Cleaved PGAM5 is released from mitochondria depending on proteasome-mediated rupture of the outer mitochondrial membrane during mitophagy

Yamaguchi, Ayane; Ishikawa, Hayate; Furuoka, Mana; Yokozeki, Masashi; Matsuda, Noriyuki; Tanimura, Susumu; Takeda, Kohsuke

doi:10.1093/jb/mvy077

Cited by 20 publications

(20 citation statements)

References 21 publications

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“…Generally, Pgam5 is identified as a moderator dephosphorylating and activating Drp1, Bcl-xL, Fundc1, etc., which involves mitochondria fission and mitophagy to maintain normal function and state of mitochondria [ 9 , 34 ]. In this present work, Pgam5 depletion alleviated LPS-induced microglia activation and Il-1β via Asc/caspase1-mediated pyroptosis.…”

Section: Discussionmentioning

confidence: 99%

Downregulation of phosphoglycerate mutase 5 improves microglial inflammasome activation after traumatic brain injury

et al. 2021

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Traumatic brain injury (TBI) is considered as the most common cause of disability and death, and therefore an effective intervention of cascade pathology of secondary brain injury promptly can be a potential therapeutic direction for TBI prognosis. Further study of the physiological mechanism of TBI is urgent and important. Phosphoglycerate mutase 5 (Pgam5), a mitochondrial protein, mediate mitochondrial homeostasis, cellular senescence, and necroptosis. This study evaluated the effects of Pgam5 on neurological deficits and neuroinflammation of controlled cortical impact-induced TBI mouse model in vivo and LPS + ATP-induced microglia model in vitro. Pgam5 was overexpressed post-TBI. Pgam5 depletion reduced pyroptosis-related molecules and improved microglia activation, neuron damage, tissue lesion, and neurological dysfunctions in TBI mice. RNA-seq analysis and molecular biology experiments demonstrated that Pgam5 might regulate inflammatory responses by affecting the post-translational modification and protein expression of related genes, including Nlrp3, caspase1, Gsdmd, and Il-1β. In microglia, Pgam5-sh abrogated LPS + ATP-induced Il-1β secretion through Asc oligomerization-mediated caspase-1 activation, which was independent of Rip3. The data demonstrate the critical role Pgam5 plays in nerve injury in the progression of TBI, which regulates Asc polymerization and subsequently caspase1 activation, and thus reveals a fundamental mechanism linking microglial inflammasome activation to Asc/caspase1-generated Il-1β-mediated neuroinflammation. Thus, our data indicate Pgam5 worsens physiological and neurological outcomes post-TBI, which may be a potential therapeutic target to improve neuroinflammation after TBI.

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Section: Discussionmentioning

confidence: 99%

Downregulation of phosphoglycerate mutase 5 improves microglial inflammasome activation after traumatic brain injury

et al. 2021

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“…Thus, Lipin1 might play a key role in PGAM5mediated suppression of UCP1. Regarding intramembrane cleavage, a recent report suggested that cleaved PGAM5 gains the potential to be released from the mitochondria (48). It has recently been reported that the cleaved form of PGAM5 dephosphorylates and stabilizes β-catenin in the cytosol, leading to intrinsic activation of Wnt signaling (25).…”

Section: Discussionmentioning

confidence: 99%

The mitochondrial protein PGAM5 suppresses energy consumption in brown adipocytes by repressing expression of uncoupling protein 1

Sugawara

Kanamaru

Sekine

et al. 2020

Journal of Biological Chemistry

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Accumulating evidence suggests that brown adipose tissue (BAT) is a potential therapeutic target for managing obesity and related diseases. PGAM family member 5, mitochondrial serine/threonine protein phosphatase (PGAM5), is a protein phosphatase that resides in the mitochondria and regulates many biological processes, including cell death, mitophagy, and immune responses. Because BAT is a mitochondria-rich tissue, we have hypothesized that PGAM5 has a physiological function in BAT. We previously reported that PGAM5-knockout (KO) mice are resistant to severe metabolic stress. Importantly, lipid accumulation is suppressed in PGAM5-KO BAT, even under unstressed conditions, raising the possibility that PGAM5 deficiency stimulates lipid consumption. However, the mechanism underlying this observation is undetermined. Here, using an array of biochemical approaches, including quantitative RT-PCR, immunoblotting, and oxygen consumption assays, we show that PGAM5 negatively regulates energy expenditure in brown adipocytes. We found that PGAM5-KO brown adipocytes have an enhanced oxygen consumption rate and increased expression of uncoupling protein 1 (UCP1), a protein that increases energy consumption in the mitochondria. Mechanistically, we found that PGAM5 phosphatase activity and intramembrane cleavage are required for suppression of UCP1 activity. Furthermore, utilizing a genome-wide siRNA screen in HeLa cells to search for regulators of PGAM5 cleavage, we identified a set of candidate genes, including phosphatidylserine decarboxylase (PISD), which catalyzes the formation of phosphatidylethanolamine at the mitochondrial membrane. Taken together, these results indicate that PGAM5 suppresses mitochondrial energy expenditure by down-regulating UCP1 expression in brown adipocytes and that its phosphatase activity and intramembrane cleavage are required for UCP1 suppression.

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“…Many more interacting partners have been found, including phosphoglycerate mutase 5 (PGAM5), which forms a complex containing both NRF2 and KEAP1, where KEAP1 binds to both proteins through their E(S/T)GE motifs [ 133 ]. PGAM5 is a serine/threonine and histidine [ 134 ] phosphatase that localizes on the mitochondrial outer membrane and can affect mitophagy, necroptosis, and overall mitochondrial dynamics [ 133 , 135 ]. Although PGAM5 is not a NRF2 target, NRF2 is still required for this complex, which serves to protect mitochondrial motility through suppression of dominant-negative KEAP1 activity [ 136 ].…”

Section: Future Perspectivesmentioning

confidence: 99%

Dissecting the Crosstalk between NRF2 Signaling and Metabolic Processes in Cancer

DeBlasi

DeNicola

2020

Cancers

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The transcription factor NRF2 (nuclear factor-erythroid 2 p45-related factor 2 or NFE2L2) plays a critical role in response to cellular stress. Following an oxidative insult, NRF2 orchestrates an antioxidant program, leading to increased glutathione levels and decreased reactive oxygen species (ROS). Mounting evidence now implicates the ability of NRF2 to modulate metabolic processes, particularly those at the interface between antioxidant processes and cellular proliferation. Notably, NRF2 regulates the pentose phosphate pathway, NADPH production, glutaminolysis, lipid and amino acid metabolism, many of which are hijacked by cancer cells to promote proliferation and survival. Moreover, deregulation of metabolic processes in both normal and cancer-based physiology can stabilize NRF2. We will discuss how perturbation of metabolic pathways, including the tricarboxylic acid (TCA) cycle, glycolysis, and autophagy can lead to NRF2 stabilization, and how NRF2-regulated metabolism helps cells deal with these metabolic stresses. Finally, we will discuss how the negative regulator of NRF2, Kelch-like ECH-associated protein 1 (KEAP1), may play a role in metabolism through NRF2 transcription-independent mechanisms. Collectively, this review will address the interplay between the NRF2/KEAP1 complex and metabolic processes.

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Cleaved PGAM5 is released from mitochondria depending on proteasome-mediated rupture of the outer mitochondrial membrane during mitophagy

Cited by 20 publications

References 21 publications

Downregulation of phosphoglycerate mutase 5 improves microglial inflammasome activation after traumatic brain injury

Downregulation of phosphoglycerate mutase 5 improves microglial inflammasome activation after traumatic brain injury

The mitochondrial protein PGAM5 suppresses energy consumption in brown adipocytes by repressing expression of uncoupling protein 1

Dissecting the Crosstalk between NRF2 Signaling and Metabolic Processes in Cancer

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