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

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Abstract

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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Mitochondrial reactive oxygen species (ROS) and ROS-induced ROS release.

Dmitry Zorov, Magdalena Juhaszova, Steven J. Sollott (2014)

Byproducts of normal mitochondrial metabolism and homeostasis include the buildup of potentially damaging levels of reactive oxygen species (ROS), Ca(2+), etc., which must be normalized. Evidence suggests that brief mitochondrial permeability transition pore (mPTP) openings play an important physiological role maintaining healthy mitochondria homeostasis. Adaptive and maladaptive responses to redox stress may involve mitochondrial channels such as mPTP and inner membrane anion channel (IMAC). Their activation causes intra- and intermitochondrial redox-environment changes leading to ROS release. This regenerative cycle of mitochondrial ROS formation and release was named ROS-induced ROS release (RIRR). Brief, reversible mPTP opening-associated ROS release apparently constitutes an adaptive housekeeping function by the timely release from mitochondria of accumulated potentially toxic levels of ROS (and Ca(2+)). At higher ROS levels, longer mPTP openings may release a ROS burst leading to destruction of mitochondria, and if propagated from mitochondrion to mitochondrion, of the cell itself. The destructive function of RIRR may serve a physiological role by removal of unwanted cells or damaged mitochondria, or cause the pathological elimination of vital and essential mitochondria and cells. The adaptive release of sufficient ROS into the vicinity of mitochondria may also activate local pools of redox-sensitive enzymes involved in protective signaling pathways that limit ischemic damage to mitochondria and cells in that area. Maladaptive mPTP- or IMAC-related RIRR may also be playing a role in aging. Because the mechanism of mitochondrial RIRR highlights the central role of mitochondria-formed ROS, we discuss all of the known ROS-producing sites (shown in vitro) and their relevance to the mitochondrial ROS production in vivo. Copyright © 2014 the American Physiological Society.

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AMPK: guardian of metabolism and mitochondrial homeostasis.

Sébastien Herzig, Reuben Shaw (2018)

Cells constantly adapt their metabolism to meet their energy needs and respond to nutrient availability. Eukaryotes have evolved a very sophisticated system to sense low cellular ATP levels via the serine/threonine kinase AMP-activated protein kinase (AMPK) complex. Under conditions of low energy, AMPK phosphorylates specific enzymes and growth control nodes to increase ATP generation and decrease ATP consumption. In the past decade, the discovery of numerous new AMPK substrates has led to a more complete understanding of the minimal number of steps required to reprogramme cellular metabolism from anabolism to catabolism. This energy switch controls cell growth and several other cellular processes, including lipid and glucose metabolism and autophagy. Recent studies have revealed that one ancestral function of AMPK is to promote mitochondrial health, and multiple newly discovered targets of AMPK are involved in various aspects of mitochondrial homeostasis, including mitophagy. This Review discusses how AMPK functions as a central mediator of the cellular response to energetic stress and mitochondrial insults and coordinates multiple features of autophagy and mitochondrial biology.

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Mitochondria as multifaceted regulators of cell death

Florian J. Bock, Stephen Tait (2019)

Through their many and varied metabolic functions, mitochondria power life. Paradoxically, mitochondria also have a central role in apoptotic cell death. Upon induction of mitochondrial apoptosis, mitochondrial outer membrane permeabilization (MOMP) usually commits a cell to die. Apoptotic signalling downstream of MOMP involves cytochrome c release from mitochondria and subsequent caspase activation. As such, targeting MOMP in order to manipulate cell death holds tremendous therapeutic potential across different diseases, including neurodegenerative diseases, autoimmune disorders and cancer. In this Review, we discuss new insights into how mitochondria regulate apoptotic cell death. Surprisingly, recent data demonstrate that besides eliciting caspase activation, MOMP engages various pro-inflammatory signalling functions. As we highlight, together with new findings demonstrating cell survival following MOMP, this pro-inflammatory role suggests that mitochondria-derived signalling downstream of pro-apoptotic cues may also have non-lethal functions. Finally, we discuss the importance and roles of mitochondria in other forms of regulated cell death, including necroptosis, ferroptosis and pyroptosis. Collectively, these new findings offer exciting, unexplored opportunities to target mitochondrial regulation of cell death for clinical benefit.

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Author and article information

Contributors

Jian-Ting Chen: chenjt@smu.edu.cn

Si-Yuan Zhu:

ORCID: http://orcid.org/0000-0002-8559-6290

zsyneo@163.com

Journal

Journal ID (nlm-ta): Cell Death Dis

Journal ID (iso-abbrev): Cell Death Dis

Title: Cell Death & Disease

Publisher: Nature Publishing Group UK (London )

ISSN (Electronic): 2041-4889

Publication date (Electronic): 7 February 2023

Publication date PMC-release: 7 February 2023

Publication date Collection: February 2023

Volume: 14

Issue: 2

Electronic Location Identifier: 88

Affiliations

[1 ]GRID grid.284723.8, ISNI 0000 0000 8877 7471, Division of Spine Surgery, Department of Orthopedics, Nanfang Hospital, , Southern Medical University, ; Guangzhou, China

[2 ]GRID grid.284723.8, ISNI 0000 0000 8877 7471, Department of Ophthalmology, Nanfang Hospital, , Southern Medical University, ; Guangzhou, China

[3 ]GRID grid.284723.8, ISNI 0000 0000 8877 7471, Department of Orthopedics, Nanfang Hospital Taihe Branch, , Southern Medical University, ; Guangzhou, China

Author information

Zhao-Ming Zhong http://orcid.org/0000-0003-1480-028X

Si-Yuan Zhu http://orcid.org/0000-0002-8559-6290

Article

Publisher ID: 5595

DOI: 10.1038/s41419-023-05595-5

PMC ID: 9905061

PubMed ID: 36750550

SO-VID: 4bc59d9c-b42a-4768-bb26-55b5ffb857ec

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 1 January 2022

Date revision received : 14 January 2023

Date accepted : 16 January 2023

Funding

Funded by: FundRef https://doi.org/10.13039/501100001809, National Natural Science Foundation of China (National Science Foundation of China);

Award ID: 82172492

Award ID: 81902254

Award Recipient : Jian-Ting Chen Si-Yuan Zhu

Funded by: FundRef https://doi.org/10.13039/501100003453, Natural Science Foundation of Guangdong Province (Guangdong Natural Science Foundation);

Award ID: 2019A1515011895

Award Recipient : Si-Yuan Zhu

Funded by: Guangzhou Science and Technology Program (202102021150)

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ScienceOpen disciplines: Cell biology

Keywords: mitophagy,calcium and phosphate metabolic disorders

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ScienceOpen disciplines: Cell biology

Keywords: mitophagy, calcium and phosphate metabolic disorders

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

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Most cited references 55

Mitochondrial reactive oxygen species (ROS) and ROS-induced ROS release.

AMPK: guardian of metabolism and mitochondrial homeostasis.

Mitochondria as multifaceted regulators of cell death

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