Abstract
Mitochondrial and nuclear genomes have to coevolve to ensure the proper functioning of the different mitochondrial complexes that are assembled from peptides encoded by both genomes. Mismatch between these genomes is believed to be strongly selected against due to the consequent impairments of mitochondrial functions and induction of oxidative stress. Here, we used a Drosophila model harboring an incompatibility between a mitochondrial tRNAtyr and its nuclear-encoded mitochondrial tyrosine synthetase to assess the cellular mechanisms affected by this incompatibility and to test the relative contribution of mitonuclear interactions and aging on the expression of impaired phenotypes. Our results show that the mitochondrial tRNA mutation caused a decrease in mitochondrial oxygen consumption in the incompatible nuclear background but no effect with the compatible nuclear background. Mitochondrial DNA copy number increased in the incompatible genotype but that increase failed to rescue mitochondrial functions. The flies harboring mismatch between nuclear and mitochondrial genomes had almost three times the relative mtDNA copy number and fifty percent higher rate of hydrogen peroxide production compared to other genome combinations at 25 days of age. We also found that aging exacerbated the mitochondrial dysfunctions. Our results reveal the tight interactions linking mitonuclear mismatch to mitochondrial dysfunction, mitochondrial DNA regulation, ROS production and aging.
Highlights
Dysfunctional mitochondria are thought to be a proximal mechanism for aging due to the dual role of mitochondria as a source and target of reactive oxygen species (ROS) associated with aging (Harman, 1972; Horan et al, 2012; Yun and Finkel, 2014)
Our results show that: (i) at 25 days old, a mitochondrial tRNA mutation expressed in two different nuclear backgrounds [combinations;Aut and;OreR] causes a decrease in oxygen consumption when mitochondrial respiration is supported by electron entrance at the level of complex I; (ii) at the same age, this decrease is alleviated upstream of complex III by an increase in respiration rate owing to the nuclear encoded mG3PDH in the mitonuclear combination;Aut; (iii) in the;OreR which harbors the incompatibility, a strong increase in mitochondrial DNA copy number was observed, leading to mtDNA excess which could indicate replication errors
It suggests that the mitochondrial tRNAtyr single nucleotide polymorphism (SNP) and the mitochondrial genome has an impact on oxygen consumption by mitochondria via the input of electrons through the electron transport system (ETS), but that this effect is more important in 25 days old flies
Summary
Dysfunctional mitochondria are thought to be a proximal mechanism for aging due to the dual role of mitochondria as a source and target of reactive oxygen species (ROS) associated with aging (Harman, 1972; Horan et al, 2012; Yun and Finkel, 2014). The oxidative phosphorylation (OXPHOS) process requires the proper assembly and function of the Effects of Mitonuclear Incompatiblity on the Mitochondrial Phenotype electron transport system (ETS) (Blier et al, 2001). The ETS consists of different complexes encoded by both the mitochondrial and the nuclear genomes (mtDNA and nuDNA, respectively) directly participating in electron transport and proton pumping (complexes I, III and IV) whilst complex V uses the created proton gradient to regenerate ATP. Harmful to macromolecules and believed to elicit oxidative stress associated to age-related diseases, ROS are important messengers inciting a retrograde (mitochondria to nucleus) response and modulate mitochondrial content and functions according to the cell requirements (Yun and Finkel, 2014; Shadel and Horvath, 2015). It is believed that replication errors, such as deletion of mtDNA are a major force driving aging and age-related diseases (Bai and Wong, 2005; Clay Montier et al, 2009; Stumpf and Copeland, 2011; DeBalsi et al, 2017; Kauppila et al, 2017)
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