Desmin mutations result in mitochondrial dysfunction regardless of their aggregation properties

Area of Science:

• Muscle biology
• Cellular pathology
• Mitochondrial research

Background:

• Desmin is crucial for muscle cell structure and mitochondrial stability.
• Desmin mutations are linked to skeletal myopathies with mitochondrial issues.
• Mutations are classified by their tendency to form aggregates.

Purpose of the Study:

• To investigate how different desmin mutant isoforms impact mitochondria and myocyte function.
• To compare the effects of aggregate-prone versus non-aggregate-prone desmin mutations.

Main Methods:

• Expression of six pathogenic desmin mutations (two non-aggregate-prone, four aggregate-prone) in skeletal muscle cells.
• Analysis of mitochondrial network morphology, respiration, membrane potential, and ADP/ATP ratio.
• Assessment of mitochondrial DNA (mtDNA) release and exosomal secretion.

Main Results:

• All tested desmin mutations impaired mitochondrial network morphology and function.
• Mitochondrial respiration, membrane potential, and ADP/ATP ratio were negatively affected by all mutations.
• Mitochondrial DNA (mtDNA) release was enhanced, with partial exosomal secretion observed.
• Mitochondrial dysfunction occurred irrespective of aggregation propensity, but aggregate-prone mutations showed a more severe phenotype.

Conclusions:

• Mitochondrial dysfunction and mtDNA release are key in desmin myopathy pathogenesis.
• The aggregation capacity of desmin mutations influences disease severity but not the fundamental mechanism of mitochondrial impairment.
• This study confirms the critical role of mitochondrial health in desmin-related skeletal myopathies.