RhTFAM treatment stimulates mitochondrial oxidative metabolism and improves memory in aged mice.
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.
Parkinson's Disease Center, Virginia Commonwealth University, Richmond, VA 23298, USA.
Ravindar R
RR
Thomas
Shaharyar M
SM
Khan
Rafal M
RM
Smigrodzki
Isaac G
IG
Onyango
Jameel
J
Dennis
Omer M
OM
Khan
Francisco R
FR
Portelli
James P
JP
Bennett
D000375:Aging; D000818:Animals; D015153:Blotting, Western; D019069:Cell Respiration / Q000187:drug effects; D004272:DNA, Mitochondrial / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects*; D006801:Humans; D018782:Maze Learning / Q000187:drug effects; D008568:Memory / Q000187:drug effects*; D051379:Mice; D008928:Mitochondria / Q000187:drug effects*; D024101:Mitochondrial Proteins / Q000494:pharmacology*; D060885:Multiplex Polymerase Chain Reaction; D020411:Oligonucleotide Array Sequence Analysis; D010085:Oxidative Phosphorylation / Q000187:drug effects; D011994:Recombinant Proteins / Q000494:pharmacology; D014157:Transcription Factors / Q000494:pharmacology*
D004272:DNA, Mitochondrial; D004268:DNA-Binding Proteins; D024101:Mitochondrial Proteins; D011994:Recombinant Proteins; C499631:TFAM protein, human; D014157:Transcription Factors