Abstract
Mitochondrial diseases disrupt cellular energy production and are among the most complex group of inherited genetic disorders. Affecting approximately 1 in 5000 live births, they are both clinically and genetically heterogeneous, and can be highly tissue specific, but most often affect cell types with high energy demands in the brain, heart, and kidneys. There are currently no clinically validated treatment options available, despite several agents showing therapeutic promise. However, modelling these disorders is challenging as many non-human models of mitochondrial disease do not completely recapitulate human phenotypes for known disease genes. Additionally, access to disease-relevant cell or tissue types from patients is often limited. To overcome these difficulties, many groups have turned to human pluripotent stem cells (hPSCs) to model mitochondrial disease for both nuclear-DNA (nDNA) and mitochondrial-DNA (mtDNA) contexts. Leveraging the capacity of hPSCs to differentiate into clinically relevant cell types, these models permit both detailed investigation of cellular pathomechanisms and validation of promising treatment options. Here we catalogue hPSC models of mitochondrial disease that have been generated to date, summarise approaches and key outcomes of phenotypic profiling using these models, and discuss key criteria to guide future investigations using hPSC models of mitochondrial disease.
Highlights
Much more than just “the powerhouse of the cell”, mitochondria handle critically important biochemical processes including cell signalling, iron-sulfur (Fe/S)cluster biogenesis, apoptosis, and calcium homeostasis [1,2]
We have focused on mitochondrial diseases for which multiple human pluripotent stem cells (hPSCs) cell lines have been reported, with similar findings uncovered from the various publications
It is clear from the publications highlighted here that hPSC models of mitochondrial disease recapitulate key aspects of human disease phenotypes in vitro and provide tissue specific insights into disease pathomechanisms
Summary
Much more than just “the powerhouse of the cell”, mitochondria handle critically important biochemical processes including cell signalling, iron-sulfur (Fe/S). One of the most complex groups of inherited genetic conditions, they can result from mutations in either nuclear (nDNA) or mitochondrial DNA (mtDNA). The ratio of mutant to wild type mtDNA (i.e., heteroplasmy) that leads to disease can be both cell type and mutation specific [11,12]. Available patient cell lines such as fibroblasts do not always display disease phenotypes [21], and accessing disease relevant tissues from patients can be difficult or limited. These efforts have been further compounded by the inability of some non-human model systems to recapitulate the human phenotypes for certain key disease genes [22]. With a relative lack of non-human models amenable to high-throughput screening approaches, human pluripotent stem cell (hPSC) models of mitochondrial disease offer a promising alternative as a drug discovery platform [3]
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