Abstract
Mitochondria are specialized organelles involved in energy production that have retained their own genome throughout evolutionary history. The mitochondrial genome (mtDNA) is maternally inherited and requires coordinated regulation with nuclear genes to produce functional enzyme complexes that drive energy production. Each mitochondrion contains 5–10 copies of mtDNA and consequently, each cell has several hundreds to thousands of mtDNAs. Due to the presence of multiple copies of mtDNA in a mitochondrion, mtDNAs with different variants may co-exist, a condition called heteroplasmy. Heteroplasmic variants can be clonally expanded, even in post-mitotic cells, as replication of mtDNA is not tied to the cell-division cycle. Heteroplasmic variants can also segregate during germ cell formation, underlying the inheritance of some mitochondrial mutations. Moreover, the uneven segregation of heteroplasmic variants is thought to underlie the heterogeneity of mitochondrial variation across adult tissues and resultant differences in the clinical presentation of mitochondrial disease. Until recently, however, the mechanisms mediating the relation between mitochondrial genetic variation and disease remained a mystery, largely due to difficulties in modeling human mitochondrial genetic variation and diseases. The advent of induced pluripotent stem cells (iPSCs) and targeted gene editing of the nuclear, and more recently mitochondrial, genomes now provides the ability to dissect how genetic variation in mitochondrial genes alter cellular function across a variety of human tissue types. This review will examine the origins of mitochondrial heteroplasmic variation and propagation, and the tools used to model mitochondrial genetic diseases. Additionally, we discuss how iPSC technologies represent an opportunity to advance our understanding of human mitochondrial genetics in disease.
Highlights
Mitochondria are double membrane-bound organelles residing ubiquitously in the cells of eukaryotic organisms
Through the use of gene-editing technologies, induced pluripotent stem cells (iPSCs)-derived cells facilitate the exploration of the mechanisms of mitochondrial genetic disease, allowing for the identification of causal relationships between mitochondrial genetic variants and cellular phenotype to drive the identification of novel therapeutics
The differences between animals and humans have raised the question: how do we effectively study mitochondrial mutations of unknown significance in a human genetic background on cell function? Historically, cybrids have been generated using human cell lines depleted of their mitochondrial DNA (mtDNA) with ethidium bromide and repopulated with mitochondria through the fusion of an enucleated cell containing the mtDNA of interest. [55,58] Cybrid cell lines have provided insights into the contribution of mitochondrial genetic variants to cellular phenotypes; the cell types utilized to generate cybrids are restricted to cancer cell lines, typically osteosarcoma cells, which already have an abnormal metabolic phenotype, very different from that of non-cancerous cells [55,58,59]
Summary
Mitochondria are double membrane-bound organelles residing ubiquitously in the cells of eukaryotic organisms. Highlighting the co-evolution of mitochondria and eukaryotic cells, the OXPHOS enzyme subunits are encoded by both the mitochondrial DNA (mtDNA) and nuclear. Patients with mitochondrial disease often have different distributions of the pathogenic heteroplasmic variant across tissues, which likely drives the phenotypic presentation. The number of mtDNA copies with the heteroplasmic variant varies widely across mitochondria and cells, as well as varying across tissue types. The advent of generation and ultra-deep sequencing has increased our ability to detect low level heteroplasmic mtDNA variants and comprehensively evaluate mitochondrial genetic variation across both genomes simultaneously. Through the use of gene-editing technologies, iPSC-derived cells facilitate the exploration of the mechanisms of mitochondrial genetic disease, allowing for the identification of causal relationships between mitochondrial genetic variants and cellular phenotype to drive the identification of novel therapeutics
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