Pgam5 released from damaged mitochondria induces mitochondrial biogenesis via Wnt signaling

Bernkopf, Dominic B.; Jalal, Kowcee; Brückner, Martina K.; Knaup, Karl X.; Gentzel, Marc; Schambony, Alexandra; Behrens, Jürgen

doi:10.1083/jcb.201708191

Cited by 77 publications

(89 citation statements)

References 31 publications

(65 reference statements)

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“…PGAM5 is a member of the phosphoglycerate mutase family, but exhibits protein phosphatase activity toward Ser/Thr (Takeda et al , ) and His (Panda et al , ). Recent studies highlighted the importance of PGAM5 in a variety of cellular processes, including mitochondrial dynamics (Wilkins et al , ; Lavie et al , ; O'Mealey et al , ), mitophagy (Chen et al , ; Wu et al , ; Hawk et al , ), programmed cell death (Wang et al , ; Lin et al , ; Zhuang et al , ; Xu et al , ; He et al , ), the WNT/β‐catenin pathway (Rauschenberger et al , ; Bernkopf et al , ), immune responses (Kang et al , ; Moriwaki et al , ), and longevity (Borch Jensen et al , ). Several lines of evidence suggest the close relationship of PGAM5 with Parkinson's disease.…”

Section: Introductionmentioning

confidence: 99%

Syntaxin 17 regulates the localization and function of PGAM5 in mitochondrial division and mitophagy

et al. 2018

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PGAM5, a mitochondrial protein phosphatase that is genetically and biochemically linked to PINK1, facilitates mitochondrial division by dephosphorylating the mitochondrial fission factor Drp1. At the onset of mitophagy, PGAM5 is cleaved by PARL, a rhomboid protease that degrades PINK1 in healthy cells, and the cleaved form facilitates the engulfment of damaged mitochondria by autophagosomes by dephosphorylating the mitophagy receptor FUNDC1. Here, we show that the function and localization of PGAM5 are regulated by syntaxin 17 (Stx17), a mitochondria-associated membrane/mitochondria protein implicated in mitochondrial dynamics in fed cells and autophagy in starved cells. In healthy cells, loss of Stx17 causes PGAM5 aggregation within mitochondria and thereby failure of the dephosphorylation of Drp1, leading to mitochondrial elongation. In Parkin-mediated mitophagy, Stx17 is prerequisite for PGAM5 to interact with FUNDC1. Our results reveal that the Stx17-PGAM5 axis plays pivotal roles in mitochondrial division and PINK1/Parkin-mediated mitophagy.

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Section: Introductionmentioning

confidence: 99%

Syntaxin 17 regulates the localization and function of PGAM5 in mitochondrial division and mitophagy

et al. 2018

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“…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). Considering the study showing that active-Wnt signaling suppresses UCP1 expression in vitro and in vivo (49), Wnt/β-catenin signaling is a potential central player in PGAM5-mediated UCP1 suppression.…”

Section: Discussionmentioning

confidence: 99%

“…Additionally, another group and our group reported that OMA1, a zinc metalloprotease, is also responsible for the cleavage of PGAM5 (23,24). A recent study showed that cytosolic PGAM5 dephosphorylates and stabilizes β-catenin, resulting in mitochondrial biogenesis (25). Further, another study revealed that the cleaved form of PGAM5 sensitizes cells to apoptosis induced by staurosporine (19).…”

Section: Introductionmentioning

confidence: 86%

“…Next, we sought to examine the mechanism by which PGAM5 regulates UCP1 expression. It is noteworthy that PGAM5 changes its subcellular localization in accordance with its cleavage, and cleaved PGAM5 contributes to cell death and mitochondrial biogenesis (19,25). Another group and our group previously demonstrated that PARL and OMA1 are the proteases that mediate processing of PGAM5 (23, 24); however, other regulators of PGAM5 cleavage are largely unknown.…”

Section: Pisd a Mitochondrial Lipid-metabolizing Enzyme Is Requiredmentioning

confidence: 94%

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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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“…This suggests that WNT4-mediated control of metabolism and/or mitochondrial function are critical to ILC cell survival. Wnt signaling (both β-catenin-dependent and -independent signaling) has been previously linked to these processes [52][53][54], but roles for WNT4 in mitochondrial function have not previously described. However, one recent study demonstrated that Wnt4 overexpression could rescue a defect in mitochondrial function and dynamics caused by deletion of PTEN-inducible kinase 1 (PINK1) in Drosophila [55].…”

Section: Discussionmentioning

confidence: 99%

Estrogen controls mTOR signaling and mitochondrial function via WNT4 in lobular carcinoma cells

Shackleford

Bordeaux

et al. 2019

Preprint

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Twitter: @mjsikoraAuthors' contributions MJS, DMR, and SO conceived of the project and experiments. MJS, DMR, EKB, and HMH designed and performed experiments. MJS and DMR developed models for the project. All authors contributed to data analysis and interpretation. MJS wrote the draft manuscript; all authors read and revised the manuscript and have read and approved of this version of the manuscript. AbstractInvasive lobular carcinoma of the breast (ILC) is strongly estrogen-driven, and represents a unique context for estrogen receptor (ER) signaling. In ILC, ER controls the expression of the Wnt ligand WNT4, which is critical for endocrine response and anti-estrogen resistance, yet signaling mediated by WNT4 is poorly understood. We utilized reverse phase protein array (RPPA) to characterize ER and WNT4-driven signaling in ILC cells, and identified WNT4 as a mediator of downstream mTOR signaling via p70-S6K. Independent of mTOR/p70-S6K, ER and WNT4 control levels of MCL-1, which is associated with mitochondrial function. In this context, knockdown of WNT4 caused accumulation of reactive oxygen species and decreased ATP production that precede cell death. WNT4 regulation of both mTOR signaling and MCL-1 levels was also observed in anti-estrogen resistant models of ILC.Further, we identified that high WNT4 expression is associated with similar mTOR pathway activation in serous ovarian cancer tumors, suggesting that this WNT4 pathway is important in multiple tumor types.The identified downstream pathways represent potential targets to inhibit WNT4 signaling in ovarian cancer and overcome anti-estrogen resistance for patients with ILC.

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Pgam5 released from damaged mitochondria induces mitochondrial biogenesis via Wnt signaling

Cited by 77 publications

References 31 publications

Syntaxin 17 regulates the localization and function of PGAM5 in mitochondrial division and mitophagy

Syntaxin 17 regulates the localization and function of PGAM5 in mitochondrial division and mitophagy

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

Estrogen controls mTOR signaling and mitochondrial function via WNT4 in lobular carcinoma cells

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