The F1Fo-ATPase inhibitor protein IF1 in pathophysiology

Gatto, Cristina; Grandi, Martina; Solaini, Giancarlo; Baracca, Alessandra; Giorgio, Valentina

doi:10.3389/fphys.2022.917203

Cited by 11 publications

(11 citation statements)

References 110 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…IF1 is overexpressed in many human tumors [ 13 , 15 , 29 , 55 ] and different hypotheses on its pro-oncogenic role have been proposed [ 13 , 16 , 29 ], although its mechanism of action is still debated. MEFs overexpressing IF1, IF1 KD, and IF1 KO HeLa cells showed that colony formation in soft agar depends on IF1 expression level.…”

Section: Discussionmentioning

confidence: 99%

“…IF1 may also play a role in promoting cancer development and growth [13,14]. Its high expression level has been found in different human tumors [15], although the mechanism through which IF1 promotes cancer growth and progression remains debated [16]. Recent findings suggest that IF1 might bind to ATP synthase when the enzyme works physiologically [i.e., ATP synthesis [17][18][19][20]] and that its role in preventing ATP hydrolysis is observed only under anoxia/near-anoxia [21].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

The mitochondrial inhibitor IF1 binds to the ATP synthase OSCP subunit and protects cancer cells from apoptosis

et al. 2023

Self Cite

View full text Add to dashboard Cite

The mitochondrial protein IF1 binds to the catalytic domain of the ATP synthase and inhibits ATP hydrolysis in ischemic tissues. Moreover, IF1 is overexpressed in many tumors and has been shown to act as a pro-oncogenic protein, although its mechanism of action is still debated. Here, we show that ATP5IF1 gene disruption in HeLa cells decreases colony formation in soft agar and tumor mass development in xenografts, underlining the role of IF1 in cancer. Notably, the lack of IF1 does not affect proliferation or oligomycin-sensitive mitochondrial respiration, but it sensitizes the cells to the opening of the permeability transition pore (PTP). Immunoprecipitation and proximity ligation analysis show that IF1 binds to the ATP synthase OSCP subunit in HeLa cells under oxidative phosphorylation conditions. The IF1–OSCP interaction is confirmed by NMR spectroscopy analysis of the recombinant soluble proteins. Overall, our results suggest that the IF1-OSCP interaction protects cancer cells from PTP-dependent apoptosis under normoxic conditions.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The mitochondrial inhibitor IF1 binds to the ATP synthase OSCP subunit and protects cancer cells from apoptosis

et al. 2023

Self Cite

View full text Add to dashboard Cite

show abstract

“…According to the literature, ATP synthase activity has been associated with proliferation, invasive capacity, and apoptosis resistance in cancer cells [ 33 , 38 , 40 ]. Indeed, most cancer cells rely on aerobic glycolysis and many of them overexpress the ATPase inhibitor factor 1 (IF1), which affects cancer development through different effects such as cristae shaping or inhibition of ATP hydrolysis, among others [ 56 ]. In addition, several mt-ATP6 mutations have been detected in different human cancer cell lines and solid tumors [ 57 , 58 , 59 , 60 ], next to the 8414 position and affecting aH5 helix ( Figure 6 A).…”

Section: Resultsmentioning

confidence: 99%

“…In addition, it has been reported that several tumor types such as colon, lung, breast, and ovarian carcinomas upregulate the expression of ATPase inhibitory factor 1 (IF1) [ 38 ] which favors cell proliferation by blocking ATP hydrolysis and, consequently, preserving the amount of ATP [ 38 , 39 ]. More recently, different effects of IF1 on cancer development have been proposed [ 56 ]. In this sense, IF1 has been reported to have effects on metastasis promotion and cristae shaping [ 68 , 69 ], as well as on inhibition of ATP hydrolysis and escape from apoptosis.…”

Section: Discussionmentioning

confidence: 99%

A Mutation in Mouse MT-ATP6 Gene Induces Respiration Defects and Opposed Effects on the Cell Tumorigenic Phenotype

Moreno‐Loshuertos

Movilla

Marco-Brualla

et al. 2023

IJMS

View full text Add to dashboard Cite

As the last step of the OXPHOS system, mitochondrial ATP synthase (or complex V) is responsible for ATP production by using the generated proton gradient, but also has an impact on other important functions linked to this system. Mutations either in complex V structural subunits, especially in mtDNA-encoded ATP6 gene, or in its assembly factors, are the molecular cause of a wide variety of human diseases, most of them classified as neurodegenerative disorders. The role of ATP synthase alterations in cancer development or metastasis has also been postulated. In this work, we reported the generation and characterization of the first mt-Atp6 pathological mutation in mouse cells, an m.8414A>G transition that promotes an amino acid change from Asn to Ser at a highly conserved residue of the protein (p.N163S), located near the path followed by protons from the intermembrane space to the mitochondrial matrix. The phenotypic consequences of the p.N163S change reproduce the effects of MT-ATP6 mutations in human diseases, such as dependence on glycolysis, defective OXPHOS activity, ATP synthesis impairment, increased ROS generation or mitochondrial membrane potential alteration. These observations demonstrate that this mutant cell line could be of great interest for the generation of mouse models with the aim of studying human diseases caused by alterations in ATP synthase. On the other hand, mutant cells showed lower migration capacity, higher expression of MHC-I and slightly lower levels of HIF-1α, indicating a possible reduction of their tumorigenic potential. These results could suggest a protective role of ATP synthase inhibition against tumor transformation that could open the door to new therapeutic strategies in those cancer types relying on OXPHOS metabolism.

show abstract

“…The online resource inside this figure was quoted or modified from Servier Medical Art the rapid development and application of proteomic techniques, multiple omics have uncovered the distinctive mechanism inside complex III during cardiac aging. Likewise, the activity of ATP synthase [also known as complex V] is negatively correlated with aging, 217,218 resulting in a substantial decrement in the efficiency of OXPHOS. Moreover, complex V serves as a potential locus of the mitochondrial permeability transition pore (mPTP), 219 while defective complex V restrains the formation of mPTP and limits the coupling of OXPHOS to the ETC.…”

Section: Electron Transportmentioning

confidence: 99%

Metabolic landscape in cardiac aging: insights into molecular biology and therapeutic implications

Xie

Deng

et al. 2023

Sig Transduct Target Ther

View full text Add to dashboard Cite

Cardiac aging is evident by a reduction in function which subsequently contributes to heart failure. The metabolic microenvironment has been identified as a hallmark of malignancy, but recent studies have shed light on its role in cardiovascular diseases (CVDs). Various metabolic pathways in cardiomyocytes and noncardiomyocytes determine cellular senescence in the aging heart. Metabolic alteration is a common process throughout cardiac degeneration. Importantly, the involvement of cellular senescence in cardiac injuries, including heart failure and myocardial ischemia and infarction, has been reported. However, metabolic complexity among human aging hearts hinders the development of strategies that targets metabolic susceptibility. Advances over the past decade have linked cellular senescence and function with their metabolic reprogramming pathway in cardiac aging, including autophagy, oxidative stress, epigenetic modifications, chronic inflammation, and myocyte systolic phenotype regulation. In addition, metabolic status is involved in crucial aspects of myocardial biology, from fibrosis to hypertrophy and chronic inflammation. However, further elucidation of the metabolism involvement in cardiac degeneration is still needed. Thus, deciphering the mechanisms underlying how metabolic reprogramming impacts cardiac aging is thought to contribute to the novel interventions to protect or even restore cardiac function in aging hearts. Here, we summarize emerging concepts about metabolic landscapes of cardiac aging, with specific focuses on why metabolic profile alters during cardiac degeneration and how we could utilize the current knowledge to improve the management of cardiac aging.

show abstract

The F1Fo-ATPase inhibitor protein IF1 in pathophysiology

Cited by 11 publications

References 110 publications

The mitochondrial inhibitor IF1 binds to the ATP synthase OSCP subunit and protects cancer cells from apoptosis

The mitochondrial inhibitor IF1 binds to the ATP synthase OSCP subunit and protects cancer cells from apoptosis

A Mutation in Mouse MT-ATP6 Gene Induces Respiration Defects and Opposed Effects on the Cell Tumorigenic Phenotype

Metabolic landscape in cardiac aging: insights into molecular biology and therapeutic implications

Contact Info

Product

Resources

About