Mitochondrial Protein PGAM5 Emerges as a New Regulator in Neurological Diseases

Liang, Min-Zong; Ke, Ting-Ling; Chen, Linyi

doi:10.3389/fnmol.2021.730604

Cited by 21 publications

(9 citation statements)

References 88 publications

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“…Deletion of PGAM5 has been shown to result in Parkinson's-like movement disorder in mice (Lu et al, 2014) and T cell dysfunction in primary cells (Panda et al, 2016). While its diverse roles largely remain to be uncovered (Liang et al, 2021), a novel PGAM5 inhibitor was recently suggested as a potential therapeutic for brain ischemic stroke (Gao et al, 2021). We observed that PGAM5 displays elevated levels in the mitochondria isolated from brain, SKM and spleen, possibly explaining the tissue-specific phenotypes induced by its absence and where in the body molecules targeting its phosphatase activity would exert their effects.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial phosphoproteomes are functionally specialized across tissues

Hansen

Kremer

Karayel

et al. 2022

Preprint

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Mitochondria are essential organelles involved in critical biological processes such as energy metabolism and cell survival. Their dysfunction is linked to numerous human pathologies that often manifest in a tissue-specific manner. Accordingly, mitochondrial fitness depends on versatile proteomes specialized to meet diverse tissue-specific requirements. Furthermore, increasing evidence suggests that phosphorylation may also play an important role in regulating tissue-specific mitochondrial functions and pathophysiology. We hypothesized that recent advances in mass spectrometry (MS)-based proteomics would now enable in-depth measurement to quantitatively profile mitochondrial proteomes along with their matching phosphoproteomes across tissues. We isolated mitochondria from mouse heart, skeletal muscle, brown adipose tissue, kidney, liver, brain, and spleen by differential centrifugation followed by separation on Percoll gradients and high-resolution MS analysis of the proteomes and phosphoproteomes. This in-depth map substantially quantifies known and predicted mitochondrial proteins and provides a resource of core and tissue modulated mitochondrial proteins (mitophos.de). We also uncover tissue-specific repertoires of dozens of kinases and phosphatases. Predicting kinase substrate associations for different mitochondrial compartments indicates tissue-specific regulation at the phosphoproteome level. Illustrating the functional value of our resource, we reproduce mitochondrial phosphorylation events on DRP1 responsible for its mitochondrial recruitment and fission initiation and describe phosphorylation clusters on MIGA2 linked to mitochondrial fusion.

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Section: Discussionmentioning

confidence: 99%

Mitochondrial phosphoproteomes are functionally specialized across tissues

Hansen

Kremer

Karayel

et al. 2022

Preprint

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“…Phosphoglycerate mutase 5 (PGAM5) is a mitochondrial serine [Ser)/threonine [Thr) phosphatase usually located in the inner mitochondrial membrane and regulates mitochondrial dynamics and programmed cell death [ 54 ]. PGAM5 also regulates mitophagy through different signaling pathways, contributing to cellular senescence, neurological diseases, and cancer [ 55 , 56 , 57 ]. SQSTM1, particularly (SQSTM1)/p62, is a soluble autophagy receptor with LIR motifs and one ubiquitin-binding domain at the C-terminus, which initiates selective autophagy in cells [ 37 , 58 ].…”

Section: Discussionmentioning

confidence: 99%

A Mitophagy-Related Gene Signature for Subtype Identification and Prognosis Prediction of Hepatocellular Carcinoma

Liu

Wang

et al. 2022

IJMS

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Globally, hepatocellular carcinoma (HCC) is the sixth most common cancer. In this study, the correlation between mitophagy and HCC prognosis was evaluated using data from The Cancer Genome Atlas (TCGA). Clinical and transcriptomic data of HCC patients were downloaded from TCGA dataset, and mitophagy-related gene (MRG) datasets were obtained from the Molecular Signature Database. Then, a consensus clustering analysis was performed to classify the patients into two clusters. Furthermore, tumor prognosis, clinicopathological features, functional analysis, immune infiltration, immune checkpoint (IC)-related gene expression level, tumor stem cells, ferroptosis status, and N6-methyladenosine analysis were compared between the two clusters. Finally, a mitophagy-related signature was developed. Two clusters (C1 and C2) were identified using the consensus clustering analysis based on the MRG signature. Patients with the C1 subtype exhibited upregulated pathways with better liver function, downregulated cancer-related pathways, lower cancer stem cell scores, lower Tumor Immune Dysfunction and Exclusion scores (TIDE), different ferroptosis status, and better prognosis compared with the patients with the C2 subtype. The C2 subtype was characterized by the increased grade of HCC, as well as the increased number of immune-related pathways and m6A-related genes. Higher immune scores were also observed for the C2 subtype. A signature containing four MRGs (PGAM5, SQSTM1, ATG9A, and GABARAPL1) which can accurately predict the prognosis of HCC patients was then identified. This four-gene signature exhibited a predictive effect in five other cancer types, namely glioma, uveal melanoma, acute myeloid leukemia, adrenocortical carcinoma, and mesothelioma. The mitophagy-associated subtypes of HCC were closely related to the immune microenvironment, immune checkpoint-related gene expression, cancer stem cells, ferroptosis status, m6A, prognosis, and HCC progression. The established MRG signature could predict prognosis in patients with HCC.

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“…PGAM family proteins possess a conserved PGAM domain that catalyzes mutase and/or phosphatase activities (Sadatomi et al, 2013;Cheng et al, 2021;Liang et al, 2021). PGAM5 lacks mutase activity, but mediates phosphatase activity and plays a regulatory role in mitochondrial dynamics and cell death (Sadatomi et al, 2013;Cheng et al, 2021;Liang et al, 2021). PGAM5 localizes to mitochondria via its N-terminal TM domain (Lo and Hannink, 2008).…”

Section: Regulation Of Bcl-rambo-induced Apoptosis and Mitophagy By P...mentioning

confidence: 99%

Biological properties of the BCL-2 family protein BCL-RAMBO, which regulates apoptosis, mitochondrial fragmentation, and mitophagy

Kataoka

2022

Front. Cell Dev. Biol.

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Mitochondria play an essential role in the regulation of cellular stress responses, including cell death. Damaged mitochondria are removed by fission and fusion cycles and mitophagy, which counteract cell death. BCL-2 family proteins possess one to four BCL-2 homology domains and regulate apoptosis signaling at mitochondria. BCL-RAMBO, also known as BCL2-like 13 (BCL2L13), was initially identified as one of the BCL-2 family proteins inducing apoptosis. Mitophagy receptors recruit the ATG8 family proteins MAP1LC3/GABARAP via the MAP1LC3-interacting region (LIR) motif to initiate mitophagy. In addition to apoptosis, BCL-RAMBO has recently been identified as a mitophagy receptor that possesses the LIR motif and regulates mitochondrial fragmentation and mitophagy. In the 20 years since its discovery, many important findings on BCL-RAMBO have been increasingly reported. The biological properties of BCL-RAMBO are reviewed herein.

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Mitochondrial Protein PGAM5 Emerges as a New Regulator in Neurological Diseases

Cited by 21 publications

References 88 publications

Mitochondrial phosphoproteomes are functionally specialized across tissues

Mitochondrial phosphoproteomes are functionally specialized across tissues

A Mitophagy-Related Gene Signature for Subtype Identification and Prognosis Prediction of Hepatocellular Carcinoma

Biological properties of the BCL-2 family protein BCL-RAMBO, which regulates apoptosis, mitochondrial fragmentation, and mitophagy

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