MGRN1 and ME

Mahogunin ring finger 1 (MGRN1) is a cytosolic ubiquitin ligase.

MGRN1 expression increases when cells are exposed to a variety of stressors.

Mice lacking MGRN1 have reduced level of many mitochondrial proteins. They have mitochondrial dysfunction and develop neurodegeneration.

MGRN1 is involved in:

• mitochondrial fusion
• mitochondrial trafficking via regulation of microtubules
• regulation af ER-associated protein degradation and ER-mitochondria junctions via interaction with the ligase GP78

(Ref1-5)

Four studies have shown the gene MGRN1 is differentially methylated in PBMC from ME patients compared to controls (6, 7, 8, 9). The DNA methylation pattern is related to quality of life in the ME patients (7) and is related to ME patient subtypes (8).

References:

1) Mitochondrial dysfunction precedes neurodegeneration in mahogunin (Mgrn1) mutant mice.
Sun K, Johnson BS, Gunn TM.
Neurobiol Aging. 2007 Dec;28(12):1840-52. Epub 2007 Aug 27.
PMID: 17720281

2) Calmodulin regulates MGRN1-GP78 interaction mediated ubiquitin proteasomal degradation system.
Mukherjee R, Bhattacharya A, Sau A, Basu S, Chakrabarti S, Chakrabarti O.
FASEB J. 2018 Sep 19:fj201701413RRR. doi: 10.1096/fj.201701413RRR. [Epub ahead of print]
PMID: 30230921

3) Ubiquitin-mediated regulation of the E3 ligase GP78 by MGRN1 in trans affects mitochondrial homeostasis.
Mukherjee R, Chakrabarti O.
J Cell Sci. 2016 Feb 15;129(4):757-73. doi: 10.1242/jcs.176537. Epub 2016 Jan 7.
PMID: 26743086

4) Regulation of Mitofusin1 by Mahogunin Ring Finger-1 and the proteasome modulates mitochondrial fusion.
Mukherjee R, Chakrabarti O.
Biochim Biophys Acta. 2016 Dec;1863(12):3065-3083. doi: 10.1016/j.bbamcr.2016.09.022. Epub 2016 Oct 4.
PMID: 27713096

5).MGRN1-mediated ubiquitination of α-tubulin regulates microtubule dynamics and intracellular transport.Mukherjee R, Majumder P, Chakrabarti O.
Traffic. 2017 Dec;18(12):791-807. doi: 10.1111/tra.12527. Epub 2017 Oct 4.PMID: 28902452

6) de Vega et al: DNA methylation Modifications associated with CFS. PlosOne, 2014, 9, 8

7) de Vega et al: Epigenetic modifications and glucocorticoid sensitivity in ME/CFS. BMC Medical Genomics, 2017, 10, 11 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5324230/

8) de Vega et al: Integration of DNA methylation & health scores identifies subtypes in ME/CFS. Epigenomics 2018, 10, 5 https://www.futuremedicine.com/doi/full/10.2217/epi-2017-015

9) Trivedi et al: Identification of ME/CFS - associated DNA methylation patterns.
Plos One 2018, 13, 7 https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0201066