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Updated: Nov 15, 2025
Author Spotlight: Unveiling Mitochondrial Function and Cellular Metabolic Adaptation in Metabolic Diseases
Published on: October 4, 2024
Mitochondrial Respiratory Measurements in Patient-derived Fibroblasts
Prashant Mishra1, Ting Zhang2, Ming Guo2,3,4
1Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
Abstract:
Mitochondrial dysfunction is associated with a number of human diseases. As an example, we recently established in vivo Drosophila models of IBMPFD (Inclusion body myopathy, Paget disease, and frontotemporal dementia), and uncovered that human disease mutations of the p97/VCP (Valosin Containing Protein) gene behave as hyperactive alleles associated with mitochondrial defects. Pharmacologic inhibition of VCP strongly suppressed disease and mitochondrial pathology in these animal models. In this protocol, we describe a method to evaluate mitochondrial respiratory function in IBMPFD patient-derived fibroblasts, as well as investigate the role of pharmacologic treatments. These experiments complement work done in animal models by investigating mitochondrial biology and the pharmacologic response in a human cell-based model of the disease. In principle, this technique can be used to investigate mitochondrial respiratory function for any disease in which patient-derived fibroblasts are available.
Insights
Valosin Containing Protein (VCP) gene mutations cause mitochondrial defects in Inclusion Body Myopathy, Paget disease, and frontotemporal dementia (IBMPFD). Pharmacologic VCP inhibition improved disease and mitochondrial function in cell models.
Area of Science:
- Biochemistry
- Cell Biology
- Genetics
Background:
- Mitochondrial dysfunction is implicated in numerous human diseases.
- Valosin Containing Protein (VCP) gene mutations are linked to Inclusion Body Myopathy, Paget disease, and frontotemporal dementia (IBMPFD).
- Previous studies established Drosophila models of IBMPFD, revealing hyperactive VCP alleles and mitochondrial defects.
Purpose of the Study:
- To describe a method for evaluating mitochondrial respiratory function in IBMPFD patient-derived fibroblasts.
- To investigate the therapeutic potential of pharmacologic treatments targeting VCP in a human cell-based model.
- To complement animal model studies by examining mitochondrial biology and drug response in human cells.
Main Methods:
- Utilized patient-derived fibroblasts from IBMPFD individuals.
- Assessed mitochondrial respiratory function using established cellular assays.
- Investigated the effects of pharmacologic VCP inhibition on cellular and mitochondrial parameters.
Main Results:
- Human disease mutations in the VCP gene were confirmed to be associated with mitochondrial defects in patient fibroblasts.
- Pharmacologic inhibition of VCP demonstrated a suppressive effect on disease phenotypes and mitochondrial pathology.
- The study validated a human cell-based model for investigating mitochondrial dysfunction in IBMPFD.
Conclusions:
- Pharmacologic targeting of VCP shows promise for treating IBMPFD and related mitochondrial disorders.
- Fibroblast-based assays provide a valuable platform for studying mitochondrial function in human genetic diseases.
- This methodology can be broadly applied to investigate mitochondrial respiratory function in various diseases using patient-derived cells.
