# Variant load of mitochondrial DNA in single human mesenchymal stem cells

## TL;DR

This study shows that human mesenchymal stem cells contain harmful mitochondrial DNA variants, which may contribute to osteoporosis.

## Contribution

The study is the first to identify pathogenic somatic mtDNA variants in human mesenchymal stem cells.

## Key findings

- Somatic heteroplasmic mtDNA variants are present in individual patient-derived MSCs.
- These variants can reach high heteroplasmic fractions and may be pathogenic.
- Mitochondrial dysfunction in MSCs could contribute to osteoporosis development.

## Abstract

Heteroplasmic mitochondrial DNA (mtDNA) variants accumulate as humans age, particularly in the stem-cell compartments, and are an important contributor to age-related disease. Mitochondrial dysfunction has been observed in osteoporosis and somatic mtDNA pathogenic variants have been observed in animal models of osteoporosis. However, this has never been assessed in the relevant human tissue. Mesenchymal stem cells (MSCs) are the progenitors to many cells of the musculoskeletal system and are critical to skeletal tissues and bone vitality. Investigating mtDNA in MSCs could provide novel insights into the role of mitochondrial dysfunction in osteoporosis. To determine if this is possible, we investigated the landscape of somatic mtDNA variation in MSCs through a combination of fluorescence-activated cell sorting and single-cell next-generation sequencing. Our data show that somatic heteroplasmic variants are present in individual patient-derived MSCs, can reach high heteroplasmic fractions and have the potential to be pathogenic. The identification of somatic heteroplasmic variants in MSCs of patients highlights the potential for mitochondrial dysfunction to contribute to the pathogenesis of osteoporosis.