Multiple Molecular Mechanisms Rescue mtDNA Disease in C. elegans

Abstract

SUMMARYGenetic instability of the mitochondrial genome (mtDNA) plays an important role in human aging and disease. Thus far, it has proven difficult to develop successful treatment strategies for diseases that are caused by mtDNA instability. To address this issue, we developed a model of mtDNA disease in the nematode C. elegans, an animal model that can rapidly be screened for genes and biological pathways that reduce mitochondrial pathology. These worms recapitulate all the major hallmarks of mtDNA disease in humans, including increased mtDNA instability, loss of respiration, reduced neuromuscular function, and a shortened lifespan. We found that these phenotypes could be rescued by intervening in numerous biological pathways, including IGF-1/insulin signaling, mitophagy, and the mitochondrial unfolded protein response, suggesting that it may be possible to ameliorate mtDNA disease through multiple molecular mechanisms.

Mitochondrially-targeted APOBEC1 is a potent mtDNA mutator affecting mitochondrial function and organismal fitness in Drosophila

“…However, the mutational heterogeneity that arises in this model, which includes point mutations as well as small indels, large deletions, and mtDNA depletion, has led to considerable debate about the pathogenic entity and whether point mutations are actually driving ageing 11–14 . Recently described fly and worm POLG mtDNA mutators, which offer an attractive system for their powerful genetic approaches, also show evidence of this mutational heterogeneity 15,16,33 . However, while the first fly model equivalent to the POLG- mutator was homozygous lethal 15 , a similar model recently reported is not lethal 16 , raising uncertainty about the cause of the lethality.…”

Deleterious mitochondrial DNA point mutations are overrepresented in Drosophila expressing a proofreading-defective DNA polymerase γ

“…Work in the nematode C . elegans has also shown that autophagy is required for the elimination of radiation-induced mtDNA damage [49], and that inactivation of the mitophagy-promoting factor Parkin results in increased abundance of point mutations in a mitochondrial mutator background and increased abundance of a deleterious mtDNA deletion when the mitochondrial unfolded protein stress pathway is activated [50–52]. Overexpression of autophagy-promoting factors in Drosophila also reduced the frequency of a heteroplasmic deletion created by expression of a mitochondrially-targeted restriction endonuclease [53].…”

“…However, reducing the activity of PINK1 and Parkin in an otherwise WT C . elegans genetic background did not significantly influence the frequency of point mutations or a large mtDNA deletion, suggesting that this pathway does not ordinarily select against deleterious mtDNA mutations [50–52]. Moreover, mutator mice do not exhibit an altered NS/S mutation ratio relative to WT mice [20, 26, 55], and mutator mice lacking the mitophagy-promoting factor Parkin do not exhibit an increased mtDNA mutation frequency or an altered NS/S mutation ratio relative to mutator mice [26].…”

Age‐induced mitochondrial DNA point mutations are inadequate to alter metabolic homeostasis in response to nutrient challenge

“…Normal chow‐fed postabsorptive mice showed increased muscle mtDNA copy number at ages 6 and 12 months which is suggestive of increased mtDNA replication or reduced mitophagic flux, or both. These data are in contrast to the mtDNA depletion phenotype of the PolG mut/mut mouse and polg‐1(srh1) C. elegans in which copy number was reduced > 50% (Haroon et al., 2018; Trifunovic et al, 2004; Vermulst et al., 2008). Moreover, in contrast to PolG mut/mut , PolG +/mut mice showed no change in mtDNA replication capacity (He, Shumate, White, Molineux, & Yin, 2013); therefore, increased mitochondrial DNA replication is a possible mechanism of compensation to elevate the abundance of healthy DNA in muscle of PolG +/mut mice.…”