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At least 19 recordsLinked to original sources
PubMed2000

Assembly of the cellular powerhouse: current issues in muscle mitochondrial biogenesis.

Mitochondrial biogenesis occurs in muscle in response to chronic exercise, resulting in fatigue resistance. The assembly of the organelle is initiated by contraction-induced signals, which lead to the transcriptional activation of nuclear genes. This is accompanied by alterations in mRNA stability, as well as increases in protein import and mitochondrial DNA copy number, leading to a greater muscle mitochondrial content.

Exercise↗
PubMed2005

Mitochondrial biogenesis and mitochondrial DNA maintenance of mammalian cells under oxidative stress.

Mitochondrial biogenesis and mitochondrial DNA (mtDNA) maintenance depend on coordinated expression of genes in the nucleus and mitochondria. A variety of intracellular and extracellular signals transmitted by hormones and second messengers have to be integrated to provide mammalian cells with a suitable abundance of mitochondria and mtDNA to meet their energy demand. It has been proposed that reactive oxygen species (ROS) and free radicals generated from respiratory chain are involved in the signaling from mitochondria to the nucleus. Increased oxidative stress may contribute to alterations in the abundance of mitochondria as well as the copy number and integrity of mtDNA in human cells in pathological conditions and in aging process. Within a certain level, ROS may induce stress responses by altering expression of specific nuclear genes to uphold the energy metabolism to rescue the cell. Once beyond the threshold, ROS may cause oxidative damage to mtDNA and other components of the affected cells and to elicit apoptosis by induction of mitochondrial membrane permeability transition and release of pro-apoptotic proteins such as cytochrome c. On the basis of recent findings gathered from this and other laboratories, we review the alterations in the abundance of mitochondria and mtDNA copy number of mammalian cells in response to oxidative stress and the signaling pathways that are involved.

Animals↗
PubMed1988

Mitochondrial biogenesis and mitochondrial activity during the progression of the cell cycle of human leukemic cells.

Mitochondrial (mt) biogenesis and mt function were investigated during the cell cycle of leukemic cells. The study shows that the activity of enzymes involved in oxidative phosphorylation increases in the early G1 phase. This increase in activity precedes that of other mt enzymes such as citrate synthase and adenylate kinase. Therefore, the synthesis of mt enzymes, needed for the reduplication of the mt mass in the course of the cell cycle, occurs in a sequential order. The enzymes of the system for oxidative phosphorylation are composed of several subunits. Some of these subunits are encoded on mtDNA and synthesized by mt-specific RNA and protein synthesis. This explains why inhibition of mt protein synthesis during the progression of the cell cycle of G1-enriched cells results in an increasing shortage of ATP. This lack of ATP results first in progression delay and, subsequently, in a cell cycle block in early G1. Furthermore, shortage of ATP impairs the increase in activity of at least one mt matrix enzyme. This study offers new information about a number of aspects of mt biogenesis and mt function during cell cycle progression and elucidates the cytostatic mechanism resulting from prolonged inhibition of mt protein synthesis.

Adenosine Diphosphate↗
PubMed2005

How is mitochondrial biogenesis affected in mitochondrial disease?

Mitochondrial biogenesis occurs when the tissue energy demand is chronically increased to stress the ATP producing capacity of the preexisting mitochondria. In muscle, endurance training is a metabolic stress that is capable of inducing mitochondrial biogenesis, the consequence of which is improved performance during exercise. Expansion of the mitochondrial volume requires the coordinated response of the nuclear and mitochondrial genomes. During acute exercise, the initial signaling events are the perturbations in ATP turnover and calcium (Ca) concentrations caused by the contractile process. These alterations activate signal transduction pathways which target transcription factors involved in gene expression. Nuclear gene products are then posttranslationally imported into mitochondria. One of these, Tfam, is important for the regulation of mitochondrial DNA (mtDNA) gene expression. In muscle, a broad range of mitochondrial-specific diseases due to mutations in nuclear DNA or mtDNA exist, termed mitochondrial myopathies. These mutations result in dysfunctional mitochondrial assembly which ultimately leads to reduced ATP production. Mitochondrial myopathy patients exhibit a variety of compensatory responses which attempt to reconcile this energy deficiency, but the extent and the type of compensatory adaptations are disease-specific. Understanding the role of exercise in mediating these compensatory responses leading to mitochondrial biogenesis could help us in prescribing exercise designed to improve mitochondrial function in patients with mitochondrial myopathies. In addition, numerous other diseases (e.g., neurological disorders, cancer, diabetes, and cardiomyopathies), as well as the aging process, have etiologies or consequences attributed, in part, to mitochondrial dysfunction. Thus, insight gained by investigating the steps involved in exercise-induced mitochondrial biogenesis may help us to understand the underlying basis of these other disease states.

DNA Mutational Analysis↗
PubMed1999

Oxidative stress and upregulation of mitochondrial biogenesis genes in mitochondrial DNA-depleted HeLa cells.

The signaling mechanism through which deficitary mitochondrial function would activate nuclear genes required for mitochondrial biogenesis, has not been established. To explore the hypothesis that reactive oxygen species (ROS), a mitochondrial product, constitute part of the mitochondria-nuclei signaling pathway, we obtained HeLa cells depleted of mitochondrial DNA (rho0 cells) through exposure to ethidium bromide. We found evidences of oxidative stress in rho0 cells, employing a fluorescent probe and measuring NF-kappaB activation. Nuclear Respiratory Factor-1 (NRF-1) and Mitochondrial Transcription Factor A (Tfam) mRNA were measured by RT-PCR. For both transcription factors, rho0 cells revealed significantly higher levels of mRNA. These results support several hypothesis: that endogenous ROS enhance the expression of nuclear mitochondrial biogenesis genes NRF-1 and Tfam; that DNA deprived mitochondria lead to cellular oxidative stress, probably because of incomplete biogenesis of the mitochondrial electron transport chain, and consequently, that ROS are part of a mitochondria-nuclei regulatory signaling pathway.

Base Sequence↗
PubMed2000

Peroxisome proliferator-activated receptor gamma coactivator-1 promotes cardiac mitochondrial biogenesis.

Cardiac mitochondrial function is altered in a variety of inherited and acquired cardiovascular diseases. Recent studies have identified the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator-1 (PGC-1) as a regulator of mitochondrial function in tissues specialized for thermogenesis, such as brown adipose. We sought to determine whether PGC-1 controlled mitochondrial biogenesis and energy-producing capacity in the heart, a tissue specialized for high-capacity ATP production. We found that PGC-1 gene expression is induced in the mouse heart after birth and in response to short-term fasting, conditions known to increase cardiac mitochondrial energy production. Forced expression of PGC-1 in cardiac myocytes in culture induced the expression of nuclear and mitochondrial genes involved in multiple mitochondrial energy-transduction/energy-production pathways, increased cellular mitochondrial number, and stimulated coupled respiration. Cardiac-specific overexpression of PGC-1 in transgenic mice resulted in uncontrolled mitochondrial proliferation in cardiac myocytes leading to loss of sarcomeric structure and a dilated cardiomyopathy. These results identify PGC-1 as a critical regulatory molecule in the control of cardiac mitochondrial number and function in response to energy demands.

Animals↗
PubMed2001

Unique aspects of mitochondrial biogenesis in trypanosomatids.

Mitochondrial biogenesis consists of the sum of all processes required for the formation of the mitochondrial membranes as well as the soluble compartments they contain. Furthermore, it includes the replication of the mitochondrial genome and correct segregation of the organelles during cell division. Mitochondrial proteins come from two sources, a limited but essential set of inner membrane proteins is encoded by the mitochondrial genome, whereas the large majority (90-95%) is derived from nucleus-encoded genes and are posttranslationally imported into the organelle. Trypanosomatids belong to the earliest diverging branches of the eukaryotic evolutionary tree which have mitochondria. This is reflected in the organisation of their mitochondrial DNA that consists of a network of two classes of topologically interlocked circular DNA molecules as well as many unique features in their mitochondrial biogenesis. The proteins encoded on the mitochondrial genome are conventional for a mitochondrial genome, their expression, however, involves a complex series of processes. Many genes represent incomplete open reading frames and their primary transcripts have to remodelled by RNA editing to convert them into translatable mRNAs. RNA editing is mediated by small mitochondria-encoded transcripts, the guide RNAs, and is in that form specific for trypanosomatids and closely related organisms. Mitochondrial translation is also unconventional. No tRNA genes are encoded on the mitochondrial genome. Instead, mitochondrial protein synthesis functions exclusively with imported cytosolic, eukaryotic-type tRNAs. The composition of mitochondrial ribosomes is also unusual in that they contain the smallest known rRNAs. They are about 30% shorter than the already much reduced rRNAs in human mitochondria. Furthermore, the topological organisation of the mitochondrial genome requires an elaborate replication machinery involving topoisomerases. Finally, some trypanosomatids have life cycle stages exhibiting very different mitochondrial activities and can therefore serve as a model system for the regulation of mitochondrial biogenesis.

Animals↗
PubMed2005

Coordination of nuclear and mitochondrial genome expression during mitochondrial biogenesis in Arabidopsis.

Mitochondrial biogenesis and function require the regulated and coordinated expression of nuclear and mitochondrial genomes throughout plant development and in response to cellular and environmental signals. To investigate the levels at which the expression of nuclear and mitochondrially encoded proteins is coordinated, we established an Arabidopsis thaliana cell culture system to modulate mitochondrial biogenesis in response to sugar starvation and refeeding. Sucrose deprivation led to structural changes in mitochondria, a decrease in mitochondrial volume, and a reduction in the rate of cellular respiration. All these changes could be reversed by the readdition of sucrose. Analysis of the relative mRNA transcript abundance of genes encoding nuclear and mitochondrially encoded proteins revealed that there was no coordination of expression of the two genomes at the transcript level. An analysis of changes in abundance and assembly of nuclear-encoded and mitochondrially encoded subunits of complexes I to V of the mitochondrial inner membrane in organello protein synthesis and competence for protein import by isolated mitochondria suggested that coordination occurs at the level of protein-complex assembly. These results further suggest that expression of the mitochondrial genome is insensitive to the stress imposed by sugar starvation and that mitochondrial biogenesis is regulated by changes in nuclear gene expression and coordinated at the posttranslational level.

Arabidopsis↗
PubMed2006

Signaling of mitochondrial biogenesis following oxidant injury.

Mitochondrial dysfunction is a common consequence of ischemia-reperfusion and drug injuries. For example, sublethal injury of renal proximal tubular cells (RPTCs) with the model oxidant tert-butylhydroperoxide (TBHP) causes mitochondrial injury that recovers over the course of six days. Although regeneration of mitochondrial function is integral to cell repair and function, the signaling pathway of mitochondrial biogenesis following oxidant injury has not been examined. A 10-fold overexpression of the mitochondrial biogenesis regulator PPAR-gamma cofactor-1alpha (PGC-1alpha) in control RPTCs resulted in a 52% increase in mitochondrial number, a 27% increase in respiratory capacity, and a 30% increase in mitochondrial protein markers, demonstrating that PGC-1alpha mediates mitochondrial biogenesis in RPTCs. RPTCs sublethally injured with TBHP exhibited a 50% decrease in mitochondrial function and increased mitochondrial autophagy. Compared with the controls, PGC-1alpha levels increased 12-fold on days 1, 2, and 3 post-injury and returned to base line on day 4 as mitochondrial function returned. Inhibition p38 MAPK blocked the up-regulation of PGC-1alpha following oxidant injury, whereas inhibition of calcium-calmodulin-dependent protein kinase, calcineurin A, nitric-oxide synthase, and phosphoinositol 3-kinase had no effect. The epidermal growth factor receptor (EGFR) was activated following TBHP exposure, and the EGFR inhibitor AG1478 blocked the up-regulation of PGC-1alpha. Additional inhibitor studies revealed that the sequential activation of Src, p38 MAPK, EGFR, and p38 MAPK regulate the expression of PGC-1alpha following oxidant injury. In contrast, although Akt was activated following oxidant injury, it did not play a role in PGC-1alpha expression. We suggest that mitochondrial biogenesis following oxidant injury is mediated by p38 and EGFR activation of PGC-1alpha.

Animals↗
PubMed1977

Mitochondrial biogenesis: inhibitors of mitochondrial protein synthesis.

The effects of erythromycin, chloramphenicol, cycloheximide, pyrimethamine, chromate, cadmium, lead, nickel, 4-nitro-quinoline-1-oxide and thioacetamide on yeast and human cells were studied. Inhibition of the synthesis of mitochondrial proteins resulted in the loss of cytochromes as well as in morphological changes in the cellular membranes and mitotic arrest. The data are discussed.

4-Nitroquinoline-1-oxide↗
PubMed1994

Mitochondrial biogenesis in striated muscle.

Mitochondrial biogenesis (synthesis) has been observed to occur in skeletal muscle in response to chronic use. It also occurs in cardiac muscle during growth and hypertrophy, and it may be impaired during the aging process. This review summarizes the literature on the processes of mitochondrial biogenesis at the biochemical and molecular levels, with particular reference to striated muscles. Mitochondrial biogenesis involves the expression of nuclear and mitochondrial genes and the coordination of these two genomes, the synthesis of proteins and phospholipids and their import into the organelle, and the incorporation of these lipids and proteins into their appropriate locations within the matrix, inner or outer membranes. The emphasis is on the regulation of these events, with information derived in part from other cellular systems. Although descriptions of mitochondrial content changes in heart and skeletal muscle during altered physiological states are plentiful, much work is needed at the molecular level to investigate the regulatory processes involved. A knowledge of biochemical and molecular biology techniques is essential for continued progress in the field. This is a promising area, and potential new avenues for future research are suggested.

Animals↗
PubMed2006

Acetyl-L-carnitine feeding to unloaded rats triggers in soleus muscle the coordinated expression of genes involved in mitochondrial biogenesis.

The expressional profile of mitochondrial transcripts and of genes involved in the mitochondrial biogenesis pathway induced by ALCAR daily supplementation in soleus muscle of control and unloaded 3-month-old rats has been analyzed. It has been found that ALCAR treatment is able to upregulate the expression level of mitochondrial transcripts (COX I, ATP6, ND6, 16 S rRNA) in both control and unloaded animals. Interestingly, ALCAR feeding to unloaded rats resulted in the increase of transcript level for master factors involved in mitochondrial biogenesis (PGC-1alpha, NRF-1, TFAM). It also prevented the unloading-induced downregulation of mRNA levels for kinases able to transduce metabolic (AMPK) and neuronal stimuli (CaMKIIbeta) into mitochondrial biogenesis. No significant effect on the expressional level of such genes was found in control ALCAR-treated rats. In addition, ALCAR feeding was able to prevent the loss of mitochondrial protein content due to unloading condition. Correlation analysis revealed a strong coordination in the expression of genes involved in mitochondrial biogenesis only in ALCAR-treated suspended animals, supporting a differentiated effect of ALCAR treatment in relation to the loading state of the soleus muscle. In conclusions, we demonstrated the ability of ALCAR supplementation to promote only in soleus muscle of hindlimb suspended rats an orchestrated expression of genes involved in mitochondrial biogenesis, which might counteract the unloading-induced metabolic changes, preventing the loss of mitochondrial proteins.

Acetylcarnitine↗
PubMed1999

Enhanced mitochondrial biogenesis is associated with increased expression of the mitochondrial ATP-dependent Lon protease.

Rats bearing the Zajdela hepatoma tumor and T3-treated hypothyroid rats were used to study the role of protein degradation in the process of mitochondrial biogenesis. It was shown that the activity, protein and mRNA levels of the ATP-dependent Lon protease increased in rapidly growing Zajdela hepatoma cells. The increase in the rate of mitochondrial biogenesis by thyroid hormone was similarly accompanied by enhanced expression of the Lon protease. The results imply that mitochondrial biogenesis in mammalian cells is, at least partially, regulated by the matrix Lon protease.

ATP-Dependent Proteases↗
PubMed2005

Myc stimulates nuclearly encoded mitochondrial genes and mitochondrial biogenesis.

Although several genes involved in mitochondrial function are direct Myc targets, the role of Myc in mitochondrial biogenesis has not been directly established. We determined the effects of ectopic Myc expression or the loss of Myc on mitochondrial biogenesis. Induction of Myc in P493-6 cells resulted in increased oxygen consumption and mitochondrial mass and function. Conversely, compared to wild-type Myc fibroblasts, Myc null rat fibroblasts have diminished mitochondrial mass and decreased number of normal mitochondria. Reconstitution of Myc expression in Myc null fibroblasts partially restored mitochondrial mass and function and normal-appearing mitochondria. Concordantly, we also observed in primary hepatocytes that acute deletion of floxed murine Myc by Cre recombinase resulted in diminished mitochondrial mass in primary hepatocytes. Our microarray analysis of genes responsive to Myc in human P493-6 B lymphocytes supports a role for Myc in mitochondrial biogenesis, since genes involved in mitochondrial structure and function are overrepresented among the Myc-induced genes. In addition to the known direct binding of Myc to many genes involved in mitochondrial structure and function, we found that Myc binds the TFAM gene, which encodes a key transcriptional regulator and mitochondrial DNA replication factor, both in P493-6 lymphocytes with high ectopic MYC expression and in serum-stimulated primary human 2091 fibroblasts with induced endogenous MYC. These observations support a pivotal role for Myc in regulating mitochondrial biogenesis.

Animals↗
PubMed2001

Direct influence of the p53 tumor suppressor on mitochondrial biogenesis and function.

Mitochondrial localization of p53 has been observed in several cell systems, but an understanding of its organelle-based physiological activity remains incomplete. The purpose of the present study was to investigate the mitochondrial DNA genomic response to dominant-negative p53 mutant miniprotein (p53DD) fused to a mitochondrial import signal. Constructs were generated to express mitochondrial targeted enhanced green fluorescent protein (mEGFP) or dominant-negative mutant p53 miniprotein (m53DD) by in-frame fusion to the signal peptide sequence of murine Cox8l. Control cytosolic vectors (cEGFP, c53DD) had the signal sequence placed in antisense orientation. NIH 3T3 cells were transiently transfected with these vectors in various combinations. Mitochondrial 16S ribosomal RNA (16S rRNA) expression and fluorochrome staining with Mitotracker Red CMXRos (DeltaPsim) were decreased in cells expressing m53DD. Both alterations were specific for mitochondrial import competence (e.g., m53DD vs. c53DD) as well as the passenger protein (e.g., m53DD vs. mEGFP). The normal functional state of mitochondria was restored with PK11195, a specific ligand of the mitochondrial peripheral-type benzodiazepine receptor. Negative dominance of m53DD on 16S rRNA expression and CMXRos staining, and rescue of these parameters with PK11195, imply a direct positive effect of p53 on mitochondrial biogenesis and function.

3T3 Cells↗
PubMed2006

Role of calcineurin in exercise-induced mitochondrial biogenesis.

Raising cytosolic Ca2+ induces an increase in mitochondrial biogenesis in myotubes. This phenomenon mimics the adaptive responses of skeletal muscle to exercise. It has been hypothesized that increases in cytosolic Ca2+ during motor nerve activity stimulate mitochondrial biogenesis by activating calcineurin. Overexpression of constitutively active calcineurin increases expression of peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) and induction of genes involved in mitochondrial energy metabolism in muscle cells. The purpose of this study was to determine whether calcineurin plays a role in the stimulation of mitochondrial biogenesis by exercise. Rats were exercised on 5 successive days by means of swimming. Inhibition of calcineurin with cyclosporin did not prevent the exercise-induced increases in PGC-1alpha and a range of mitochondrial proteins. In contrast to the other mitochondrial proteins, the increases in cytochrome oxidase (COX)-I and -IV proteins were blocked by cyclosporin treatment. This inhibitory effect of cyclosporin occurred at the posttranscriptional level, as evidenced by normal increases in COX-I and COX-IV mRNAs in response to exercise in the cyclosporin-treated rats. This toxic effect of cyclosporin may account for the decrease in muscle respiratory capacity reported to occur with cyclosporin treatment. In conclusion, inhibition of calcineurin does not prevent the exercise-induced increase in mitochondrial biogenesis in skeletal muscles, providing evidence that the adaptive response is not mediated by activation of calcineurin.

Animals↗
PubMed2002

AMP kinase is required for mitochondrial biogenesis in skeletal muscle in response to chronic energy deprivation.

Mitochondrial biogenesis is a critical adaptation to chronic energy deprivation, yet the signaling mechanisms responsible for this response are poorly understood. To examine the role of AMP-activated protein kinase (AMPK), an evolutionarily conserved fuel sensor, in mitochondrial biogenesis we studied transgenic mice expressing a dominant-negative mutant of AMPK in muscle (DN-AMPK). Both DN-AMPK and WT mice were treated with beta-guanidinopropionic acid (GPA), a creatine analog, which led to similar reductions in the intramuscular ATPAMP ratio and phosphocreatine concentrations. In WT mice, GPA treatment resulted in activation of muscle AMPK and mitochondrial biogenesis. However, the same GPA treatment in DN-AMPK mice had no effect on AMPK activity or mitochondrial content. Furthermore, AMPK inactivation abrogated GPA-induced increases in the expression of peroxisome proliferator-activated receptor gamma coactivator 1alpha and calciumcalmodulin-dependent protein kinase IV (both master regulators of mitochondrial biogenesis). These data demonstrate that by sensing the energy status of the muscle cell, AMPK is a critical regulator involved in initiating mitochondrial biogenesis.

Adenine Nucleotides↗