Phosphorylation of Human TFAM in Mitochondria Impairs DNA Binding and Promotes Degradation by the AAA+ Lon Protease

Lü, Bin; Lee, Jae; Nie, Xiaobo; Li, Min; Morozov, Yaroslav I.; Venkatesh, Sundararajan; Bogenhagen, Daniel F.; Temiakov, Dmitry; Suzuki, Carolyn K.

doi:10.1016/j.molcel.2012.10.023

Cited by 270 publications

(299 citation statements)

References 65 publications

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“…Several of the proteins that control mitochondrial DNA transcription have posttranslational modifications, including phosphorylation and acetylation. For example, TFAM is specifically phosphorylated (Lu et al 2013) and acetylated (Dinardo et al 2003), suggesting that its activity could be modified through cycles of acetylation/deacetylation in response to energetic signals. Another level of control of this mitochondrial transcriptional machinery is by inducing amounts of its components.…”

Section: Mitochondrial Transcriptionmentioning

confidence: 99%

Mitochondrial Biogenesis through Activation of Nuclear Signaling Proteins

Dominy

Puigserver

2013

Cold Spring Harbor Perspectives in Biology

205

171

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Section: Mitochondrial Transcriptionmentioning

confidence: 99%

Mitochondrial Biogenesis through Activation of Nuclear Signaling Proteins

Dominy

Puigserver

2013

Cold Spring Harbor Perspectives in Biology

205

171

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“…For a long time, the coordination of the two genomes (nuclear versus mitochondrial) was considered to be exclusively achieved by the nucleus-encoded proteins TFAM, TFB1M and TFB2M; among these, TFAM was believed to be essential for transcription, replication and maintenance of mitochondrial DNA (mtDNA) (Lu et al, 2013). Importantly, we have demonstrated that PGC-1a also resides in mitochondria and, at the mitochondrial matrix, associates with TFAM and with mtDNA, thereby coactivating the transcription of mtDNAencoded genes (Pagliei et al, 2013).…”

Section: Regulation Of Carbohydrate Metabolismmentioning

confidence: 99%

The role of nNOS and PGC-1α in skeletal muscle cells

Baldelli

Barbato

Tatulli

et al. 2014

Journal of Cell Science

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Neuronal nitric oxide synthase (nNOS) and peroxisome proliferator activated receptor c co-activator 1a (PGC-1a) are two fundamental factors involved in the regulation of skeletal muscle cell metabolism. nNOS exists as several alternatively spliced variants, each having a specific pattern of subcellular localisation. Nitric oxide (NO) functions as a second messenger in signal transduction pathways that lead to the expression of metabolic genes involved in oxidative metabolism, vasodilatation and skeletal muscle contraction. PGC1a is a transcriptional coactivator and represents a master regulator of mitochondrial biogenesis by promoting the transcription of mitochondrial genes. PGC-1a can be induced during physical exercise, and it plays a key role in coordinating the oxidation of intracellular fatty acids with mitochondrial remodelling. Several lines of evidence demonstrate that NO could act as a key regulator of PGC-1a expression; however, the link between nNOS and PGC-1a in skeletal muscle remains only poorly understood. In this Commentary, we review important metabolic pathways that are governed by nNOS and PGC-1a, and aim to highlight how they might intersect and cooperatively regulate skeletal muscle mitochondrial and lipid energetic metabolism and contraction.

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“…Upon import to mitochondria it performs multiple regulatory functions including mtDNA transcription, maintenance of mtDNA looping, coating and packaging (mitochondrial nucleoids) [59,69,70]. It contains facets for binding nuclear respiratory factor (NRF) 1 and NRF2 which act on the promoter of D-loop region leading to increased mtDNA copy number [71].…”

Section: Mitochondrial Transcription Factor a (Tfam)mentioning

confidence: 99%

Anticancer Strategy Targeting Mitochondrial Biogenesis in Ovarian Cancer

Uddin¹,

Kim²,

Suh³

et al. 2014

J Cancer Sci Ther

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IntroductionOvarian cancer is the most lethal gynecologic malignancy worldwide typically in the post-menopausal women and 5 th leading cause of death in the United States [1][2][3]. About 80% of women are diagnosed at the advanced-stage of disease and have poor prognosis. The 5-year overall survival rate is 45% or below [4][5][6]. Despite the first complete response after the front-line platinum-based chemotherapeutic drugs [7,8], approximately 25% patients suffer from relapse within 6 months who are thought, by definition, to have a chemoresistance [9][10][11][12]. Combination of platinum and other drugs might improve the survival rate [13], but is not out of the danger of additive toxicity [14].Several genetic alterations have been observed in ovarian cancer, involving deactivation mutations in tumor suppressor genes, such as p53, BRCA1 and BRCA2, and activation mutation and/or amplification of proto-oncogenes, like c-MYC, KRAS and AKT [15]. Recent genomic analysis of The Cancer Genome Atlas reported mutations in p53 gene in 96% of 316 cases of high-grade ovarian serous carcinoma (HGOSC) [16]. Other important genetic changes affect phosphatidyinositol-3-kinase (PI3K)-AKT-mammalian target of rapamycin (mTOR) cascade. The mTOR plays a central role in energy metabolism, cell growth/division through macromolecular synthesis and is found to be activated in ovarian cancer [6], which indicates a close relationship between genetic alteration and energy metabolism. It was observed that hexokinase (HK) II, the rate limiting initial enzyme in glycolysis, is overexpressed in ovarian cancer [12]. The genetic alterations and subsequent metabolic remodeling have been found to be associated with the chemoresistance [17], such as association of rictor (mTORC2 component) with resistance to cisplatin [2]. Cisplatin-induced caspase activation causing PTEN cleavage has also been reported as a potential mechanism of chemoresistance in ovarian cancer [18].Mitochondria is a well-adapted endosymbiotic intracellular organelles, became efficient for energy production through-out the course of evolution [19]. They are critical for survival and proliferation of living organisms under aerobic conditions and produce ATP through oxidative phosphorylation (OXPHOS) [20]. Beyond the conventional function they have crucial role in certain neurodegenerative diseases and cancer [21][22][23]. Cellular proliferation largely depends on mitochondrial amount, governed by the process of MtBIO [20]. MtBIO is the production of daughter mitochondria usually from previously existed one through a division process of called fission, subsequent growth, and maintenance by fusion and autophagy of mitochondria (mitophagy) [24]. Currently it has been observed that MtBIO is associated with cancer chemoresistance [25,26] through the modulation of associated proteins such as methylation-controlled J-protein (MCJ, also known as DNAJC15) [25,27], prohibitin 1 (PHB-1) [28][29][30], myeloid cell leukemia sequence 1 (MCL-1) [31,32] etc. in ovarian cancer. Thus it can be s...

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Phosphorylation of Human TFAM in Mitochondria Impairs DNA Binding and Promotes Degradation by the AAA+ Lon Protease

Cited by 270 publications

References 65 publications

Mitochondrial Biogenesis through Activation of Nuclear Signaling Proteins

Mitochondrial Biogenesis through Activation of Nuclear Signaling Proteins

The role of nNOS and PGC-1α in skeletal muscle cells

Anticancer Strategy Targeting Mitochondrial Biogenesis in Ovarian Cancer

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