Abstract
The mitochondrion is the only organelle in the human cell, besides the nucleus, with its own DNA (mtDNA). Since the mitochondrion is critical to the energy metabolism of the eukaryotic cell, it should be unsurprising, then, that a primary driver of cellular aging and related diseases is mtDNA instability over the life of an individual. The mutation rate of mammalian mtDNA is significantly higher than the mutation rate observed for nuclear DNA, due to the poor fidelity of DNA polymerase and the ROS-saturated environment present within the mitochondrion. In this review, we will discuss the current literature showing that mitochondrial dysfunction can contribute to age-related common diseases such as cancer, diabetes, and other commonly occurring diseases. We will then turn our attention to the likely role that mtDNA mutation plays in aging and senescence. Finally, we will use this context to develop a mathematical formula for estimating for the accumulation of somatic mtDNA mutations with age. This resulting model shows that almost 90% of non-proliferating cells would be expected to have at least 100 mutations per cell by the age of 70, and almost no cells would have fewer than 10 mutations, suggesting that mtDNA mutations may contribute significantly to many adult onset diseases.
Highlights
The mitochondrial organelle, a double-membraned organelle with its evolutionary origins in the eubacterial kingdom [1], is the central factor in the energy metabolism of the eukaryotic cell. It is responsible for the vast majority of the ATP produced in the cell (~90% under normal circumstances), which it produces through oxidative phosphorylation (OXPHOS) by way of a multi-subunit complex called the electron transport chain (ETC) [2]
We have shown that accumulating evidence strongly supports the hypothesis that aging is linked to mitochondrial damage, mainly due to the progressive accumulation of mutant mitochondria
Most individuals will acquire at least some deleterious mtDNA mutations over their lifetime, and many of the diseases that we associate with advanced age may be a direct consequence of this accumulated mutational load
Summary
The mitochondrial organelle, a double-membraned organelle with its evolutionary origins in the eubacterial kingdom [1], is the central factor in the energy metabolism of the eukaryotic cell. Most of the proteins required by the mitochondrion to both propagate itself as well as to maintain its vital biochemical functions are produced from genes located in the nuclear genome. Since human cells contain hundreds or even thousands of copies of mtDNA (with each cell containing different proportions of mutant and wild-type mtDNA), great variability in mtDNA occurs as humans age This may contribute significantly to the variability of common diseases. Since the first disease linked directly to an mtDNA mutation was discovered by Douglas Wallace in 1988 [5], more than 300 pathogenic mtDNA variants have been linked to various forms of primary mitochondrial dysfunction This makes a thorough discussion of each of these variants (much less the thousands of variants in nuclear mitochondrial genes) beyond the scope of this review. For the purposes of this review, we will focus primarily on a discussion of mtDNA mutations, how they are acquired, and how they may lead to disease in patients with common disease conditions
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