Abstract
The mitochondrial free radical theory of aging (mFRTA) implicates Reactive Oxygen Species (ROS)-induced mutations of mitochondrial DNA (mtDNA) as a major cause of aging. However, fifty years after its inception, several of its premises are intensely debated. Much of this uncertainty is due to the large range of values in the reported experimental data, for example on oxidative damage and mutational burden in mtDNA. This is in part due to limitations with available measurement technologies. Here we show that sample preparations in some assays necessitating high dilution of DNA (single molecule level) may introduce significant statistical variability. Adding to this complexity is the intrinsically stochastic nature of cellular processes, which manifests in cells from the same tissue harboring varying mutation load. In conjunction, these random elements make the determination of the underlying mutation dynamics extremely challenging. Our in silico stochastic study reveals the effect of coupling the experimental variability and the intrinsic stochasticity of aging process in some of the reported experimental data. We also show that the stochastic nature of a de novo point mutation generated during embryonic development is a major contributor of different mutation burdens in the individuals of mouse population. Analysis of simulation results leads to several new insights on the relevance of mutation stochasticity in the context of dividing tissues and the plausibility of ROS ”vicious cycle” hypothesis.
Highlights
Mitochondria are the main energy producing organelles present in eukaryotic cells
One of the predictions of the mitochondrial Free Radical Theory of Aging (mFRTA) is the possibility of reactive oxygen species (ROS) ‘vicious cycle’ (Figure 1), referring to the hypothesized positive feedback mechanism in which mitochondrial DNA (mtDNA) mutations cause an increase in the ROS production resulting in a higher de novo mutation rate [3]
In contrast to the original interpretation of the data, our analysis reveals that the existence of an exponential dynamics in point mutations cannot be inferred with certainty, and no contradiction between the observed point mutation dynamics and the apparent absence of evidence for elevated oxidative stress exists
Summary
Mitochondria are the main energy producing organelles present in eukaryotic cells. Mitochondria are the only organelles aside from the nucleus which harbor their own genetic material. Mitochondrial DNA (mtDNA) encodes a small number of polypeptides needed for the electron transfer chain (ETC). The ETC is responsible for cellular energy synthesis via oxidative phosphorylation (OXPHOS), during which some of the electrons leak from the ETC and are captured by oxygen to form reactive oxygen species (ROS) [1]. Mitochondrial DNA may be susceptible to such oxidative insult due to its proximity to the ROS production sites of the ETC [3]. Oxidative damage of mtDNA and its implications on cellular aging form the basis of the mitochondrial Free Radical Theory of Aging (mFRTA) [3]. One of the predictions of the mFRTA is the possibility of ROS ‘vicious cycle’ (Figure 1), referring to the hypothesized positive feedback mechanism in which mtDNA mutations cause an increase in the ROS production resulting in a higher de novo mutation rate [3]. Major challenges and questions with respect to the mFRTA have been summarized in some of the recent reviews [4,5]
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