Apoptotic priming is defined by the dynamic exchange of Bcl-2 proteins between mitochondria and cytosol

King, Louise; Rodriguez-Enriquez, Ricardo; Pedley, Robert; Mellor, Charlotte E L; Wang, Pengbo; Zindy, Egor; White, Michael R. H.; Brennan, Keith; Gilmore, Andrew

doi:10.1038/s41418-022-01013-z

Cited by 17 publications

(13 citation statements)

References 45 publications

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“…Mitochondria are key players in the intrinsic apoptosis pathway [ 43 , 44 ]. The interplay between mitophagy and apoptosis has been well studied in recent years.…”

Section: Discussionmentioning

confidence: 99%

PINK1/Parkin-mediated mitophagy inhibits osteoblast apoptosis induced by advanced oxidation protein products

Jiang

et al. 2023

Cell Death Dis

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Osteoblast apoptosis plays an important role in age-related bone loss and osteoporosis. Our previous study revealed that advanced oxidation protein products (AOPPs) could induce nicotinamide adenine dinucleotide phosphate oxidase (NOX)-derived reactive oxygen species (ROS) production, cause mitochondrial membrane potential (ΔΨm) depolarization, trigger the mitochondria-dependent intrinsic apoptosis pathway, and lead to osteoblast apoptosis and ultimately osteopenia and bone microstructural destruction. In this study, we found that AOPPs also induced mitochondrial ROS (mtROS) generation in osteoblastic MC3T3-E1 cells, which was closely related to NOX-derived ROS, and aggravated the oxidative stress condition, thereby further promoting apoptosis. Removing excessive ROS and damaged mitochondria is the key factor in reversing AOPP-induced apoptosis. Here, by in vitro studies, we showed that rapamycin further activated PINK1/Parkin-mediated mitophagy in AOPP-stimulated MC3T3-E1 cells and significantly alleviated AOPP-induced cell apoptosis by eliminating ROS and damaged mitochondria. Our in vivo studies revealed that PINK1/Parkin-mediated mitophagy could decrease the plasma AOPP concentration and inhibit AOPP-induced osteoblast apoptosis, thus ameliorating AOPP accumulation-related bone loss, bone microstructural destruction and bone mineral density (BMD) loss. Together, our study indicated that therapeutic strategies aimed at upregulating osteoblast mitophagy and preserving mitochondrial function might have potential for treating age-related osteoporosis.

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“…Mitochondria are key players in the intrinsic apoptosis pathway [ 43 , 44 ]. The interplay between mitophagy and apoptosis has been well studied in recent years.…”

Section: Discussionmentioning

confidence: 99%

PINK1/Parkin-mediated mitophagy inhibits osteoblast apoptosis induced by advanced oxidation protein products

Jiang

et al. 2023

Cell Death Dis

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“…5j, the apoptosis rate of chondrocytes was gradually decreased by the CeO 2 (22.4%), PtCuO X /CeO 2 − X (15.2%), and PtCuO X /CeO 2 − X +NIR (10.6%) groups compared with the IL-1β group (37.7%). Mechanistically, Bax, caspase-3, and Bcl-2 [37][38][39], as key apoptotic factors in their activated state, can provide insights into the intrinsic properties of PtCuO X /CeO 2 − X nanozymes in inhibiting apoptosis. Fig.…”

Section: Dft Studies On the Enzyme Activity Of Ptcuo X /Ceo 2 − X Nan...mentioning

confidence: 99%

Oxygen Vacancy-engineered CeO 2 Mediated by Cu-Pt Exhibit Enhanced SOD/CAT-mimicking Activities to Regulate the Microenvironment for Osteoarthritis Therapy

Yang,

Xiao,

Deng

et al. 2024

Preprint

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Cerium oxide (CeO2) nanospheres have limited enzymatic activity that hinders further application in catalytic therapy, but they have an "oxidation switch" to enhance their catalytic activity by increasing oxygen vacancies. In this study, according to the defect-engineering strategy, we developed PtCuOX/CeO2 − X nanozymes as highly efficient SOD/CAT mimics by introducing bimetallic Cu and Pt into CeO2 nanospheres to enhance the oxygen vacancies, in an attempt to combine near-infrared (NIR) irradiation to regulate microenvironment for osteoarthritis (OA) therapy. As expected, the Cu and Pt increased the Ce3+/Ce4+ ratio of CeO2 to significantly enhance the oxygen vacancies, and simultaneously CeO2 (111) facilitated the uniform dispersion of Cu and Pt. The strong metal-carrier interaction synergy endowed the PtCuOX/CeO2 − X nanozymes with highly efficient SOD/CAT-like activity by the decreased formation energy of oxygen vacancy, promoted electron transfer, the increased adsorption energy of intermediates, and the decreased reaction activation energy. Besides, the nanozymes have excellent photothermal conversion efficiency (55.41%). Further, the PtCuOX/CeO2 − X antioxidant system effectively scavenged intracellular ROS and RNS, protected mitochondrial function, and inhibited the inflammatory factors, thus reducing chondrocyte apoptosis. In vivo, experiments demonstrated the biosafety of PtCuOX/CeO2 − X and its potent effect on OA suppression. In particular, NIR radiation further enhanced the effects. Mechanistically, PtCuOX/CeO2 − X nanozymes reduced ras-related C3 botulinum toxin substrate 1 (Rac-1) and p-p65 protein expression, as well as ROS levels to remodel the inflammatory microenvironment by inhibiting the ROS/Rac1/nuclear factor kappa-B (NF-κB) signaling pathway. This study introduces new clinical concepts and perspectives that can be applied to inflammatory diseases.

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“…Consequently, Bcl-2 proteins are considered a particularly challenging class of undruggable targets. 490 , 491…”

Section: Targeted Proteins’ Regulationmentioning

confidence: 99%

Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials

Xie,

Yu,

et al. 2023

Sig Transduct Target Ther

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Undruggable proteins are a class of proteins that are often characterized by large, complex structures or functions that are difficult to interfere with using conventional drug design strategies. Targeting such undruggable targets has been considered also a great opportunity for treatment of human diseases and has attracted substantial efforts in the field of medicine. Therefore, in this review, we focus on the recent development of drug discovery targeting “undruggable” proteins and their application in clinic. To make this review well organized, we discuss the design strategies targeting the undruggable proteins, including covalent regulation, allosteric inhibition, protein–protein/DNA interaction inhibition, targeted proteins regulation, nucleic acid-based approach, immunotherapy and others.

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Apoptotic priming is defined by the dynamic exchange of Bcl-2 proteins between mitochondria and cytosol

Cited by 17 publications

References 45 publications

PINK1/Parkin-mediated mitophagy inhibits osteoblast apoptosis induced by advanced oxidation protein products

PINK1/Parkin-mediated mitophagy inhibits osteoblast apoptosis induced by advanced oxidation protein products

Oxygen Vacancy-engineered CeO 2 Mediated by Cu-Pt Exhibit Enhanced SOD/CAT-mimicking Activities to Regulate the Microenvironment for Osteoarthritis Therapy

Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials

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