Mitochondrial Microheteroplasmy and a Theory of Aging and Age-Related Disease

Abstract

We implicate a recently described form of mitochondrial mutation, mitochondrial microheteroplasmy, as a candidate for the principal component of aging. Microheteroplasmy is the presence of hundreds of independent mutations in one organism, with each mutation usually found in 1-2% of all mitochondrial genomes. Despite the low abundance of single mutations, the vast majority of mitochondrial genomes in all adults are mutated. This mutational burden includes inherited mutations, de novo germline mutations, as well as somatic mutations acquired either during early embryonic development or later in adult life. We postulate that microheteroplasmy is sufficient to explain the pathomechanism of several age-associated diseases, especially in conditions with known mitochondrial involvement, such as diabetes (DM), cardiovascular disease, Parkinson's disease (PD), and Alzheimer's disease (AD) and cancer. The genetic properties of microheteroplasmy reconcile the results of disease models (cybrids, hypermutable PolG variants and mitochondrial toxins), with the relatively low levels of maternal inheritance in the aforementioned diseases, and provide an explanation of their delayed, progressive course.

Mitochondrial Gene Therapy Augments Mitochondrial Physiology in a Parkinson's Disease Cell Model

“…The causal involvement of mtDNA in the pathogenesis of sporadic PD at any stage remains controversial and will not be confirmed until abnormalities in mtDNAs from PD brains or neurons are shown to reproduce essential PD pathogenic events after expression in cells or animals. Unique mtDNA deletions in individual nigral neurons (Bender et al, 2006Krishnan et al, 2008;Reeve et al, 2008) or clustered heteroplasmic mutations in PD frontal cortex homogenates (Smigrodzki et al, 2004;Parker and Parks, 2005;Smigrodzki and Khan, 2005), although suggestive of mtDNA involvement in disease pathogenesis, are restricted logically to being compelling correlations. Although our findings demonstrate that mtDNA-derived biogenic deficiencies of cybrid cells expressing platelet mtDNAs of PD patients can be substantially improved, they do not demonstrate mtDNA causality for PD pathogenesis.…”

Cell and animal models of mtDNA biology: progress and prospects

“…A comprehensive discussion of sporadic neurodegenerative disease cybrid studies is beyond the scope of this review; those interested in a more detailed discussion of some of these data may wish to consult other reviews dealing with this subject (38,90,107,113,119). To nevertheless summarize the available data, a large number of fairly large studies using either human neuroblastoma (SH-SY5Y) or human teratocarcinoma (NT2) 0 cell backgrounds found that transfer of mtDNA from persons with Alzheimer disease generated cybrid cell lines manifesting reduced complex IV activity, increased oxidative stress, altered calcium homeostasis, mitochondrial depolarization, increased ␤-amyloid production, increased cytoplasmic cytochrome c levels, caspase 3 activation, altered intracellular stress responses, decreased mitochondrial movement, and enhanced susceptibility to exogenous ␤-amyloid exposure (10,13,17,27,29,38,54,86,88,100,115,122,125,127,128).…”

“…Third, a particular mtDNA sequence deviation may only prove phenotypically relevant when expressed against a particular nuclear DNA context. Fourth, it has recently become clear that microheteroplasmies are rampant throughout an individual's mtDNA (25,69,75,104,106,107). Important questions about this molecular phenomenon remain unanswered, such as whether these micro heteroplasmies are distributed evenly between the cells of a tissue or concentrated within a limited number of cells in a tissue and whether these mutations are inherited or somatically acquired (for review see Ref.…”

“…Important questions about this molecular phenomenon remain unanswered, such as whether these micro heteroplasmies are distributed evenly between the cells of a tissue or concentrated within a limited number of cells in a tissue and whether these mutations are inherited or somatically acquired (for review see Ref. 107).…”

Mitochondrial DNA Mutations May Contribute to Aging Via Cell Death Caused by Peptides that Induce CytochromecRelease

“…28 Error rates are modeled to increase exponentially with age (reflecting, for instance, mutagenesis arising from oxidative damage) consistent with the observed age-related exponential increase in mutation frequencies, 12 so that by 3 years of age normal nice have frequencies of point mutations of about 1 per 10 4 bp, as typically reported in aging. 31 Lethal mutations are modeled to arise randomly at a ratio of 1 per 16,000 nonpathogenic mutations. Biochemical fractionation of the cytochrome c releasing activity from mitochondria with elevated levels of mtDNA mutations indicates that it consists of a single factor (see Results), suggesting that it arises by mutagenesis of a unique target in the mitochondrial genome.…”