Plectin isoform P1b and P1d deficiencies differentially affect mitochondrial morphology and function in skeletal muscle
Winter L, Kuznetsov AV, Grimm M, Zeoeld A, Fischer I, Wiche G (2015)
Publication Type: Journal article
Publication year: 2015
Journal
Book Volume: 24
Pages Range: 4530-44
Journal Issue: 16
DOI: 10.1093/hmg/ddv184
Abstract
Plectin, a versatile 500-kDa cytolinker protein, is essential for muscle fiber integrity and function. The most common disease caused by mutations in the human plectin gene, epidermolysis bullosa simplex with muscular dystrophy (EBS-MD), is characterized by severe skin blistering and progressive muscular dystrophy. Besides displaying pathological desmin-positive protein aggregates and degenerative changes in the myofibrillar apparatus, skeletal muscle specimens of EBS-MD patients and plectin-deficient mice are characterized by massive mitochondrial alterations. In this study, we demonstrate that structural and functional alterations of mitochondria are a primary aftermath of plectin deficiency in muscle, contributing to myofiber degeneration. We found that in skeletal muscle of conditional plectin knockout mice (MCK-Cre/cKO), mitochondrial content was reduced, and mitochondria were aggregated in sarcoplasmic and subsarcolemmal regions and were no longer associated with Z-disks. Additionally, decreased mitochondrial citrate synthase activity, respiratory function and altered adenosine diphosphate kinetics were characteristic of plectin-deficient muscles. To analyze a mechanistic link between plectin deficiency and mitochondrial alterations, we comparatively assessed mitochondrial morphology and function in whole muscle and teased muscle fibers of wild-type, MCK-Cre/cKO and plectin isoform-specific knockout mice that were lacking just one isoform (either P1b or P1d) while expressing all others. Monitoring morphological alterations of mitochondria, an isoform P1b-specific phenotype affecting the mitochondrial fusion-fission machinery and manifesting with upregulated mitochondrial fusion-associated protein mitofusin-2 could be identified. Our results show that the depletion of distinct plectin isoforms affects mitochondrial network organization and function in different ways.
Involved external institutions
Austria (AT)How to cite
APA:
Winter, L., Kuznetsov, A.V., Grimm, M., Zeoeld, A., Fischer, I., & Wiche, G. (2015). Plectin isoform P1b and P1d deficiencies differentially affect mitochondrial morphology and function in skeletal muscle. Human Molecular Genetics, 24(16), 4530-44. https://doi.org/10.1093/hmg/ddv184
MLA:
Winter, Lilli, et al. "Plectin isoform P1b and P1d deficiencies differentially affect mitochondrial morphology and function in skeletal muscle." Human Molecular Genetics 24.16 (2015): 4530-44.
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