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Mitochondrial Dysfunction in the Pathophysiology of Alzheimer’s Disease
Published in Shamim I. Ahmad, Handbook of Mitochondrial Dysfunction, 2019
Mitochondrial biogenesis is regulated by the “master regulator” peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) which in turn activates different transcription factors, including nuclear respiratory factors 1 and 2 proteins (NRF-1 and NRF-2), estrogen-related receptor alpha (ERR-α) and mitochondrial transcription factor A (TFAM) [8,55,56]. NRF-1 and NRF-2 regulate transcription of nuclear and mitochondrial genes involved in OxPhos, electron transport (complex I–V), mtDNA transcription/replication, heme biosynthesis, protein import/assembly, ion channels, shuttles, and translation [57].
Mitochondrial dysfunction in age-related macular degeneration: melatonin as a potential treatment
Published in Expert Opinion on Therapeutic Targets, 2020
Saeed Mehrzadi, Karim Hemati, Russel J. Reiter, Azam Hosseinzadeh
Within mitochondria, melatonin stimulates the activity of SOD2; this effect may be mediated by regulation of SIRT3 activity [123]. SIRT3 is a member of the mammalian sirtuin family of proteins located in the mitochondrial matrix, which possess NAD+-dependent deacetylase activity. Due to its location, SIRT3 directly regulates a variety of mitochondrial processes including fatty acid and amino acid metabolism, ETC function, mitochondrial biogenesis and mitochondrial dynamics, mitochondrial mediated programmed cell death, and endogenous antioxidant defenses [124]. The binding of SIRT3 with SOD2 causes the deacetylation of lysine 122, 68, 53, and 89 which this leads to the elevation of SOD2 activity. Furthermore, interaction of SIRT3 with forkhead box O3a (FoxO3a) augments the transcription of FoxO3a-dependent antioxidant-encoding genes including SOD2 and catalase. Melatonin has been reported to increase the SIRT3 transcription through activating the peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α); PGC-1α is a critical downstream molecule of adenosine monophosphate (AMP)-activated protein kinase (AMPK), which plays an important role in the regulation of mitochondrial biogenesis and oxidative stress. The interaction of PGC-1α with the estrogen-related receptor alpha (ERRα), a well‐known mitochondrial regulator binding to the ERR‐binding element (ERRE), stimulates SIRT3 expression [125]. Therefore, melatonin enhances mitochondrial biogenesis and the deacetylation of mitochondrial anti-oxidative enzymes through activating AMPK-PGC-1α-SIRT3 signaling (Figure 1).
Targeting mitochondrial quality control for treating sarcopenia: lessons from physical exercise
Published in Expert Opinion on Therapeutic Targets, 2019
Anna Picca, Riccardo Calvani, Christiaan Leeuwenburgh, Hélio José Coelho-Junior, Roberto Bernabei, Francesco Landi, Emanuele Marzetti
The generation of new mitochondria is attained through the coordinated expression of nuclear and mitochondrial DNA encoded genes (Figure 1). The process is orchestrated by members of the peroxisome proliferator-activated receptor (PPAR) gamma coactivator-1 (PGC-1) family of transcriptional co-activators, namely PGC-1α and PGC-1β (reviewed in [18]). Their interaction with several transcription factors [i.e., nuclear respiratory factors 1 and 2 (NRF1 and NRF2), estrogen-related receptor alpha (ERRα), and the PPAR family of transcription factors] regulates the expression of mitochondrial proteins, including mitochondrial transcription factor A (TFAM) and B2 (TFB2M) (reviewed in [18]). Once synthesized, TFAM and TFB2M are imported into the mitochondrion where they serve important housekeeping activities [18]. Specifically, TFAM binds to mitochondrial DNA (mtDNA) either as a histone-like protein that unwinds and bends mtDNA or to specific non-coding regions (NCRs) [19]. Dysregulation of TFAM binding to NCRs has been indicated as a potential mechanism underlying the impairment of mitochondrial biogenesis in aged rat tissues, including the skeletal muscle [20]. Recent evidence also indicates that TFAM binds more avidly to oxidized D-loop regions, the major site of transcriptional regulation, and contributes to impairing mitochondrial function in the aged heart [21]. Whether such a mechanism plays a role in the setting of muscle aging is yet to be established.
Emerging data on improving response to hormone therapy: the role of novel targeted agents
Published in Expert Review of Anticancer Therapy, 2018
Another mechanism of hormone resistance may involve the substitution of the estrogen-related receptor-alpha (ERRα) for ER. In one preclinical study, genome-wide profiling of MCF-7 breast cancer cells was conducted. In cells resistant to tamoxifen and fulvestrant, inhibition of ERRα partially restored response to hormone therapy [5]. ERRα in patient tumor specimens correlated with increased tumor proliferation, increased p53 tumor expression, and decreased overall survival (OS).