Date Published: September 30, 2012
Publisher: Impact Journals LLC
Author(s): Ravindar R. Thomas, Shaharyar M. Khan, Rafal M. Smigrodzki, Isaac G. Onyango, Jameel Dennis, Omer M. Khan, Francisco R. Portell, James P. Bennett.
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.
Diseases of aging represent substantial socioeconomic burdens for modern societies that are increasingly composed of aged individuals. Aging in postmitotic tissues such as brain, heart and skeletal muscle increases risk of neurodegenerative diseases, cardiomyopathy with heart failure and sarcopenia, respectively. Overcoming these impairments would improve quality of life for aged individuals and markedly lessen burdens on caregivers and societies.
By using qPCR normalized to geometric means of three major housekeeping genes, we have shown that aging in exercised mice results in substantial losses of mtDNA gene copy numbers, mtDNA gene expression and mitobiogenesis signaling in brain and heart with minimal changes in skeletal muscle. We observed the greatest age-related losses of all categories of genes related to mitochondrial function in brain. If our findings reflect the consequences of the mitochondrial theory of aging, then brain is the most vulnerable post-mitotic tissue of those examined. Age-related losses of mitochondrial gene regulation in brain are profound, and compensatory mechanisms we uncovered are minimal. On a relative basis, the expression of mtDNA genes is increased relative to the loss of mtDNA gene copy numbers, but this is not sufficient to compensate.
All the procedures involving animals were carried out in accordance with NIH guidelines and approved by either the University of Virginia or Jackson Labs West Institutional Animal Care and Use Committee.