A novel role of KEAP1/PGAM5 complex: ROS sensor for inducing mitophagy

Zeb, Akbar; Choubey, Vinay; Gupta, Ruby; Kuum, Malle; Safiulina, Dzhamilja; Vaarmann, Annika; Gogichaishvili, Nana; Liiv, Mailis; Ilves, Ivar; Tämm, Kaido; Veksler, Vladimir; Kaasik, Allen

doi:10.1016/j.redox.2021.102186

Cited by 48 publications

(26 citation statements)

References 68 publications

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“…Some studies have also proved that the oxidative imbalance caused by the large production of ROS in mitochondria is the main reason for the induction of adaptive mitophagy (Zeb et al 2021 ). Oxidative stress caused by ROS can not only induce mitophagy through HIF-1 mediated pathway, but also regulate apoptosis by activating other signal molecule controlled pathways (Forte et al 2021 ; Sumi et al 2022 ).…”

Section: Discussionmentioning

confidence: 99%

BNIP3 mediates the different adaptive responses of fibroblast-like synovial cells to hypoxia in patients with osteoarthritis and rheumatoid arthritis

Deng

Wang

et al. 2022

Mol Med

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Background Hypoxia is one of the important characteristics of synovial microenvironment in rheumatoid arthritis (RA), and plays an important role in synovial hyperplasia. In terms of cell survival, fibroblast-like synovial cells (FLSs) are relatively affected by hypoxia. In contrast, fibroblast-like synovial cells from patients with RA (RA-FLSs) are particularly resistant to hypoxia-induced cell death. The purpose of this study was to evaluate whether fibroblast-like synovial cells in patients with osteoarthritis (OA-FLSs) and RA-FLSs have the same adaptation to hypoxia. Methods CCK-8, flow cytometry and BrdU were used to detect the proliferation of OA-FLSs and RA-FLSs under different oxygen concentrations. Apoptosis was detected by AV/PI, TUNEL and Western blot, mitophagy was observed by electron microscope, laser confocal microscope and Western blot, the state of mitochondria was detected by ROS and mitochondrial membrane potential by flow cytometry, BNIP3 and HIF-1α were detected by Western blot and RT-qPCR. The silencing of BNIP3 was achieved by stealth RNA system technology. Results After hypoxia, the survival rate of OA-FLSs decreased, while the proliferation activity of RA-FLSs further increased. Hypoxia induced an increase in apoptosis and inhibition of mitophagy in OA-FLSs, but not in RA-FLSs. Hypoxia led to a more lasting adaptive response. RA-FLSs displayed a more significant increase in the expression of genes transcriptionally regulated by HIF-1α. Interestingly, they showed higher BNIP3 expression than OA-FLSs, and showed stronger mitophagy and proliferation activities. BNIP3 siRNA experiment confirmed the potential role of BNIP3 in the survival of RA-FLSs. Inhibition of BNIP3 resulted in the decrease of cell proliferation, mitophagy and the increase of apoptosis. Conclusion In summary, RA-FLSs maintained intracellular redox balance through mitophagy to promote cell survival under hypoxia. The mitophagy of OA-FLSs was too little to maintain the redox balance of mitochondria, resulting in apoptosis. The difference of mitophagy between OA-FLSs and RA-FLSs under hypoxia is mediated by the level of BNIP3 expression.

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Section: Discussionmentioning

confidence: 99%

BNIP3 mediates the different adaptive responses of fibroblast-like synovial cells to hypoxia in patients with osteoarthritis and rheumatoid arthritis

Deng

Wang

et al. 2022

Mol Med

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“…Later, the same group proposed that 52 kDa PINK1 localizes at the mitochondrial–endoplasmic reticulum (ER) interface, where components of ER-associated degradation pathway, such as the E3 ligases GP78 and HRD1, catalyze PINK1 ubiquitination and promote its proteasomal degradation to maintain PINK1 content low in healthy mitochondria [ 47 ]. Contrary to the PINK1 degradation mechanism, it is largely accepted that the full-length PINK1 is stabilized on the MOM upon mitochondrial membrane potential dissipation [ 36 ], excessive mitochondrial reactive oxygen species (ROS) generation [ 48 , 49 ] and/or mitochondrial protein aggregation [ 50 , 51 ]. The mitochondrial depolarization or bioenergetic deficit leads to the inhibition of the TIM23-mediated import of PINK1 via indirect modulation by the adenine nucleotide translocator (ANT) [ 52 ].…”

Section: Ubiquitin-dependent Mitophagymentioning

confidence: 99%

Molecular Mechanisms and Regulation of Mammalian Mitophagy

Choubey

Zeb

Kaasik

2021

Cells

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Mitochondria in the cell are the center for energy production, essential biomolecule synthesis, and cell fate determination. Moreover, the mitochondrial functional versatility enables cells to adapt to the changes in cellular environment and various stresses. In the process of discharging its cellular duties, mitochondria face multiple types of challenges, such as oxidative stress, protein-related challenges (import, folding, and degradation) and mitochondrial DNA damage. They mitigate all these challenges with robust quality control mechanisms which include antioxidant defenses, proteostasis systems (chaperones and proteases) and mitochondrial biogenesis. Failure of these quality control mechanisms leaves mitochondria as terminally damaged, which then have to be promptly cleared from the cells before they become a threat to cell survival. Such damaged mitochondria are degraded by a selective form of autophagy called mitophagy. Rigorous research in the field has identified multiple types of mitophagy processes based on targeting signals on damaged or superfluous mitochondria. In this review, we provide an in-depth overview of mammalian mitophagy and its importance in human health and diseases. We also attempted to highlight the future area of investigation in the field of mitophagy.

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“…When we evaluated minimal essential networks (MEN) within our datasets we identified VDAC1 as a dominator of upregulated networks and PGAM5 and HSPA8 as dominators of downregulated networks in CLN7 disease. Intriguingly, all three are involved in quality control of mitochondria through Parkin/PINK1 mitophagy (26)(27)(28). We have discovered a novel nuclear defect in CLN7 disease as well as further defining vesicular and mitochondrial defects.…”

Section: Discussionmentioning

confidence: 88%

“…While PGAM5, UCHL5 and HSPA8 are dominators to downregulated networks in CLN7 BD iNPCs. Intriguingly HSPA8 (also known as HSC70) and PGAM5 both mechanistically stabilize PINK1, whilst VDAC1 is a target for Parkin-mediated ubiquitylation during ROS-induced mitophagy (26)(27)(28). UCLH5 is a deubiquitinase that elevates proteasomal proteostasis (29).…”

Section: Proteomics Reveal a Profound Nuclear Defect In Cln7 Inpcmentioning

confidence: 99%

CLN7 mutation causes aberrant redistribution of protein isoforms and contributes to Batten disease pathobiology

Sharaireh

Guevara-Ferrer

Herranz-Martín

et al. 2022

Preprint

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The variant late infantile form of the inherited neurodegenerative Batten disease (BD) is caused by mutations in the CLN7/MFSD8 gene and represents a strong candidate for gene therapy. Post-natal intracerebral administration of AAV9-hCLN7 to Cln7Δex2 knockout mice resulted in extended lifespan but dose escalation resulted in reduced acuity in neurophysiology tests, cerebral atrophy and elevated neuroinflammation. Comparing patient and control iPSC-derived neural progenitor cells (iNPC) we discovered that CLN7 localizes to the nucleus as well as the endolysosomal network and is differentially distributed in BD iNPC. Proteomics identified a profound nuclear defect in BD iNPC that compounds with mitochondrial and lysosomal metabolic defects resulting in elevated apoptosis. We further identified a 50kDa common nuclear CLN7 isoform and a 37kDa isoform that accumulates only in BD iNPC nuclei. Our findings suggest that successful treatment of CLN7 BD will require combinatorial therapies addressing both loss and aberrant gain of protein function.

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A novel role of KEAP1/PGAM5 complex: ROS sensor for inducing mitophagy

Cited by 48 publications

References 68 publications

BNIP3 mediates the different adaptive responses of fibroblast-like synovial cells to hypoxia in patients with osteoarthritis and rheumatoid arthritis

BNIP3 mediates the different adaptive responses of fibroblast-like synovial cells to hypoxia in patients with osteoarthritis and rheumatoid arthritis

Molecular Mechanisms and Regulation of Mammalian Mitophagy

CLN7 mutation causes aberrant redistribution of protein isoforms and contributes to Batten disease pathobiology

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