Regulation of Mitochondrial Structure and Function by the F1Fo-ATPase Inhibitor Protein, IF1

Abstract

When mitochondrial respiration is compromised, the F(1)F(o)-ATP synthase reverses and consumes ATP, serving to maintain the mitochondrial membrane potential (Delta psi(m)). This process is mitigated by IF(1). As little is known of the cell biology of IF(1), we have investigated the functional consequences of varying IF(1) expression. We report that, (1) during inhibition of respiration, IF(1) conserves ATP at the expense of Delta psi(m); (2) overexpression of IF(1) is protective against ischemic injury; (3) relative IF(1) expression level varies between tissues and cell types and dictates the response to inhibition of mitochondrial respiration; (4) the density of mitochondrial cristae is increased by IF(1) overexpression and decreased by IF(1) suppression; and (5) IF(1) overexpression increases the formation of dimeric ATP synthase complexes and increases F(1)F(o)-ATP synthase activity. Thus, IF(1) regulates mitochondrial function and structure under both physiological and pathological conditions.

Transglutaminase 2 ablation leads to mitophagy impairment associated with a metabolic shift towards aerobic glycolysis

“…36,37 In fact, IF1 plays a key role in the preservation of mitochondrial morphology and cristae architecture, supporting its role in the modulation of cytochrome c release and activation of the apoptosis via the intrinsic pathway. 37 In addition, IF1 has been identified as an essential factor for PARK2 recruitment and consequently mitophagy activation.…”

Low-Level Laser Therapy Effectively Prevents Secondary Brain Injury Induced by Immediate Early Responsive Gene X-1 Deficiency

“…Mechanistically, we have demonstrated that IEX-1 controls oxidative phosphorylation at mitochondria by facilitation of F 1 F 0 -ATPase inhibitor (IF1) degradation. 13 Null mutation of IEX-1 stabilized IF1 giving rise to its accumulation that reduced oxidative phosphorylation while increasing aerobic glycolysis, as suggested by more active glucose uptake and lactate production in hypoxic conditions, and accelerated cell death upon glucosedeprivation in IEX-1-deficient cells compared with WT counterparts. 17 The current investigation extends this observation demonstrating that ATP synthesis is compromised in injured KO cortex ( Figure 6C).…”

Up-regulation of the ATPase Inhibitory Factor 1 (IF1) of the Mitochondrial H+-ATP Synthase in Human Tumors Mediates the Metabolic Shift of Cancer Cells to a Warburg Phenotype

“…These findings are of utmost importance for understanding the metabolism of cancer cells (9,27). The functional role of IF1 as a natural inhibitor of the activity of the ATP synthase is debated (21,23,28). In this regard, a recent study claims that the overexpression of IF1 in HeLa cells triggers the down-regulation of ⌬⌿ m (23).…”

“…Luminescence was registered using a FLUOstar OPTIMA (BMG Labtech) plate luminometer. siRNA (Qiagen S100908075) was used to suppress the expression of IF1 (23). An inefficient siRNA sequence, Silencer Select Negative Control number 1 plasmid (Ambion/ Applied Biosystems), was used as a control.…”

“…The substitution of histidine 49 in IF1 by a lysine residue renders a mutant form (H49K) that inhibits the ATP hydrolase activity in a pH-insensitive way (22). The structure and in vitro mechanism of action of IF1 has been studied in detail, and its role as an inhibitor of the hydrolase activity of the H ϩ -ATP synthase is well documented (19,20,23). However, the information on IF1 expression in human tissues and its putative contribution to the development of human pathology are unknown.…”