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A human mitofusin 2 mutation can cause mitophagic cardiomyopathy

Cardiac muscle has the highest mitochondrial density of any human tissue, but mitochondrial dysfunction is not a recognized cause of isolated cardiomyopathy. Here, we determined that the rare mitofusin (MFN) 2 R400Q mutation is 15–20× over-represented in clinical cardiomyopathy, whereas this specifi...

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Autores principales: Franco, Antonietta, Li, Jiajia, Kelly, Daniel P, Hershberger, Ray E, Marian, Ali J, Lewis, Renate M, Song, Moshi, Dang, Xiawei, Schmidt, Alina D, Mathyer, Mary E, Edwards, John R, Strong, Cristina de Guzman, Dorn, Gerald W
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10619978/
https://www.ncbi.nlm.nih.gov/pubmed/37910431
http://dx.doi.org/10.7554/eLife.84235
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author Franco, Antonietta
Li, Jiajia
Kelly, Daniel P
Hershberger, Ray E
Marian, Ali J
Lewis, Renate M
Song, Moshi
Dang, Xiawei
Schmidt, Alina D
Mathyer, Mary E
Edwards, John R
Strong, Cristina de Guzman
Dorn, Gerald W
author_facet Franco, Antonietta
Li, Jiajia
Kelly, Daniel P
Hershberger, Ray E
Marian, Ali J
Lewis, Renate M
Song, Moshi
Dang, Xiawei
Schmidt, Alina D
Mathyer, Mary E
Edwards, John R
Strong, Cristina de Guzman
Dorn, Gerald W
author_sort Franco, Antonietta
collection PubMed
description Cardiac muscle has the highest mitochondrial density of any human tissue, but mitochondrial dysfunction is not a recognized cause of isolated cardiomyopathy. Here, we determined that the rare mitofusin (MFN) 2 R400Q mutation is 15–20× over-represented in clinical cardiomyopathy, whereas this specific mutation is not reported as a cause of MFN2 mutant-induced peripheral neuropathy, Charcot–Marie–Tooth disease type 2A (CMT2A). Accordingly, we interrogated the enzymatic, biophysical, and functional characteristics of MFN2 Q400 versus wild-type and CMT2A-causing MFN2 mutants. All MFN2 mutants had impaired mitochondrial fusion, the canonical MFN2 function. Compared to MFN2 T105M that lacked catalytic GTPase activity and exhibited normal activation-induced changes in conformation, MFN2 R400Q and M376A had normal GTPase activity with impaired conformational shifting. MFN2 R400Q did not suppress mitochondrial motility, provoke mitochondrial depolarization, or dominantly suppress mitochondrial respiration like MFN2 T105M. By contrast to MFN2 T105M and M376A, MFN2 R400Q was uniquely defective in recruiting Parkin to mitochondria. CRISPR editing of the R400Q mutation into the mouse Mfn2 gene induced perinatal cardiomyopathy with no other organ involvement; knock-in of Mfn2 T105M or M376V did not affect the heart. RNA sequencing and metabolomics of cardiomyopathic Mfn2 Q/Q400 hearts revealed signature abnormalities recapitulating experimental mitophagic cardiomyopathy. Indeed, cultured cardiomyoblasts and in vivo cardiomyocytes expressing MFN2 Q400 had mitophagy defects with increased sensitivity to doxorubicin. MFN2 R400Q is the first known natural mitophagy-defective MFN2 mutant. Its unique profile of dysfunction evokes mitophagic cardiomyopathy, suggesting a mechanism for enrichment in clinical cardiomyopathy.
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spelling pubmed-106199782023-11-02 A human mitofusin 2 mutation can cause mitophagic cardiomyopathy Franco, Antonietta Li, Jiajia Kelly, Daniel P Hershberger, Ray E Marian, Ali J Lewis, Renate M Song, Moshi Dang, Xiawei Schmidt, Alina D Mathyer, Mary E Edwards, John R Strong, Cristina de Guzman Dorn, Gerald W eLife Developmental Biology Cardiac muscle has the highest mitochondrial density of any human tissue, but mitochondrial dysfunction is not a recognized cause of isolated cardiomyopathy. Here, we determined that the rare mitofusin (MFN) 2 R400Q mutation is 15–20× over-represented in clinical cardiomyopathy, whereas this specific mutation is not reported as a cause of MFN2 mutant-induced peripheral neuropathy, Charcot–Marie–Tooth disease type 2A (CMT2A). Accordingly, we interrogated the enzymatic, biophysical, and functional characteristics of MFN2 Q400 versus wild-type and CMT2A-causing MFN2 mutants. All MFN2 mutants had impaired mitochondrial fusion, the canonical MFN2 function. Compared to MFN2 T105M that lacked catalytic GTPase activity and exhibited normal activation-induced changes in conformation, MFN2 R400Q and M376A had normal GTPase activity with impaired conformational shifting. MFN2 R400Q did not suppress mitochondrial motility, provoke mitochondrial depolarization, or dominantly suppress mitochondrial respiration like MFN2 T105M. By contrast to MFN2 T105M and M376A, MFN2 R400Q was uniquely defective in recruiting Parkin to mitochondria. CRISPR editing of the R400Q mutation into the mouse Mfn2 gene induced perinatal cardiomyopathy with no other organ involvement; knock-in of Mfn2 T105M or M376V did not affect the heart. RNA sequencing and metabolomics of cardiomyopathic Mfn2 Q/Q400 hearts revealed signature abnormalities recapitulating experimental mitophagic cardiomyopathy. Indeed, cultured cardiomyoblasts and in vivo cardiomyocytes expressing MFN2 Q400 had mitophagy defects with increased sensitivity to doxorubicin. MFN2 R400Q is the first known natural mitophagy-defective MFN2 mutant. Its unique profile of dysfunction evokes mitophagic cardiomyopathy, suggesting a mechanism for enrichment in clinical cardiomyopathy. eLife Sciences Publications, Ltd 2023-11-01 /pmc/articles/PMC10619978/ /pubmed/37910431 http://dx.doi.org/10.7554/eLife.84235 Text en © 2023, Franco et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Developmental Biology
Franco, Antonietta
Li, Jiajia
Kelly, Daniel P
Hershberger, Ray E
Marian, Ali J
Lewis, Renate M
Song, Moshi
Dang, Xiawei
Schmidt, Alina D
Mathyer, Mary E
Edwards, John R
Strong, Cristina de Guzman
Dorn, Gerald W
A human mitofusin 2 mutation can cause mitophagic cardiomyopathy
title A human mitofusin 2 mutation can cause mitophagic cardiomyopathy
title_full A human mitofusin 2 mutation can cause mitophagic cardiomyopathy
title_fullStr A human mitofusin 2 mutation can cause mitophagic cardiomyopathy
title_full_unstemmed A human mitofusin 2 mutation can cause mitophagic cardiomyopathy
title_short A human mitofusin 2 mutation can cause mitophagic cardiomyopathy
title_sort human mitofusin 2 mutation can cause mitophagic cardiomyopathy
topic Developmental Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10619978/
https://www.ncbi.nlm.nih.gov/pubmed/37910431
http://dx.doi.org/10.7554/eLife.84235
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