RhTFAM treatment stimulates mitochondrial oxidative metabolism and improves memory in aged mice

Thomas, Ravindar R.; Khan, Shaharyar M.; Smigrodzki, Rafal; Onyango, Isaac G.; Dennis, Jameel; Khan, Omer; Portelli, Francisco R; Bennett, James P.

doi:10.18632/aging.100488

Cited by 43 publications

(25 citation statements)

References 45 publications

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“…Similarly, Thomas et al . found that aging produced a marked 90% reduction in mtDNA copy number relative to the control group in the mouse brain (and to a lesser degree in the heart). Not only mtDNA levels but also mitochondrial biogenesis signaling, is substantially reduced in the aging brain and heart compared to the control group.…”

Section: Changes In the Mtdna Levels Or Tfam In Neurodegenerative Conmentioning

confidence: 95%

The mitochondrial transcription factor TFAM in neurodegeneration: emerging evidence and mechanisms

2018

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The mitochondrial transcription factor A, or TFAM, is a mitochondrial DNA (mtDNA)‐binding protein essential for genome maintenance. TFAM functions in determining the abundance of the mitochondrial genome by regulating packaging, stability, and replication. More recently, TFAM has been shown to play a central role in the mtDNA stress‐mediated inflammatory response. Emerging evidence indicates that decreased mtDNA copy number is associated with several aging‐related pathologies; however, little is known about the association of TFAM abundance and disease. In this Review, we evaluate the potential associations of altered TFAM levels or mtDNA copy number with neurodegeneration. We also describe potential mechanisms by which mtDNA replication, transcription initiation, and TFAM‐mediated endogenous danger signals may impact mitochondrial homeostasis in Alzheimer, Huntington, Parkinson, and other neurodegenerative diseases.

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Section: Changes In the Mtdna Levels Or Tfam In Neurodegenerative Conmentioning

confidence: 95%

The mitochondrial transcription factor TFAM in neurodegeneration: emerging evidence and mechanisms

2018

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“…A recombinant form of human TFAM was designed, in which an exogenous amino-terminal domain allows rapid translocation across cell membranes, whereas its mitochondrial targeting signal stimulates mitochondrial uptake 147 . Treatment of aged mice with recombinant human TFAM stimulated oxidative metabolism and improved memory 148 . In addition, treatment of cells derived from patients with Leber’s hereditary optic neuropathy (LHON) and Leigh syndrome using recombinant human TFAM and non-mutated mtDNA restored mitochondrial biogenesis and respiration 149 .…”

Section: Pathways To Restore Mitochondrial Functionmentioning

confidence: 97%

Pharmacological approaches to restore mitochondrial function

Andreux

Houtkooper

Auwerx

2013

Nat Rev Drug Discov

330

279

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Mitochondrial dysfunction is not only a hallmark of rare inherited mitochondrial disorders, but is also implicated in age-related diseases, including those that affect the metabolic and nervous system, such as type 2 diabetes and Parkinson’s disease. Numerous pathways maintain and/or restore proper mitochondrial function, including mitochondrial biogenesis, mitochondrial dynamics, mitophagy, and the mitochondrial unfolded protein response. New and powerful phenotypic assays in cell-based models, as well as multicellular organisms, have been developed to explore these different aspects of mitochondrial function. Modulating mitochondrial function has therefore emerged as an attractive therapeutic strategy for a range of diseases, which has spurred active drug discovery efforts in this area.

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“…Additionally, SIRT3 (a major mitochondrial deacetylase) was increased post treatment. Increases in levels of mitochondrial electron transport chain subunits including complexes I & IV, ATP activity and reduced oxidative stress were found post treatment [141]. Increased delivery systems using TFAM may lead to enhanced functional components within mitochondria.…”

Section: Tfam Directed Therapeuticsmentioning

confidence: 99%

Mitochondrial pathways to cardiac recovery: TFAM

2016

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Mitochondrial dysfunction underlines a multitude of pathologies; however, studies are scarce that rescue the mitochondria for cellular resuscitation. Exploration into the protective role of mitochondrial Transcription factor A (TFAM) and its mitochondrial functions respective to cardiomyocyte death are in need of further investigation. TFAM is a gene regulator that acts to mitigate calcium mishandling and ROS production by wrapping around mitochondrial DNA (mtDNA) complexes. TFAM’s regulatory functions over serca2a, NFAT and Lon protease contribute to cardiomyocyte stability. Calcium and ROS dependent proteases, calpains and matrix metallo-proteinases (MMP’s) are abundantly found upregulated in the failing heart. TFAM’s regulatory role over ROS production and calcium mishandling leads to further investigation into the cardioprotective role of exogenous TFAM. In an effort to restabilize physiological and contractile activity of cardiomyocytes in HF models, we propose that TFAM-packed exosomes (TFAM-PE) will act therapeutically by mitigating mitochondrial dysfunction. Notably, this is the first mention of exosomal delivery of transcription factors in the literature. Here we elucidate the role of TFAM in mitochondrial rescue and focus on its therapeutic potential.

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RhTFAM treatment stimulates mitochondrial oxidative metabolism and improves memory in aged mice

Cited by 43 publications

References 45 publications

The mitochondrial transcription factor TFAM in neurodegeneration: emerging evidence and mechanisms

The mitochondrial transcription factor TFAM in neurodegeneration: emerging evidence and mechanisms

Pharmacological approaches to restore mitochondrial function

Mitochondrial pathways to cardiac recovery: TFAM

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