In vitro studies in VCP-associated multisystem proteinopathy suggest altered mitochondrial bioenergetics

Area of Science:

• Cell Biology
• Neuroscience
• Mitochondrial Biology

Background:

• Mitochondrial dysfunction is linked to neurodegenerative diseases like Parkinson's, Alzheimer's, and ALS.
• Valosin-containing protein (VCP)-associated multisystem proteinopathy (MSP) is a hereditary disorder involving myopathy, Paget's disease of bone, frontotemporal dementia, and ALS.
• VCP plays a role in cellular pathways including autophagy, apoptosis, and mitophagy.

Purpose of the Study:

• To characterize mitochondrial dynamics and bioenergetics in VCP patient and mouse fibroblasts and myoblasts.
• To investigate the impact of VCP mutations on cellular energy production and mitochondrial function.

Main Methods:

• Utilized Seahorse XF-24 technology to analyze mitochondrial respiration and glycolysis.
• Assessed ATP levels, membrane potential, and mitochondrial enzyme complex activities (II+III, IV) in VCP fibroblasts and myoblasts.
• Compared VCP patient-derived cells with age- and sex-matched healthy controls.

Main Results:

• VCP fibroblasts exhibited reduced spare respiratory capacity, increased extracellular acidification rate (ECAR), and elevated proton leak compared to controls.
• VCP myoblasts showed decreased ATP levels and membrane potential.
• Mitochondrial enzyme complexes II+III and IV activities were higher in VCP myoblasts than in control cell lines, suggesting a compensatory response.

Conclusions:

• Mutations in VCP disrupt mitochondrial ATP production, triggering compensatory increases in mitochondrial complex activity.
• This study establishes a novel in vitro model for VCP-related multisystem proteinopathies.
• The model may aid in understanding disease pathophysiology and identifying therapeutic targets for mitochondrial dysfunction in VCP and related disorders.