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Powering Up Mitochondria Could Boost Military and Civilian Health

Discussion in 'Other Health News and Research' started by pattismith, Nov 2, 2017.

  1. pattismith

    pattismith Senior Member

    February/March 2017


    Liming Pei, PhD
    , and Douglas Wallace, PhD, of the Center for Mitochondrial and Epigenomic Medicine (CMEM) at Children’s Hospital of Philadelphia and Pathology and Laboratory Medicine at the Perelman School of Medicine at the University of Pennsylvania are now returning to the study of mitochondrial function in a military setting with a grant from the U.S. Army.

    Their powerful collaboration builds on the strength of both scientists’ labs. Dr. Pei specializes in the study of how mitochondrial genes are transcribed and function within the cell, and Dr. Wallace is an expert in mitochondrial genetics and mitochondrial diseases and a founder of the field of mitochondrial medicine.

    “Mitochondrial disease affects many parts of the body, and the parts most affected are the brain, heart, and skeletal muscles, because those parts of the body have a lot of mitochondria and use a lot of energy,” Dr. Pei said. “

    Their project could help improve mitochondrial function for the benefit of U.S. service members and their families, veterans, and civilians, including children and adults with mitochondrial diseases. Mitochondrial DNA is distinct from the DNA in the cell’s nucleus. Mitochondrial diseases are inherited conditions caused by a number of different mutations in mitochondrial DNA and in nuclear genes that are involved in the functions of mitochondria.

    Over the last few years, Dr. Pei identified a family of transcription factor proteins to be essential for the production of mitochondria and of proteins involved in energy generation in neurons (ERR gamma) and heart cells (ERR alpha and ERR gamma).

    “Our idea was that, if you increase the level of these particular proteins, that would cause the cell to make more mitochondria, and that might in fact then increase the energy output of the cell and make the cell healthier,” Dr. Pei said.

    While other efforts to develop therapies for mitochondrial diseases take a precision approach, Drs. Wallace and Pei aim to power up mitochondria broadly, regardless of the underlying mutation that might cause dysfunction or disease. This is a plausible option because patients with mitochondrial disease often have a combination of some damaged mitochondria and some healthy ones. If their method increases the number of healthy mitochondria or increases healthy proteins to aid the function of unhealthy mitochondria, the net effect could be improvements in energy production.

    If the principle proves successful, it opens the possibility that this type of method for boosting mitochondrial function could benefit many people with mitochondrial dysfunction, since mitochondrial defects are being associated with a broad range of common diseases such as diabetes, obesity, and neurological diseases. For military personnel and veterans, these approaches might ameliorate some of the negative effects of conflict toxicity such as exposure to Agent Orange and conditions such as Gulf War syndrome. Improving mitochondrial function could benefit people who are not sick — such as soldiers fighting in the mountains.

    from here
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  2. pattismith

    pattismith Senior Member

    PPARs and ERRs: molecular mediators of mitochondrial metabolism

    The nuclear receptors PPARs and ERRs have been shown to be key transcriptional factors in regulating mitochondrial oxidative metabolism and executing the inducible effects of PGC1α and NCOR1.
    A well-known inducer of mitochondrial oxidative metabolism is the peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α) [
    6], a nuclear cofactor which is abundantly expressed in high energy demand tissues such as heart, skeletal muscle, and brown adipose tissue (BAT) [7]. Induction by cold-exposure, fasting, and exercise allows PGC1α to regulate mitochondrial oxidative metabolism by activating genes involved in the tricarboxylic acid cycle (TCA cycle), beta-oxidation, oxidative phosphorylation (OXPHOS), as well as mitochondrial biogenesis.

    The effect of PGC1α on mitochondrial regulation is antagonized by transcriptional corepressors such as the nuclear receptor corepressor 1 (NCOR1) [
    9,10]. In contrast to PGC1α, the expression of NCOR1 is suppressed in conditions where PGC1α is induced such as during fasting, high-fat-diet challenge, and exercise [9,11]. Moreover, the knockout of NCOR1 phenotypically mimics PGC1α overexpression in regulating mitochondrial oxidative metabolism [9]. Therefore, coactivators and corepressors collectively regulate mitochondrial metabolism in a Yin-Yang fashion.

    PPARs: master executors controlling fatty acid oxidation
    Both PGC1α and NCOR1 are co-factors for the peroxisome proliferator-activated receptors (PPARα, γ, and δ) [7,11–13]. It is now clear that all three PPARs play essential roles in lipid and fatty acid metabolism by directly binding to and modulating genes involved in fat metabolism [13–19]. While PPARγ is known as a master regulator for adipocyte differentiation and does not seem to be involved with oxidative metabolism [14,20], both PPARα and PPARδ are essential regulators of fatty acid oxidation
    ERRS: master executors controlling mitochondrial OXPHOS
    ERRs are essential regulators of mitochondrial energy metabolism [4]. ERRα is ubiquitously expressed but particularly abundant in tissues with high energy demands such as brain, heart, muscle, and BAT. ERRβ and ERRγ have similar expression patterns, both are selectively expressed in highly oxidative tissues including brain, heart, and oxidative muscle [45]. Instead of endogenous ligands, the transcriptional activity of ERRs is primarily regulated by co-factors such as PGC1α and NCOR1 [4,46] (Figure 1).

    Of the three ERRs, ERRβ is the least studied and its role in regulating mitochondrial function is unclear [4,47]. In contrast, when PGC1α is induced, ERRα is the master regulator of the mitochondrial biogenic gene network. As ERRα binds to its own promoter, PGC1α can also induce an autoregulatory loop to enhance overall ERRα activity [48]. Without ERRα, the ability of PGC1α to induce the expression of mitochondrial genes is severely impaired. However, the basal-state levels of mitochondrial target genes are not affected by ERRα deletion, suggesting induced mitochondrial biogenesis is a transient process and that other transcriptional factors such as ERRγ may be important maintaining baseline mitochondrial OXPHOS [41•,42,43]. Consistent with this idea, ERRγ (which is active even when PGC1α is not induced) shares many target genes with ERRα [49,50]....


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