissue immune responses. Overall, the results highlight that IF1 is required for ATP synthase oligomerization and that it acts as a brake to prevent ATP hydrolysis under in vivo phosphorylating conditions in intestinal cells.

show abstract

Section: Introductionmentioning

confidence: 99%

IF1 ablation prevents ATP synthase oligomerization, enhances mitochondrial ATP turnover and promotes an adenosine-mediated pro-inflammatory phenotype

Domínguez-Zorita,

Romero-Carramiñana,

Santacatterina

et al. 2023

Cell Death Dis

View full text Add to dashboard Cite

show abstract

“…Additionally, mitochondrial dysfunction is imminent because many proteins along the respiratory chain contain iron–sulfur clusters. The latest research shows that mitochondrial dysfunction is intimately associated with AD pathophysiology [ 121 ] and the development of type 2 diabetes [ 122 ].…”

Section: Cellular Mechanisms To Cope With the Energy Crisismentioning

confidence: 99%

Why Is Iron Deficiency/Anemia Linked to Alzheimer’s Disease and Its Comorbidities, and How Is It Prevented?

Fehsel

2023

Biomedicines

View full text Add to dashboard Cite

Impaired iron metabolism has been increasingly observed in many diseases, but a deeper, mechanistic understanding of the cellular impact of altered iron metabolism is still lacking. In addition, deficits in neuronal energy metabolism due to reduced glucose import were described for Alzheimer’s disease (AD) and its comorbidities like obesity, depression, cardiovascular disease, and type 2 diabetes mellitus. The aim of this review is to present the molecular link between both observations. Insufficient cellular glucose uptake triggers increased ferritin expression, leading to depletion of the cellular free iron pool and stabilization of the hypoxia-induced factor (HIF) 1α. This transcription factor induces the expression of the glucose transporters (Glut) 1 and 3 and shifts the cellular metabolism towards glycolysis. If this first line of defense is not adequate for sufficient glucose supply, further reduction of the intracellular iron pool affects the enzymes of the mitochondrial electron transport chain and activates the AMP-activated kinase (AMPK). This enzyme triggers the translocation of Glut4 to the plasma membrane as well as the autophagic recycling of cell components in order to mobilize energy resources. Moreover, AMPK activates the autophagic process of ferritinophagy, which provides free iron urgently needed as a cofactor for the synthesis of heme- and iron–sulfur proteins. Excessive activation of this pathway ends in ferroptosis, a special iron-dependent form of cell death, while hampered AMPK activation steadily reduces the iron pools, leading to hypoferremia with iron sequestration in the spleen and liver. Long-lasting iron depletion affects erythropoiesis and results in anemia of chronic disease, a common condition in patients with AD and its comorbidities. Instead of iron supplementation, drugs, diet, or phytochemicals that improve energy supply and cellular glucose uptake should be administered to counteract hypoferremia and anemia of chronic disease.

show abstract

“…41,42 Recent studies have revealed that ecto-F 1 -ATPase serves as a high-affinity cell surface receptor for apoA-I in hepatocytes and endothelial cells and that it mediates key metabolic and vascular atheroprotective functions of HDL. 41,43 The clinical relevance of ecto-F 1 -ATPase in humans has been revealed by the finding that levels of circulating IF1 (ATPase inhibitory factor 1)—an endogenous inhibitor of the mitochondrial ATP synthase—are associated with the risk for cardiovascular disease and T2D. 41–43 In cultured hepatocytes and endothelial cells, the introduction of an active form of recombinant IF1 induced a decrease in the production of extracellular ADP, leading to the attenuation of HDL effects.…”

mentioning

confidence: 99%

“…41,43 The clinical relevance of ecto-F 1 -ATPase in humans has been revealed by the finding that levels of circulating IF1 (ATPase inhibitory factor 1)—an endogenous inhibitor of the mitochondrial ATP synthase—are associated with the risk for cardiovascular disease and T2D. 41–43 In cultured hepatocytes and endothelial cells, the introduction of an active form of recombinant IF1 induced a decrease in the production of extracellular ADP, leading to the attenuation of HDL effects. 44–49 With IF1 treatment in Ins-1E cells and isolated mouse islets, Manandhar et al observed an attenuation of apoA-I internalization and increased oxidative stress.…”

mentioning

confidence: 99%

New Player in an Old Field? Ecto-F ₁ -ATPase in Antidiabetic Actions of HDL in Pancreatic β-Cells

Mineo,

Shaul

2024

ATVB

View full text Add to dashboard Cite

Plasma level of ATPase inhibitory factor 1 (IF1) is associated with type 2 diabetes risk in humans: A prospective cohort study

Cited by 8 publications

References 45 publications

IF1 ablation prevents ATP synthase oligomerization, enhances mitochondrial ATP turnover and promotes an adenosine-mediated pro-inflammatory phenotype

IF1 ablation prevents ATP synthase oligomerization, enhances mitochondrial ATP turnover and promotes an adenosine-mediated pro-inflammatory phenotype

Why Is Iron Deficiency/Anemia Linked to Alzheimer’s Disease and Its Comorbidities, and How Is It Prevented?

New Player in an Old Field? Ecto-F ₁ -ATPase in Antidiabetic Actions of HDL in Pancreatic β-Cells

Contact Info

Product

Resources

About

Plasma level of ATPase inhibitory factor 1 (IF1) is associated with type 2 diabetes risk in humans: A prospective cohort study

Cited by 8 publications

References 45 publications

IF1 ablation prevents ATP synthase oligomerization, enhances mitochondrial ATP turnover and promotes an adenosine-mediated pro-inflammatory phenotype

IF1 ablation prevents ATP synthase oligomerization, enhances mitochondrial ATP turnover and promotes an adenosine-mediated pro-inflammatory phenotype

Why Is Iron Deficiency/Anemia Linked to Alzheimer’s Disease and Its Comorbidities, and How Is It Prevented?

New Player in an Old Field? Ecto-F 1 -ATPase in Antidiabetic Actions of HDL in Pancreatic β-Cells

Contact Info

Product

Resources

About

New Player in an Old Field? Ecto-F ₁ -ATPase in Antidiabetic Actions of HDL in Pancreatic β-Cells