Regulation of Mitochondrial Biogenesis in Skeletal Muscle by CaMK

Wu, Hai Yan; Kanatous, Shane B.; Thurmond, Frederick A.; Gallardo, Teresa; Isotani, Eiji; Bassel‐Duby, Rhonda; Williams, R. Sanders

doi:10.1126/science.1071163

Cited by 581 publications

(492 citation statements)

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“…(12) In addition, several signal transduction pathways that regulate PGC1a expression independent of changes in intracellular cGMP levels have also been described. (2,6,7,13) Do the data in the present experiments support the contention that the observed NO effects on PGC1a expression are transduced exclusively through a sGC-sensitive, cGMP-dependent signaling pathway? Some insight into this question comes from their studies on the human monocytic cell line U937.…”

Section: Introductionsupporting

confidence: 67%

“…Signal transduction pathways that modulate mitochondrial biogenesis through the control of PGC1a expression in mammalian tissues. (1,2,4,6,7,13,23) Changes in the levels or ratio of metabolic indices [blue boxes] are sensed by specific protein-modifying enzymes (i.e., kinases, phosphatases). These proteins in turn activate diverse signaling cascades [gold circles] that ultimately affect the expression of PGC1a [pink oval].…”

Section: Perspectivesmentioning

confidence: 99%

“…(5) Despite significant advances in our understanding of the role of transcription factors and co-activators in mediating the transcriptional control of respiratory gene expression, the mechanisms by which the expression of these proteins is in turn regulated remain largely unknown. Investigations of the control of mitochondrial biogenesis in the skeletal muscle of transgenic mice have demonstrated that increases in PGC1a levels and mitochondrial content are dependent on the activity of at least two proteins, CaMKIV (6) and AMP kinase, (7) which are regulated by changes in intracellular calcium concentrations and the ATP:AMP ratio, respectively. Thus, an attractive hypothesis is that the expression and activity of PGC1a and other determinants of mitochondrial content are controlled by effector proteins that are capable of monitoring changes in intracellular energy metabolism by virtue of their sensitivity to metabolic activity.…”

Section: Introductionmentioning

confidence: 99%

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Mitochondrial biogenesis: Which part of “NO” do we understand?

Leary

Shoubridge

2003

BioEssays

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SummaryA recent paper by Nisoli et al. (1) provides the first evidence that elevated levels of nitric oxide (NO) stimulate mitochondrial biogenesis in a number of cell lines via a soluble guanylate-cyclase-dependent signaling pathway that activates PGC1a (peroxisome proliferator-activated receptor g coactivator-1a), a master regulator of mitochondrial content. These results raise intriguing possibilities for a role of NO in modulating mitochondrial content in response to physiological stimuli such as exercise or cold exposure. However, whether this signaling cascade represents a widespread mechanism by which mammalian tissues regulate mitochondrial content, and how it might integrate with other pathways that control PGC1a expression,remainunclear. BioEssays25:538-541,2003. ß 2003 Wiley Periodicals, Inc. IntroductionMitochondria produce the bulk of the ATP required for the normal function of most tissues. As such, the mitochondrial content of a given tissue largely reflects its specific demands for respiratory energy. In specialized tissues such as brown fat, which has a thermogenic role in neonates and hibernating animals, mitochondria express an uncoupling protein (UCP1) that functionally dissociates electron transport from oxidative phosphorylation, allowing the energy released in this process to be dissipated as heat. (2) Increased physiological demand for aerobic ATP production or the generation of heat results in mitochondrial proliferation. Several families of unrelated transcription factors, most notably the nuclear respiratory factors (NRFs), modulate the increased expression of nuclearencoded mitochondrial proteins necessary for increased biogenesis of the organelle. (3) The activity of many of these transcription factors is in turn controlled by the co-activator PGC1a, and its related family members. (4) PGC1a also potentiates the expression of a large number of additional genes via its interactions with members of the nuclear hormone receptor superfamily. (5)

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Section: Introductionsupporting

confidence: 67%

Section: Perspectivesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Mitochondrial biogenesis: Which part of “NO” do we understand?

Leary

Shoubridge

2003

BioEssays

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“…18 Calcium signalling modulates mitochondrial biogenesis through the calcium/calmodulin-dependent protein kinase II (CaMKII), p38 mitogen activated protein kinase (MAPK) and PGC-1α. 19,20 Although, no clear PGC-1a homolog is present in the nematode genome, we found that SKN-1 activity is modulated by cytoplasmic calcium levels via the CaMKII homolog, UNC-43, upon mitochondrial dysfunction.…”

mentioning

confidence: 73%

Balancing mitochondrial biogenesis and mitophagy to maintain energy metabolism homeostasis

2015

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Mitochondria, the main energy hub of the cell, are highly dynamic organelles, playing essential roles in fundamental cellular processes. Mitochondrial function impinges on several signalling pathways modulating cellular metabolism, cell survival and healthspan. Accordingly, impairment of mitochondria has been associated with numerous pathological conditions and ageing. Maintenance of cellular and organismal homeostasis thus hinges on fine-tuning mitochondrial quality control. Mitochondrial biogenesis and mitochondrial selective autophagy (mitophagy), two opposing cellular pathways, coordinately regulate mitochondrial content to sustain energy metabolism, in response to cellular metabolic state, stress and other intracellular or environmental signals. It is not surprising, therefore, that disequilibrium or imbalance between mitochondrial proliferation and degradation processes underlies the onset and progressive unfolding of several pathological conditions in humans, including neurodegenerative diseases, myopathies and other age-associated disorders.Mitochondrial biogenesis is a complex and multistep cellular process, which involves mtDNA transcription and translation, translation of transcripts derived from nucleus, recruitment of newly synthesized proteins and lipids, import and assembly of mitochondrial and nuclear products in the expanding mitochondrial network. Spatiotemporal control of mitochondrial biogenesis is mediated by numerous transcription factors in response to diverse stimuli, including both intracellular signals and environmental stimuli (nutrient availability, growth factors and hormones, toxins, temperature and oxygen fluctuations, among others). The master regulator of mitochondrial energy metabolism is the peroxisome proliferator-activated receptor gamma co-activator 1-alpha (PGC-1α), the best-studied member of the peroxisome proliferator activated receptor family of transcription co-activators, which orchestrates the activity of several transcription factors involved in mitochondrial biogenesis and function. 1 These include the nuclear respiratory factors (NRF1 and NRF2), the estrogen-related receptors (ERR-α, -β and -γ) and the nuclear factor erythroid 2-related factor 2 (NRF2/NFE2L2) that are part of a complex transcriptional network that regulates mitochondrial biogenesis and energy metabolism. 1,2 Alongside their essential roles in cell and animal physiology, mitochondria are also the major source of potentially hazardous reactive oxygen species as by-products of respiration. Thus, eukaryotic cells have evolved a wide arsenal of quality control mechanisms to preserve mitochondrial homeostasis and prevent cellular damage and eventual death. Mitophagy, a selective type of autophagy, is triggered upon accumulation of damaged or superfluous mitochondria. Dysfunctional mitochondria are targeted and engulfed by double-membrane vesicles known as autophagosomes and are transferred for degradation in lysosomes. Cells induce mitophagy to regulate the size and quality of their mitochondrial network...

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“…Ppara is centrally involved in mitochondrial biogenesis and fatty acid oxidation [6]. Increased production of Ppargc1a, a key regulator of mitochondrial biogenesis, may be involved in obesity and the pre-diabetic state in skeletal muscle [7]. Therefore, regulating Pparg/a activity and adipocyte metabolism may improve insulin sensitivity and glucose disposal [2,5,8].…”

Section: Introductionmentioning

confidence: 99%

R-α-Lipoic acid and acetyl-l-carnitine complementarily promote mitochondrial biogenesis in murine 3T3-L1 adipocytes

et al. 2007

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Aims/hypothesis The aim of the study was to address the importance of mitochondrial function in insulin resistance and type 2 diabetes, and also to identify effective agents for ameliorating insulin resistance in type 2 diabetes. We examined the effect of two mitochondrial nutrients, R-α-lipoic acid (LA) and acetyl-L-carnitine (ALC), as well as their combined effect, on mitochondrial biogenesis in 3T3-L1 adipocytes. Methods Mitochondrial mass and oxygen consumption were determined in 3T3-L1 adipocytes cultured in the presence of LA and/or ALC for 24 h. Mitochondrial DNA and mRNA from peroxisome proliferator-activated receptor gamma and alpha (Pparg and Ppara) and carnitine palmitoyl transferase 1a (Cpt1a), as well as several transcription factors involved in mitochondrial biogenesis, were evaluated by real-time PCR or electrophoretic mobility shift (EMSA) assay. Mitochondrial complexes proteins were measured by western blot and fatty acid oxidation was measured by quantifying CO 2 production from [1-14 C] palmitate. Results Treatments with the combination of LA and ALC at concentrations of 0.1, 1 and 10 μmol/l for 24 h significantly increased mitochondrial mass, expression of mitochondrial DNA, mitochondrial complexes, oxygen consumption and fatty acid oxidation in 3T3L1 adipocytes. These changes were accompanied by an increase in expression of Pparg, Ppara and Cpt1a mRNA, as well as increased expression of peroxisome proliferator-activated receptor (PPAR) gamma coactivator 1 alpha (Ppargc1a), mitochondrial transcription factor A (Tfam) and nuclear respiratory factors 1 and 2 (Nrf1 and Nrf2). However, the treatments with LA or ALC alone at the same concentrations showed little effect on mitochondrial function and biogenesis. Conclusions/interpretation We conclude that the combination of LA and ALC may act as PPARG/A dual ligands to complementarily promote mitochondrial synthesis and adipocyte metabolism.

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Regulation of Mitochondrial Biogenesis in Skeletal Muscle by CaMK

Cited by 581 publications

References 23 publications

Mitochondrial biogenesis: Which part of “NO” do we understand?

Mitochondrial biogenesis: Which part of “NO” do we understand?

Balancing mitochondrial biogenesis and mitophagy to maintain energy metabolism homeostasis

R-α-Lipoic acid and acetyl-l-carnitine complementarily promote mitochondrial biogenesis in murine 3T3-L1 adipocytes

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