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.
Highlights
Mitochondria perform a multitude of cellular activities that are essential for the life and death of cells, such as energy production in the form of ATP, cell respiration, fatty acid and amino acid metabolism and the regulation of various ions, in particular calcium
These analyses suggested that the mitochondrial alterations observed in MCK-Cre/cKO muscle were an early characteristic, rather than representing a late-onset secondary effect of plectin deficiency, with the severity of the observed phenotype drastically increasing with age
Our study indicates that plectin deficiency in skeletal muscle fibers leads to major alterations of various mitochondrial aspects, including changes in shape and network organization, deficits in respiratory functions and reduced overall content
Summary
Mitochondria perform a multitude of cellular activities that are essential for the life and death of cells, such as energy production in the form of ATP, cell respiration, fatty acid and amino acid metabolism and the regulation of various ions, in particular calcium. Plectin is a highly versatile protein acting as a mechanical linker between the intermediate filament (IF) network and various cytoskeletal structures and organelles, including the subplasma membrane skeleton, specialized junctional complexes, such as focal adhesions, desmosomes, hemidesmosomes, the neuromuscular junctions and junctional complexes of Schwann cells, Z-disks and the nuclear lamina. It mediates the crosstalk of IFs with the actin and microtubule cytoskeleton [5]. On a single cell level, plectin deficiency has been reported to lead to shape changes of mitochondria, manifesting as an elongation of mitochondrial networks in plectin-deficient fibroblasts [10] and myoblasts [11]
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