Endosomal RFFL ubiquitin ligase regulates mitochondrial morphology by targeting mitofusin 2

Mitochondrial homeostasis is ensured through communication between diverse cellular organelles, including mitochondria, the endoplasmic reticulum (ER), lysosomes and endosomes. Although it is known that mitofusins regulate mitochondrial networks and ER contacts, their role in endosomal–mitochondrial...

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Published inJournal of cell science Vol. 138; no. 12
Main Authors Narendradev, Nikhil Dev, Ravindran, Rishith, Jain, Parul, Chaudhary, Shikha, Velikkakath, Anoop Kumar G., Sudharman, Abyasree, Janardhanan, Adithya, Nag, Tapas Chandra, Yadav, Subhash Chandra, Srinivasula, Srinivasa Murty
Format Journal Article
LanguageEnglish
Published England The Company of Biologists 15.06.2025
Subjects
Animals
Endosomes - enzymology
Endosomes - metabolism
GTP Phosphohydrolases - genetics
GTP Phosphohydrolases - metabolism
HEK293 Cells
HeLa Cells
Humans
Mitochondria - genetics
Mitochondria - metabolism
Mitochondria - ultrastructure
Mitochondrial Proteins - genetics
Mitochondrial Proteins - metabolism
Ubiquitin-Protein Ligases - genetics
Ubiquitin-Protein Ligases - metabolism
Ubiquitination
Mitofusin 2
E3 ubiquitin ligase
RFFL
Mitochondrial morphology
Ubiquitylation
Endosomes
Online AccessGet full text
ISSN0021-9533
1477-9137
1477-9137
DOI10.1242/jcs.263830

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Abstract Mitochondrial homeostasis is ensured through communication between diverse cellular organelles, including mitochondria, the endoplasmic reticulum (ER), lysosomes and endosomes. Although it is known that mitofusins regulate mitochondrial networks and ER contacts, their role in endosomal–mitochondrial interactions remains unclear. Previously, we have reported that vesicles positive for the endosomal ubiquitin ligase RFFL are associated with damaged mitochondria and prime the organelle for PRKN recruitment. Now, we establish that RFFL is a ubiquitin ligase for mitofusin 2 (MFN2). Using electron microscopy and confocal imaging analyses, we demonstrate that RFFL-knockout cells exhibit enlarged mitochondrial morphology. RFFL interacts at an endogenous level with MFN2 and contributes to its ubiquitylation upon mitochondrial damage. Recombinant RFFL interacts and ubiquitylates MFN2 protein in vitro. Furthermore, exogenous RFFL, in a ligase-dependent manner, specifically reduces the exogenous protein levels of both MFN1 and MFN2, but not that of DRP1, and also perturbs lipid homeostasis. Importantly, we show that the hyperfused mitochondria morphology reported with expression of pathogenic disease mutants of MFN2 (T206I and R364W) of Charcot–Marie–Tooth disease type 2A can be rescued by RFFL co-expression. The study unravels novel mechanisms involving endosomal ubiquitin ligases in mitochondrial networks.
AbstractList Mitochondrial homeostasis is ensured through communication between diverse cellular organelles, including mitochondria, the endoplasmic reticulum (ER), lysosomes and endosomes. Although it is known that mitofusins regulate mitochondrial networks and ER contacts, their role in endosomal–mitochondrial interactions remains unclear. Previously, we have reported that vesicles positive for the endosomal ubiquitin ligase RFFL are associated with damaged mitochondria and prime the organelle for PRKN recruitment. Now, we establish that RFFL is a ubiquitin ligase for mitofusin 2 (MFN2). Using electron microscopy and confocal imaging analyses, we demonstrate that RFFL-knockout cells exhibit enlarged mitochondrial morphology. RFFL interacts at an endogenous level with MFN2 and contributes to its ubiquitylation upon mitochondrial damage. Recombinant RFFL interacts and ubiquitylates MFN2 protein in vitro . Furthermore, exogenous RFFL, in a ligase-dependent manner, specifically reduces the exogenous protein levels of both MFN1 and MFN2, but not that of DRP1, and also perturbs lipid homeostasis. Importantly, we show that the hyperfused mitochondria morphology reported with expression of pathogenic disease mutants of MFN2 (T206I and R364W) of Charcot–Marie–Tooth disease type 2A can be rescued by RFFL co-expression. The study unravels novel mechanisms involving endosomal ubiquitin ligases in mitochondrial networks. Highlighted Article: The endosomal ubiquitin ligase RFFL associates with and primes mitochondria for PRKN recruitment, targets mitofusins for degradation and contributes to mitochondrial networks and lipid homeostasis.
Mitochondrial homeostasis is ensured through communication between diverse cellular organelles, including mitochondria, the endoplasmic reticulum (ER), lysosomes and endosomes. Although it is known that mitofusins regulate mitochondrial networks and ER contacts, their role in endosomal-mitochondrial interactions remains unclear. Previously, we have reported that vesicles positive for the endosomal ubiquitin ligase RFFL are associated with damaged mitochondria and prime the organelle for PRKN recruitment. Now, we establish that RFFL is a ubiquitin ligase for mitofusin 2 (MFN2). Using electron microscopy and confocal imaging analyses, we demonstrate that RFFL-knockout cells exhibit enlarged mitochondrial morphology. RFFL interacts at an endogenous level with MFN2 and contributes to its ubiquitylation upon mitochondrial damage. Recombinant RFFL interacts and ubiquitylates MFN2 protein in vitro. Furthermore, exogenous RFFL, in a ligase-dependent manner, specifically reduces the exogenous protein levels of both MFN1 and MFN2, but not that of DRP1, and also perturbs lipid homeostasis. Importantly, we show that the hyperfused mitochondria morphology reported with expression of pathogenic disease mutants of MFN2 (T206I and R364W) of Charcot-Marie-Tooth disease type 2A can be rescued by RFFL co-expression. The study unravels novel mechanisms involving endosomal ubiquitin ligases in mitochondrial networks.
Mitochondrial homeostasis is ensured through communication between diverse cellular organelles, including mitochondria, the endoplasmic reticulum (ER), lysosomes, and endosomes. While mitofusins regulate mitochondrial networks and ER contacts, their role in endosomal-mitochondrial interactions remains unclear. Previously, we reported that endosomal ubiquitin ligase, RFFL-positive vesicles are associated with damaged mitochondria and prime the organelle for PRKN recruitment. Now, we establish that RFFL is a ubiquitin ligase for MFN2. Using electron microscopy and confocal imaging analyses, we demonstrate that RFFL knockout cells exhibit enlarged mitochondrial morphology. RFFL interacts at an endogenous level with MFN2 and contributes to its ubiquitination upon mitochondrial damage. Recombinant RFFL interacts and ubiquitinates MFN2 protein in vitro. Furthermore, exogenous RFFL in a ligase-dependent manner specifically reduces the exogenous protein levels of both MFN1 and MFN2, but not that of DRP1, and also perturbs lipid homeostasis. Importantly, we show that hyperfused mitochondria morphology reported with expression of pathogenic disease mutants of MFN2 (T206I and R364W) of Charcot-Marie-Tooth disease type 2A can be rescued by RFFL co-expression. The study unravels novel mechanisms involving endosomal ubiquitin ligases in mitochondrial networks.Mitochondrial homeostasis is ensured through communication between diverse cellular organelles, including mitochondria, the endoplasmic reticulum (ER), lysosomes, and endosomes. While mitofusins regulate mitochondrial networks and ER contacts, their role in endosomal-mitochondrial interactions remains unclear. Previously, we reported that endosomal ubiquitin ligase, RFFL-positive vesicles are associated with damaged mitochondria and prime the organelle for PRKN recruitment. Now, we establish that RFFL is a ubiquitin ligase for MFN2. Using electron microscopy and confocal imaging analyses, we demonstrate that RFFL knockout cells exhibit enlarged mitochondrial morphology. RFFL interacts at an endogenous level with MFN2 and contributes to its ubiquitination upon mitochondrial damage. Recombinant RFFL interacts and ubiquitinates MFN2 protein in vitro. Furthermore, exogenous RFFL in a ligase-dependent manner specifically reduces the exogenous protein levels of both MFN1 and MFN2, but not that of DRP1, and also perturbs lipid homeostasis. Importantly, we show that hyperfused mitochondria morphology reported with expression of pathogenic disease mutants of MFN2 (T206I and R364W) of Charcot-Marie-Tooth disease type 2A can be rescued by RFFL co-expression. The study unravels novel mechanisms involving endosomal ubiquitin ligases in mitochondrial networks.
Author Sudharman, Abyasree
Janardhanan, Adithya
Chaudhary, Shikha
Narendradev, Nikhil Dev
Srinivasula, Srinivasa Murty
Velikkakath, Anoop Kumar G.
Nag, Tapas Chandra
Jain, Parul
Yadav, Subhash Chandra
Ravindran, Rishith
AuthorAffiliation 2 Electron Microscope Facility, Department of Anatomy , All India Institute of Medical Sciences , 110029 New Delhi , India
1 School of Biology, Indian Institute of Science Education and Research Thiruvananthapuram , Thiruvananthapuram 695551 Kerala , India
3 Center for Systems Biology and Molecular Medicine, Yenepoya Research Centre, Yenepoya University , Deralakatte 575018, Mangalore , India
AuthorAffiliation_xml – name: 3 Center for Systems Biology and Molecular Medicine, Yenepoya Research Centre, Yenepoya University , Deralakatte 575018, Mangalore , India
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– name: 1 School of Biology, Indian Institute of Science Education and Research Thiruvananthapuram , Thiruvananthapuram 695551 Kerala , India
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Issue 12
Keywords Mitofusin 2
E3 ubiquitin ligase
RFFL
Mitochondrial morphology
Ubiquitylation
Endosomes
Language English
License http://creativecommons.org/licenses/by/4.0
2025. Published by The Company of Biologists.
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The authors declare no competing or financial interests.
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Snippet Mitochondrial homeostasis is ensured through communication between diverse cellular organelles, including mitochondria, the endoplasmic reticulum (ER),...
SourceID pubmedcentral
proquest
pubmed
crossref
SourceType Open Access Repository
Aggregation Database
Index Database
SubjectTerms Animals
Endosomes - enzymology
Endosomes - metabolism
GTP Phosphohydrolases - genetics
GTP Phosphohydrolases - metabolism
HEK293 Cells
HeLa Cells
Humans
Mitochondria - genetics
Mitochondria - metabolism
Mitochondria - ultrastructure
Mitochondrial Proteins - genetics
Mitochondrial Proteins - metabolism
Ubiquitin-Protein Ligases - genetics
Ubiquitin-Protein Ligases - metabolism
Ubiquitination
Title Endosomal RFFL ubiquitin ligase regulates mitochondrial morphology by targeting mitofusin 2
URI https://www.ncbi.nlm.nih.gov/pubmed/40444323
https://www.proquest.com/docview/3214306401
https://pubmed.ncbi.nlm.nih.gov/PMC12211564
Volume 138
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