Publications by authors named "Francisco Mendoza Hoffmann"

6 Publications

  • Page 1 of 1

Lipid metabolism and oxidative stress in HPV-related cancers.

Free Radic Biol Med 2021 Jun 12;172:226-236. Epub 2021 Jun 12.

IHuman Institute, ShanghaiTech University, China; Laboratorio F-206, Departamento de Biología, Facultad de Química, Universidad Nacional Autónoma de México, 04510, Ciudad de México, Mexico. Electronic address:

High-risk human papillomavirus (HR-HPVs) are associated with the development of cervical, anus, vagina, vulva, penis, and oropharynx cancer. HR-HPVs target and modify the function of different cell biomolecules such as glucose, amino acids, lipids, among others. The latter induce cell proliferation, cell death evasion, and genomic instability resulting in cell transformation. Moreover, lipids are essential biomolecules in HR-HPVs infection and cell vesicular trafficking. They are also critical in producing cellular energy, the epithelial-mesenchymal transition (EMT) process, and therapy resistance of HPV-related cancers. HPV proteins induce oxidative stress (OS), which in turn promotes lipid peroxidation and cell damage, resulting in cell death such as apoptosis, autophagy, and ferroptosis. HR-HPV-related cancer cells cope with OS and lipid peroxidation, preventing cell death; however, these cells are sensitized by OS, which could be used as a target for redox therapies to induce their elimination. This review focuses on the role of lipids in HR-HPV infection and HPV-related cancer development, maintenance, resistance to therapy, and the possible treatments associated with lipids. Furthermore, we emphasize the significant role of OS in lipid peroxidation to induce cell death through apoptosis, autophagy, and ferroptosis to eliminate HPV-related cancers.
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http://dx.doi.org/10.1016/j.freeradbiomed.2021.06.009DOI Listing
June 2021

The 3 × 120° rotary mechanism of F-ATPase is different from that of the bacterial and mitochondrial F-ATPases.

Proc Natl Acad Sci U S A 2020 11 9;117(47):29647-29657. Epub 2020 Nov 9.

Department of Applied Chemistry, Graduate School of Engineering, The University of Tokyo, 113-8656 Tokyo, Japan;

The rotation of F-ATPase (PdF) was studied using single-molecule microscopy. At all concentrations of adenosine triphosphate (ATP) or a slowly hydrolyzable ATP analog (ATPγS), above or below , PdF showed three dwells per turn, each separated by 120°. Analysis of dwell time between steps showed that PdF executes binding, hydrolysis, and probably product release at the same dwell. The comparison of ATP binding and catalytic pauses in single PdF molecules suggested that PdF executes both elementary events at the same rotary position. This point was confirmed in an inhibition experiment with a nonhydrolyzable ATP analog (AMP-PNP). Rotation assays in the presence of adenosine diphosphate (ADP) or inorganic phosphate at physiological concentrations did not reveal any obvious substeps. Although the possibility of the existence of substeps remains, all of the datasets show that PdF is principally a three-stepping motor similar to bacterial vacuolar (V)-ATPase from This contrasts with all other known F-ATPases that show six or nine dwells per turn, conducting ATP binding and hydrolysis at different dwells. Pauses by persistent Mg-ADP inhibition or the inhibitory ζ-subunit were also found at the same angular position of the rotation dwell, supporting the simplified chemomechanical scheme of PdF Comprehensive analysis of rotary catalysis of F from different species, including PdF, suggests a clear trend in the correlation between the numbers of rotary steps of F and F domains of F-ATP synthase. F motors with more distinctive steps are coupled with proton-conducting F rings with fewer proteolipid subunits, giving insight into the design principle the FF of ATP synthase.
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http://dx.doi.org/10.1073/pnas.2003163117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7703542PMC
November 2020

Control of rotation of the FF-ATP synthase nanomotor by an inhibitory α-helix from unfolded ε or intrinsically disordered ζ and IF proteins.

J Bioenerg Biomembr 2018 10 28;50(5):403-424. Epub 2018 Sep 28.

Departamento de Biología, Facultad de Química, Ciudad Universitaria, Universidad Nacional Autónoma de México (U.N.A.M.), Circuito Escolar s/n. Laboratorio 203, Edificio "F"., Delegación Coyoacán, 04510, Mexico City, CP, Mexico.

The ATP synthase is a ubiquitous nanomotor that fuels life by the synthesis of the chemical energy of ATP. In order to synthesize ATP, this enzyme is capable of rotating its central rotor in a reversible manner. In the clockwise (CW) direction, it functions as ATP synthase, while in counter clockwise (CCW) sense it functions as an proton pumping ATPase. In bacteria and mitochondria, there are two known canonical natural inhibitor proteins, namely the ε and IF subunits. These proteins regulate the CCW FF-ATPase activity by blocking γ subunit rotation at the α/β/γ subunit interface in the F domain. Recently, we discovered a unique natural F-ATPase inhibitor in Paracoccus denitrificans and related α-proteobacteria denoted the ζ subunit. Here, we compare the functional and structural mechanisms of ε, IF, and ζ, and using the current data in the field, it is evident that all three regulatory proteins interact with the α/β/γ interface of the F-ATPase. In order to exert inhibition, IF and ζ contain an intrinsically disordered N-terminal protein region (IDPr) that folds into an α-helix when inserted in the α/β/γ interface. In this context, we revised here the mechanism and role of the ζ subunit as a unidirectional F-ATPase inhibitor blocking exclusively the CCW FF-ATPase rotation, without affecting the CW-FF-ATP synthase turnover. In summary, the ζ subunit has a mode of action similar to mitochondrial IF, but in α-proteobacteria. The structural and functional implications of these intrinsically disordered ζ and IF inhibitors are discussed to shed light on the control mechanisms of the ATP synthase nanomotor from an evolutionary perspective.
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http://dx.doi.org/10.1007/s10863-018-9773-9DOI Listing
October 2018

Unidirectional regulation of the FF-ATP synthase nanomotor by the ζ pawl-ratchet inhibitor protein of Paracoccus denitrificans and related α-proteobacteria.

Biochim Biophys Acta Bioenerg 2018 09 8;1859(9):762-774. Epub 2018 Jun 8.

Departamento de Biología, Facultad de Química, Ciudad Universitaria, Universidad Nacional Autónoma de México (U.N.A.M.), Delegación Coyoacán, Ciudad de México (CDMX), CP 04510, Mexico. Electronic address:

The ATP synthase is a reversible nanomotor that gyrates its central rotor clockwise (CW) to synthesize ATP and in counter clockwise (CCW) direction to hydrolyse it. In bacteria and mitochondria, two natural inhibitor proteins, namely the ε and IF subunits, prevent the wasteful CCW FF-ATPase activity by blocking γ rotation at the α/β/γ interface of the F portion. In Paracoccus denitrificans and related α-proteobacteria, we discovered a different natural F-ATPase inhibitor named ζ. Here we revise the functional and structural data showing that this novel ζ subunit, although being different to ε and IF, it also binds to the α/β/γ interface of the F of P. denitrificans. ζ shifts its N-terminal inhibitory domain from an intrinsically disordered protein region (IDPr) to an α-helix when inserted in the α/β/γ interface. We showed for the first time the key role of a natural ATP synthase inhibitor by the distinctive phenotype of a Δζ knockout mutant in P. denitrificans. ζ blocks exclusively the CCW FF-ATPase rotation without affecting the CW-FF-ATP synthase turnover, confirming that ζ is important for respiratory bacterial growth by working as a unidirectional pawl-ratchet PdFF-ATPase inhibitor, thus preventing the wasteful consumption of cellular ATP. In summary, ζ is a useful model that mimics mitochondrial IF but in α-proteobacteria. The structural, functional, and endosymbiotic evolutionary implications of this ζ inhibitor are discussed to shed light on the natural control mechanisms of the three natural inhibitor proteins (ε, ζ, and IF) of this unique ATP synthase nanomotor, essential for life.
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http://dx.doi.org/10.1016/j.bbabio.2018.06.005DOI Listing
September 2018

The Biological Role of the ζ Subunit as Unidirectional Inhibitor of the FF-ATPase of Paracoccus denitrificans.

Cell Rep 2018 01 28;22(4):1067-1078. Epub 2018 Jan 28.

Departamento de Biología, Facultad de Química, Ciudad Universitaria, Universidad Nacional Autónoma de México (U.N.A.M.), Delegación Coyoacán, Ciudad de México (CDMX) 04510, México. Electronic address:

The biological roles of the three natural FF-ATPase inhibitors, ε, ζ, and IF, on cell physiology remain controversial. The ζ subunit is a useful model for deletion studies since it mimics mitochondrial IF, but in the FF-ATPase of Paracoccus denitrificans (PdFF), it is a monogenic and supernumerary subunit. Here, we constructed a P. denitrificans 1222 derivative (PdΔζ) with a deleted ζ gene to determine its role in cell growth and bioenergetics. The results show that the lack of ζ in vivo strongly restricts respiratory P. denitrificans growth, and this is restored by complementation in trans with an exogenous ζ gene. Removal of ζ increased the coupled PdFF-ATPase activity without affecting the PdFF-ATP synthase turnover, and the latter was not affected at all by ζ reconstitution in vitro. Therefore, ζ works as a unidirectional pawl-ratchet inhibitor of the PdFF-ATPase nanomotor favoring the ATP synthase turnover to improve respiratory cell growth and bioenergetics.
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http://dx.doi.org/10.1016/j.celrep.2017.12.106DOI Listing
January 2018

The Inhibitory Mechanism of the ζ Subunit of the F1FO-ATPase Nanomotor of Paracoccus denitrificans and Related α-Proteobacteria.

J Biol Chem 2016 Jan 6;291(2):538-46. Epub 2015 Nov 6.

the Departamento de Bioquímica, Facultad de Medicina, Universidad Nacional Autónoma de México, Ciudad Universitaria, Delegación Coyoacán, D.F., CP 04510, México.

The ζ subunit is a novel inhibitor of the F1FO-ATPase of Paracoccus denitrificans and related α-proteobacteria. It is different from the bacterial (ϵ) and mitochondrial (IF1) inhibitors. The N terminus of ζ blocks rotation of the γ subunit of the F1-ATPase of P. denitrificans (Zarco-Zavala, M., Morales-Ríos, E., Mendoza-Hernández, G., Ramírez-Silva, L., Pérez-Hernández, G., and García-Trejo, J. J. (2014) FASEB J. 24, 599-608) by a hitherto unknown quaternary structure that was first modeled here by structural homology and protein docking. The F1-ATPase and F1-ζ models of P. denitrificans were supported by cross-linking, limited proteolysis, mass spectrometry, and functional data. The final models show that ζ enters into F1-ATPase at the open catalytic αE/βE interface, and two partial γ rotations lock the N terminus of ζ in an "inhibition-general core region," blocking further γ rotation, while the ζ globular domain anchors it to the closed αDP/βDP interface. Heterologous inhibition of the F1-ATPase of P. denitrificans by the mitochondrial IF1 supported both the modeled ζ binding site at the αDP/βDP/γ interface and the endosymbiotic α-proteobacterial origin of mitochondria. In summary, the ζ subunit blocks the intrinsic rotation of the nanomotor by inserting its N-terminal inhibitory domain at the same rotor/stator interface where the mitochondrial IF1 or the bacterial ϵ binds. The proposed pawl mechanism is coupled to the rotation of the central γ subunit working as a ratchet but with structural differences that make it a unique control mechanism of the nanomotor to favor the ATP synthase activity over the ATPase turnover in the α-proteobacteria.
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http://dx.doi.org/10.1074/jbc.M115.688143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4705375PMC
January 2016
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