Modulating mitochondrial DNA mutations: factors shaping heteroplasmy in the germ line and somatic cells

Tissue-specific heteroplasmy segregation is accompanied by a sharp mtDNA decline in Caenorhabditis elegans soma

“…Alternatively, the heteroplasmy levels may have diverged post-mitotically. 43 To differentiate between these two possibilities, we repeated the experiments in newly hatched L1 larvae that already have most neurons in place. 44 , 45 We found no significant difference in uaDf5 levels between the two tissues and their corresponding total somatic cell controls at L1 stage ( Figures 2 C and 2D, S1 , and S2 ).…”

Challenges and opportunities to bridge translational to clinical research for personalized mitochondrial medicine

“…This clinical complexity is further accentuated among patients with a maternally inherited mitochondrial disease caused by a mitochondrial pathogenic variant, which exist under a state of heteroplasmy [ 28 ]. This stems from the fact that not all the multi-copies of the mitochondrial DNA (mtDNAs) harbor a specific pathogenic mitochondrial variant, which results in variable ratios of mutant and wildtype mtDNAs within a cell.…”

“…As a result, the phenotypic expression of a maternally inherited mitochondrial disease is dictated by heteroplasmy, which may vary over time and among organs. Moreover, heteroplasmy of specific mitochondrial pathogenic variants can alter and dictate the time course of phenotypic manifestations among unrelated and related patients [ 28 ]. Patients with high heteroplasmic or near-homoplasmic pathogenic mitochondrial variants tend to exhibit an aggravated disease burden and progression, thereby easing the path making it more likely that a PMD diagnosis is considered and confirmed.…”

“…Another level of complexity resides at the level of the nuclear genome given that it encodes the majority of mitochondrial proteins resulting in tissue-specificity of the mitochondrial proteome [ [32] , [33] , [34] ] and modulation of the penetrance of heteroplasmic mitochondrial pathogenic variants [ 28 ]. Thus, the nuclear genome acts as a major influencer of mitochondrial genome via the nucleo-mitochondria anterograde signaling, lending credence to the concept that the nuclear background of patients in part manipulate the wide spectrum of clinical phenotypes and age of onset.…”

Multiple distinct evolutionary mechanisms govern the dynamics of selfish mitochondrial genomes

“…Moreover, although prior studies have implicated diverse mito-nuclear interactions in the selfish propagation of mitochondrial mutations, 26,29,32,34,36,41 as well as substantial variation in their phenotypic effects, 42,43 this work spans multiple species. 18,27,29 Because animal species vary widely in ways that affect mitochondrial genome biology, including nuclear genome composition, development and organization of the germline, and environmental context, 29,44 these numerous confounding factors have strongly limited our ability to draw general conclusions about the evolutionary dynamics of selfish mitochondrial genomes.…”