Desmin mutations result in mitochondrial dysfunction regardless of their aggregation properties

Smolina, Natalia; Khudiakov, Aleksandr; Knyazeva, Anastasia; Zlotina, Anna; Сухарева, К. С.; Кондратов, К. А.; Gogvadze, Vladimir; Zhivotovsky, Boris; Sejersen, Thomas; Kostareva, Anna

doi:10.1016/j.bbadis.2020.165745

Cited by 27 publications

(35 citation statements)

References 47 publications

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“…Kcnj13 (inward rectifier potassium channel 13) gene was used as the nuclear reference gene (nDNA). Primers sequences for murine mitochondrial fragment and Kcnj13 are given in a Table S1 [ 31 ]. SYBR + Low ROX PCR Master Mix (PK156L, Evrogen, Moscow, Russia) was used for RT-qPCR.…”

Section: Methodsmentioning

confidence: 99%

LMNA Mutations G232E and R482L Cause Dysregulation of Skeletal Muscle Differentiation, Bioenergetics, and Metabolic Gene Expression Profile

Ignatieva

Ivanova

Komarova

et al. 2020

Genes

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Laminopathies are a family of monogenic multi-system diseases resulting from mutations in the LMNA gene which include a wide range of neuromuscular disorders. Although lamins are expressed in most types of differentiated cells, LMNA mutations selectively affect only specific tissues by mechanisms that remain largely unknown. We have employed the combination of functional in vitro experiments and transcriptome analysis in order to determine how two LMNA mutations associated with different phenotypes affect skeletal muscle development and metabolism. We used a muscle differentiation model based on C2C12 mouse myoblasts genetically modified with lentivirus constructs bearing wild-type human LMNA (WT-LMNA) or R482L-LMNA/G232E-LMNA mutations, linked to familial partial lipodystrophy of the Dunnigan type and muscular dystrophy phenotype accordingly. We have shown that both G232E/R482L-LMNA mutations cause dysregulation in coordination of pathways that control cell cycle dynamics and muscle differentiation. We have also found that R482/G232E-LMNA mutations induce mitochondrial uncoupling and a decrease in glycolytic activity in differentiated myotubes. Both types of alterations may contribute to mutation-induced muscle tissue pathology.

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Section: Methodsmentioning

confidence: 99%

LMNA Mutations G232E and R482L Cause Dysregulation of Skeletal Muscle Differentiation, Bioenergetics, and Metabolic Gene Expression Profile

Ignatieva

Ivanova

Komarova

et al. 2020

Genes

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“…Furthermore, the presence of DES mutations impaired the energetic state of skeletal muscle cells: reduced mitochondrial membrane potential, suppressed parameters of mitochondrial respiration, and increased ADP/ATP ratio, which means that the mitochondria were unable to convert effectively ADP molecules to ATP. In the other work, aggregate-prone desmin mutations were shown to suppress mitochondrial calcium uptake, presumably via the loss of desmin-mitochondria interactions due to aggregate accumulation [ 102 , 103 ].…”

Section: Mitochondrial Dysfunction In Specific Neuromuscular Disordersmentioning

confidence: 99%

Skeletal Muscle Mitochondria Dysfunction in Genetic Neuromuscular Disorders with Cardiac Phenotype

Ignatieva

Smolina

Kostareva

et al. 2021

IJMS

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Mitochondrial dysfunction is considered the major contributor to skeletal muscle wasting in different conditions. Genetically determined neuromuscular disorders occur as a result of mutations in the structural proteins of striated muscle cells and therefore are often combined with cardiac phenotype, which most often manifests as a cardiomyopathy. The specific roles played by mitochondria and mitochondrial energetic metabolism in skeletal muscle under muscle-wasting conditions in cardiomyopathies have not yet been investigated in detail, and this aspect of genetic muscle diseases remains poorly characterized. This review will highlight dysregulation of mitochondrial representation and bioenergetics in specific skeletal muscle disorders caused by mutations that disrupt the structural and functional integrity of muscle cells.

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“…On the other hand, Rac1 and its effector PAK1 can phosphorylate vimentin at mitochondrial binding sites which leads to the release of mitochondria, which then gain a higher motility and lower mitochondrial membrane potential (Matveeva et al, 2015). A recent study also revealed that mutations in another intermediate filament protein, desmin, causes mitochondrial dysfunction and alterations in mitochondrial network morphology although the underlying molecular mechanisms are still unclear (Smolina et al, 2020). It would be interesting to investigate how MTs, actin and intermediate filaments coordinate their functions to ensure proper mitochondria dynamics and positioning.…”

Section: The Influence Of the Cytoskeleton On Mitochondria Dynamicsmentioning

confidence: 99%

Complex Interactions Between Membrane-Bound Organelles, Biomolecular Condensates and the Cytoskeleton

Koppers

Özkan

Farı́as

2020

Front. Cell Dev. Biol.

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Membrane-bound and membraneless organelles/biomolecular condensates ensure compartmentalization into functionally distinct units enabling proper organization of cellular processes. Membrane-bound organelles form dynamic contacts with each other to enable the exchange of molecules and to regulate organelle division and positioning in coordination with the cytoskeleton. Crosstalk between the cytoskeleton and dynamic membrane-bound organelles has more recently also been found to regulate cytoskeletal organization. Interestingly, recent work has revealed that, in addition, the cytoskeleton and membrane-bound organelles interact with cytoplasmic biomolecular condensates. The extent and relevance of these complex interactions are just beginning to emerge but may be important for cytoskeletal organization and organelle transport and remodeling. In this review, we highlight these emerging functions and emphasize the complex interplay of the cytoskeleton with these organelles. The crosstalk between membrane-bound organelles, biomolecular condensates and the cytoskeleton in highly polarized cells such as neurons could play essential roles in neuronal development, function and maintenance.

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Desmin mutations result in mitochondrial dysfunction regardless of their aggregation properties

Cited by 27 publications

References 47 publications

LMNA Mutations G232E and R482L Cause Dysregulation of Skeletal Muscle Differentiation, Bioenergetics, and Metabolic Gene Expression Profile

LMNA Mutations G232E and R482L Cause Dysregulation of Skeletal Muscle Differentiation, Bioenergetics, and Metabolic Gene Expression Profile

Skeletal Muscle Mitochondria Dysfunction in Genetic Neuromuscular Disorders with Cardiac Phenotype

Complex Interactions Between Membrane-Bound Organelles, Biomolecular Condensates and the Cytoskeleton

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