//Expanding Our Understanding of mtDNA Deletions

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Expanding Our Understanding of mtDNA Deletions

Expanding Our Understanding of mtDNA Deletions


Clonal expansion of mtDNA deletions compromises mitochondrial function in human disease and aging, but how deleterious mtDNA genomes propagate has remained unclear. In this issue (Gitschlag et al., 2016) and in a recent Nature publication, C. elegans studies implicate the mitochondrial unfolded protein response (UPRmt) and offer mechanistic insights into this process.

The first mitochondrial genetic defect identified was the large-scale mtDNA deletion, which remains a commonly identified cause of disease, accounting for ∼12% of adult mitochondrial disorders (Gorman et al., 2015). Large-scale mtDNA deletions due to nuclear defects affecting mtDNA maintenance may account for another 20% of mitochondrial disease cases. The formation and propagation of large-scale mtDNA deletions are therefore important biological and clinical questions. Two recent papers in Nature ( Lin et al., 2016) and in this issue of Cell Metabolism ( Gitschlag et al., 2016) shed some light on this question by using a Caenorhabditis elegans (C. elegans) strain harboring an mtDNA deletion.

A challenge of mtDNA genetics is the multi-copy nature of the mitochondrial genome in individual cells, such that both normal and mutant mtDNA molecules, including selfish genomes with no advantage for cellular fitness, coexist in a state known as “heteroplasmy.” mtDNA deletions are functionally recessive; high levels of heteroplasmy (>60%) are required before a biochemical phenotype appears. In human tissues, we also see a mosaic of cells with respiratory chain deficiency related to different levels of mtDNA deletion (Sciacco et al., 1994). Interestingly, cells with high levels of mtDNA deletions in muscle biopsies show evidence of mitochondrial proliferation (the so-called ragged red fibers; Figure 1), a compensatory mechanism likely triggered by mitochondrial dysfunction. In such circumstances, deleted mtDNA molecules in a given cell will have originated clonally from a single mutant genome (Brierley et al., 1998). This process is therefore termed “clonal expansion.”


  • Picard, M., Vincent, A.E. and Turnbull, D.M (2016). Expanding Our Understanding of mtDNA Deletions. Cell Metabolism, 24(1), 3-4.

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Peoples: | Places: | Topics: mtDNA Deletions and Ragged red fibers; | DNA Type: Autosomal DNA and mtDNA

2016-07-16T11:12:15+00:00 July 16th, 2016|