PGAM5 is an MFN2 phosphatase that plays an essential role in the regulation of mitochondrial dynamics

Nag, Sudeshna; Szederkenyi, Kaitlin; Gorbenko, Olena; Tyrrell, Hannah; Yip, Christopher M.; McQuibban, G. Angus

doi:10.1016/j.celrep.2023.112895

Cited by 9 publications

(4 citation statements)

References 56 publications

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“…MFN2 is phosphorylated by PINK1 at T111 and S442 and triggers parkin association with the mitochondria inducing mitophagy (Chen and Dorn, 2013;Li et al, 2022). The dephosphorylation of MFN2 S27 by Mitochondrial Serine/Threonine protein phosphatase (PGAM5) protects MFN2 from degradation (Nag et al, 2023). In contrast, the JNK dependent phosphorylation of MFN2 recruits ubiquitination complexes which degrade MFN2 and increase the cellular sensitivity to apoptosis (Figure 5) (Leboucher et al, 2012).…”

Section: Mitochondrial Fusionmentioning

confidence: 99%

Kinase signalling adaptation supports dysfunctional mitochondria in disease

Skalka,

Tsakovska,

Murphy

2024

Front. Mol. Biosci.

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Mitochondria form a critical control nexus which are essential for maintaining correct tissue homeostasis. An increasing number of studies have identified dysregulation of mitochondria as a driver in cancer. However, which pathways support and promote this adapted mitochondrial function? A key hallmark of cancer is perturbation of kinase signalling pathways. These pathways include mitogen activated protein kinases (MAPK), lipid secondary messenger networks, cyclic-AMP-activated (cAMP)/AMP-activated kinases (AMPK), and Ca2+/calmodulin-dependent protein kinase (CaMK) networks. These signalling pathways have multiple substrates which support initiation and persistence of cancer. Many of these are involved in the regulation of mitochondrial morphology, mitochondrial apoptosis, mitochondrial calcium homeostasis, mitochondrial associated membranes (MAMs), and retrograde ROS signalling. This review will aim to both explore how kinase signalling integrates with these critical mitochondrial pathways and highlight how these systems can be usurped to support the development of disease. In addition, we will identify areas which require further investigation to fully understand the complexities of these regulatory interactions. Overall, this review will emphasize how studying the interaction between kinase signalling and mitochondria improves our understanding of mitochondrial homeostasis and can yield novel therapeutic targets to treat disease.

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Section: Mitochondrial Fusionmentioning

confidence: 99%

Kinase signalling adaptation supports dysfunctional mitochondria in disease

Skalka,

Tsakovska,

Murphy

2024

Front. Mol. Biosci.

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“…Phosphoglycerate mutase family member 5 (PGAM5) is an emerging posttranslational modifier that dephosphorylates MFN2 to drive mitochondrial network formation. 134 In the context of cardiac ischemia-reperfusion injury, MFN2 and OPA1 levels are increased in cardiac-specific PGAM5 knockout mice alongside the retained phosphorylation of DRP1 at Ser-637. 135 Activation of DRP1 by phosphorylation and the accompanying fission-induced mitochondrial fragmentation are linked to cardiac dysfunction and HF.…”

Section: Dynamic Nature Of Mitochondriamentioning

confidence: 99%

Mitochondrial Structure and Function in Human Heart Failure

Hinton,

Claypool,

Neikirk

et al. 2024

Circulation Research

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Despite clinical and scientific advancements, heart failure is the major cause of morbidity and mortality worldwide. Both mitochondrial dysfunction and inflammation contribute to the development and progression of heart failure. Although inflammation is crucial to reparative healing following acute cardiomyocyte injury, chronic inflammation damages the heart, impairs function, and decreases cardiac output. Mitochondria, which comprise one third of cardiomyocyte volume, may prove a potential therapeutic target for heart failure. Known primarily for energy production, mitochondria are also involved in other processes including calcium homeostasis and the regulation of cellular apoptosis. Mitochondrial function is closely related to morphology, which alters through mitochondrial dynamics, thus ensuring that the energy needs of the cell are met. However, in heart failure, changes in substrate use lead to mitochondrial dysfunction and impaired myocyte function. This review discusses mitochondrial and cristae dynamics, including the role of the mitochondria contact site and cristae organizing system complex in mitochondrial ultrastructure changes. Additionally, this review covers the role of mitochondria-endoplasmic reticulum contact sites, mitochondrial communication via nanotunnels, and altered metabolite production during heart failure. We highlight these often-neglected factors and promising clinical mitochondrial targets for heart failure.

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“…Additionally, phosphorylation and dephosphorylation modifications of MFN2 regulate its fusion ability; phosphorylation enhances fission and degradation, while dephosphorylation enhances fusion. 60 Mitochondrial fission and fusion work together to maintain a homeostatic balance of mitochondrial dynamics.…”

Section: Pgam5 Is Involved In Mitochondrial Fission Fusion and Hfmentioning

confidence: 99%