Mechanisms Controlling Mitochondrial Biogenesis and Respiration through the Thermogenic Coactivator PGC-1

Wu, Zhidan; Puigserver, Pere; Andersson, Ulf; Zhang, Chenyu; Adelmant, Guillaume; Mootha, Vamsi K.; Troy, Amy E.; Cinti, Saverio; Lowell, Bradford B.; Scarpulla, Richard C.; Spiegelman, Bruce M.

doi:10.1016/s0092-8674(00)80611-x

Cited by 3,562 publications

(3,108 citation statements)

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“…PGC‐1α serves as a master inducer of mitochondrial biogenesis through its co‐activation of nuclear respiratory factors (NRFs), which control the expression of nuclear genes encoding mitochondrial proteins (Wu et al ., 1999; Finck & Kelly, 2006). Using adipogenesis array, we previously reported that in HGPS adipocytes, PGC‐1α was the most severely downregulated gene among the 84 genes involved in energy metabolism (Xiong et al ., 2013).…”

Section: Resultsmentioning

confidence: 99%

“…PGC‐1α is a transcriptional coactivator and a central inducer of mitochondrial biogenesis (Wu et al ., 1999; Austin & St‐Pierre, 2012). Recent works have highlighted the role of PGC‐1α in balancing ROS in neurodegenerative disorders and aging by controlling both the induction of mitochondrial metabolism and the removal of its ROS by‐products (Austin & St‐Pierre, 2012).…”

Section: Discussionmentioning

confidence: 99%

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Methylene blue alleviates nuclear and mitochondrial abnormalities in progeria

et al. 2015

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SummaryHutchinson–Gilford progeria syndrome (HGPS), a fatal premature aging disease, is caused by a single‐nucleotide mutation in the LMNA gene. Previous reports have focused on nuclear phenotypes in HGPS cells, yet the potential contribution of the mitochondria, a key player in normal aging, remains unclear. Using high‐resolution microscopy analysis, we demonstrated a significantly increased fraction of swollen and fragmented mitochondria and a marked reduction in mitochondrial mobility in HGPS fibroblast cells. Notably, the expression of PGC‐1α, a central regulator of mitochondrial biogenesis, was inhibited by progerin. To rescue mitochondrial defects, we treated HGPS cells with a mitochondrial‐targeting antioxidant methylene blue (MB). Our analysis indicated that MB treatment not only alleviated the mitochondrial defects but also rescued the hallmark nuclear abnormalities in HGPS cells. Additional analysis suggested that MB treatment released progerin from the nuclear membrane, rescued perinuclear heterochromatin loss and corrected misregulated gene expression in HGPS cells. Together, these results demonstrate a role of mitochondrial dysfunction in developing the premature aging phenotypes in HGPS cells and suggest MB as a promising therapeutic approach for HGPS.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Methylene blue alleviates nuclear and mitochondrial abnormalities in progeria

et al. 2015

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“…Mitochondrial activity and other exercise‐induced phenotypic changes of skeletal muscle are controlled by the peroxisome proliferator‐activated receptor γ coactivator 1α (PGC‐1α). For example, PGC‐1α is a master regulator of mitochondrial biogenesis (Schreiber et al., 2004; Wu et al., 1999), mitochondrial function (Wu et al., 1999), mitochondrial dynamics (Cannavino et al., 2015), fatty acid oxidation (Hoeks et al., 2012), and anti‐oxidative processes (St‐Pierre et al., 2006). Interestingly, PGC‐1α levels are increased by exercise in muscle (Safdar et al., 2011) and PGC‐1α is considered to be a key player in mitochondrial changes induced by exercise (Safdar et al., 2011; Ventura‐Clapier, Mettauer, & Bigard, 2007).…”

Section: Introductionmentioning

confidence: 99%

PGC‐1α affects aging‐related changes in muscle and motor function by modulating specific exercise‐mediated changes in old mice

et al. 2017

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SummaryThe age‐related impairment in muscle function results in a drastic decline in motor coordination and mobility in elderly individuals. Regular physical activity is the only efficient intervention to prevent and treat this age‐associated degeneration. However, the mechanisms that underlie the therapeutic effect of exercise in this context remain unclear. We assessed whether endurance exercise training in old age is sufficient to affect muscle and motor function. Moreover, as muscle peroxisome proliferator‐activated receptor γ coactivator 1α (PGC‐1α) is a key regulatory hub in endurance exercise adaptation with decreased expression in old muscle, we studied the involvement of PGC‐1α in the therapeutic effect of exercise in aging. Intriguingly, PGC‐1α muscle‐specific knockout and overexpression, respectively, precipitated and alleviated specific aspects of aging‐related deterioration of muscle function in old mice, while other muscle dysfunctions remained unchanged upon PGC‐1α modulation. Surprisingly, we discovered that muscle PGC‐1α was not only involved in improving muscle endurance and mitochondrial remodeling, but also phenocopied endurance exercise training in advanced age by contributing to maintaining balance and motor coordination in old animals. Our data therefore suggest that the benefits of exercise, even when performed at old age, extend beyond skeletal muscle and are at least in part mediated by PGC‐1α.

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“…On the other hand, PGC1β expression also potentiates oxygen consumption with increased mitochondrial DNA copies and intracellular ATP levels. This can be explained because PGC1β is the coactivator of NRF1; it binds and activates mitochondrial transcription factor A (mtTFA) (Lelliott et al ., 2006; Vianna et al ., 2006), which directly regulates mitochondrial DNA replication (Wu et al ., 1999). In addition, we show that PGC1β expression slightly increases ROS formation in MM cells (Gomez de Cedron et al ., 2017).…”

Section: Discussionmentioning

confidence: 99%

PGC1β regulates multiple myeloma tumor growth through LDHA‐mediated glycolytic metabolism

Zhang

Chen

et al. 2018

Molecular Oncology

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Multiple myeloma (MM) is an incurable hematologic malignancy due to inevitable relapse and chemoresistance development. Our preliminary data show that MM cells express high levels of PGC1β and LDHA. In this study, we investigated the mechanism behind PGC1β‐mediated LDHA expression and its contribution to tumorigenesis, to aid in the development of novel therapeutic approaches for MM. Real‐time PCR and western blotting were first used to evaluate gene expression of PGC1β and LDHA in different MM cells, and then, luciferase reporter assay, chromatin immunoprecipitation, LDHA deletion report vectors, and siRNA techniques were used to investigate the mechanism underlying PGC1β‐induced LDHA expression. Furthermore, knockdown cell lines and lines stably overexpressing PGC1β or LDHA lentivirus were established to evaluate in vitro glycolysis metabolism, mitochondrial function, reactive oxygen species (ROS) formation, and cell proliferation. In addition, in vivo xenograft tumor development studies were performed to investigate the effect of PGC1β or LDHA expression on tumor growth and mouse survival. We found that PGC1β and LDHA are highly expressed in different MM cells and LDHA is upregulated by PGC1β through the PGC1β/RXRβ axis acting on the LDHA promoter. Overexpression of PGC1β or LDHA significantly potentiated glycolysis metabolism with increased cell proliferation and tumor growth. On the other hand, knockdown of PGC1β or LDHA largely suppressed glycolysis metabolism with increased ROS formation and apoptosis rate, in addition to suppressing tumor growth and enhancing mouse survival. This is the first time the mechanism underlying PGC1β‐mediated LDHA expression in multiple myeloma has been identified. We conclude that PGC1β regulates multiple myeloma tumor growth through LDHA‐mediated glycolytic metabolism. Targeting the PGC1β/LDHA pathway may be a novel therapeutic strategy for multiple myeloma treatment.

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Mechanisms Controlling Mitochondrial Biogenesis and Respiration through the Thermogenic Coactivator PGC-1

Cited by 3,562 publications

References 44 publications

Methylene blue alleviates nuclear and mitochondrial abnormalities in progeria

Methylene blue alleviates nuclear and mitochondrial abnormalities in progeria

PGC‐1α affects aging‐related changes in muscle and motor function by modulating specific exercise‐mediated changes in old mice

PGC1β regulates multiple myeloma tumor growth through LDHA‐mediated glycolytic metabolism

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