Thomas 2016 Neurodegeneration Therapeutics

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Thomas RR, Keeney PM, Berr SB, Khan SM, Portell FR, Shakenov MZ, Antkowiak PF, Kundu B, Tustison N, Brohawn DG, Bennett JP (2016) Recombinant human TFAM stimulates rat brain, rat cervical spinal cord and human neural stem cell mitochondrial bioenergetics. Neurodegeneration Therapeutics p41.

» Open Access

Thomas RR, Keeney PM, Berr SB, Khan SM, Portell FR, Shakenov MZ, Antkowiak PF, Kundu B, Tustison N, Brohawn DG, Bennett JP (2016) Neurodegeneration Therapeutics

Abstract: To develop a treatment for human mitochondrial diseases, we engineered a recombinant human mitochondrial transcription factor A (rhTFAM) that enters brain mitochondria of animals, rapidly localizes to mitochondria of human cells and increases mitochondrial respiration and OXPHOS capacity in human cells and animals. As part of developing rhTFAM for use in humans, we treated rats with single or weekly i.v. injections of highly purified rhTFAM protein and assayed brain [18F]fluorodeoxyglucose (FDG) uptake by PET scan, forebrain mitochondrial states 3 and 4 respiration, forebrain and cervical spinal cord mitochondrial respiratory gene expression and forebrain and cervical spinal cord OXPHOS protein levels. rhTFAM treatments increased mitochondrial OXPHOS function in brain and spinal cord. Total brain FDG uptake did not change, but the rate of FDG uptake appeared to increase in the rhTFAM treated animals. Human neural stem cells (NSC’s) exposed to 5 nM rhTFAM and analyzed by RNA-seq showed increased expression of mitochondrial respiratory genes. 3-D gene expression visualization (Miru®) followed by protein interaction network analysis (STRING) revealed enrichment after rhTFAM in mRNA splicing and ribosome functions. Ingenuity Pathways Analysis showed significant overrepresentation in E2F/E2F1 signaling that can modulate mitochondrial gene expression. rhTFAM treatment could overcome mitochondrial bioenergetic deficits reported in various human neurodegenerative conditions as well as in many “mitochondrial” diseases affecting multiple organ systems and may use E2F signaling.

Keywords: Mitochondria, Respiration, Brain, Spinal cord, Neural stem cells, TFAM, FDG-PET

O2k-Network Lab: US VA Richmond Bennett JP, US VA Richmond Iyer S


Labels: MiParea: Respiration, mt-Medicine, Pharmacology;toxicology 

Stress:Mitochondrial disease  Organism: Rat  Tissue;cell: Nervous system  Preparation: Isolated mitochondria  Enzyme: Complex I, Complex II;succinate dehydrogenase, Complex III, Complex IV;cytochrome c oxidase, Complex V;ATP synthase 

Coupling state: LEAK, OXPHOS  Pathway: N, S, CIV  HRR: Oxygraph-2k 

2016-08