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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.

Recombinant human mitochondrial transcription factor A protein (rhTFAM) was evaluated for its acute effects on cultured cells and chronic effects in mice. Fibroblasts incubated with rhTFAM acutely increased respiration in a chloramphenicol-sensitive manner. SH-SY5Y cells showed rhTFAM concentration-dependent reduction of methylpyridinium (MPP + )-induced oxidative stress and increases in lowered ATP levels and viability. Mice treated with weekly i.v. rhTFAM showed increased mitochondrial gene copy number, complex I protein levels and ATP production rates; oxidative damage to proteins was decreased ~50%. rhTFAM treatment improved motor recovery rate after treatment with MPTP and dose-dependently improved survival in the lipopolysaccharide model of endotoxin sepsis.

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Mitochondrial function declines with age in postmitotic tissues such as brain, heart and skeletal muscle. Despite weekly exercise, aged mice showed substantial losses of mtDNA gene copy numbers and reductions in mtDNA gene transcription and mitobiogenesis signaling in brain and heart. We treated these mice with weekly intravenous injections of recombinant human mitochondrial transcription factor A (rhTFAM). RhTFAM treatment for one month increased mitochondrial respiration in brain, heart and muscle, POLMRT expression and mtDNA gene transcription in brain, and PGC-1 alpha mitobiogenesis signaling in heart. RhTFAM treatment reduced oxidative stress damage to brain proteins, improved memory in Morris water maze performance and increased brain protein levels of BDNF and synapsin. Microarray analysis showed co-expression of multiple Gene Ontology families in rhTFAM-treated aged brains compared to young brains. RhTFAM treatment reverses age-related memory impairments associated with loss of mitochondrial energy production in brain, increases levels of memory-related brain proteins and improves mitochondrial respiration in brain and peripheral tissues.