Mitochondrial Phenotypes in Genetically Diverse Neurodegenerative Diseases and Their Response to Mitofusin Activation

Xiawei Dang; Emily K Walton; Barbara Zablocka; Robert H Baloh; Michael E Shy; Gerald W Dorn II

doi:10.3390/cells11061053

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Mitochondrial Phenotypes in Genetically Diverse Neurodegenerative Diseases and Their Response to Mitofusin Activation

Journal article

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Mitochondrial Phenotypes in Genetically Diverse Neurodegenerative Diseases and Their Response to Mitofusin Activation

Xiawei Dang, Emily K Walton, Barbara Zablocka, Robert H Baloh, Michael E Shy and Gerald W Dorn II

Cells (Basel, Switzerland), Vol.11(6), p.1053

03/21/2022

DOI: 10.3390/cells11061053

PMCID: PMC8947610

PMID: 35326504

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Abstract

Mitochondrial fusion is essential to mitochondrial fitness and cellular health. Neurons of patients with genetic neurodegenerative diseases often exhibit mitochondrial fragmentation, reflecting an imbalance in mitochondrial fusion and fission (mitochondrial dysdynamism). Charcot-Marie-Tooth (CMT) disease type 2A is the prototypical disorder of impaired mitochondrial fusion caused by mutations in the fusion protein mitofusin (MFN)2. Yet, cultured CMT2A patient fibroblast mitochondria are often reported as morphologically normal. Metabolic stress might evoke pathological mitochondrial phenotypes in cultured patient fibroblasts, providing a platform for the pre-clinical individualized evaluation of investigational therapeutics. Here, substitution of galactose for glucose in culture media was used to redirect CMT2A patient fibroblasts (MFN2 T105M, R274W, H361Y, R364W) from glycolytic metabolism to mitochondrial oxidative phosphorylation, which provoked characteristic mitochondrial fragmentation and depolarization and induced a distinct transcriptional signature. Pharmacological MFN activation of metabolically reprogrammed fibroblasts partially reversed the mitochondrial abnormalities in CMT2A and CMT1 and a subset of Parkinson's and Alzheimer's disease patients, implicating addressable mitochondrial dysdynamism in these illnesses.

Neurodegenerative Diseases

mitofusin

mitochondrial dynamics

Details

Title: Subtitle: Mitochondrial Phenotypes in Genetically Diverse Neurodegenerative Diseases and Their Response to Mitofusin Activation
Creators: Xiawei Dang - Center for Pharmacogenomics, Department of Internal Medicine, Washington University School of Medicine, 660 S. Euclid Ave, St. Louis, MO 63110, USA
Emily K Walton - Center for Pharmacogenomics, Department of Internal Medicine, Washington University School of Medicine, 660 S. Euclid Ave, St. Louis, MO 63110, USA
Barbara Zablocka - Polish Academy of Sciences
Robert H Baloh - Cedars-Sinai Medical Center
Michael E Shy - University of Iowa
Gerald W Dorn II - Center for Pharmacogenomics, Department of Internal Medicine, Washington University School of Medicine, 660 S. Euclid Ave, St. Louis, MO 63110, USA
Resource Type: Journal article
Publication Details: Cells (Basel, Switzerland), Vol.11(6), p.1053
DOI: 10.3390/cells11061053
PMID: 35326504
PMCID: PMC8947610
NLM abbreviation: Cells
eISSN: 2073-4409
Grant note: R35135736 / NIH HHS Research Grant / Muscular Dystrophy Association R42NS115184 / NIH HHS
Language: English
Date published: 03/21/2022
Academic Unit: Neurology; Molecular Physiology and Biophysics; Stead Family Department of Pediatrics; Iowa Neuroscience Institute
Record Identifier: 9984229997302771

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