Review
Special Issue: The evolving role of mitochondria in metabolism
Transcriptional integration of mitochondrial biogenesis

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Gene regulatory factors encoded by the nuclear genome are essential for mitochondrial biogenesis and function. Some of these factors act exclusively within the mitochondria to regulate the control of mitochondrial transcription, translation, and other functions. Others govern the expression of nuclear genes required for mitochondrial metabolism and organelle biogenesis. The peroxisome proliferator-activated receptor γ coactivator-1 (PGC-1) family of transcriptional coactivators play a major role in transducing and integrating physiological signals governing metabolism, differentiation, and cell growth to the transcriptional machinery controlling mitochondrial functional capacity. Thus, the PGC-1 coactivators serve as a central component of the transcriptional regulatory circuitry that coordinately controls the energy-generating functions of mitochondria in accordance with the metabolic demands imposed by changing physiological conditions, senescence, and disease.

Section snippets

Regulation of mitochondrial biogenesis

A set of nucleus-encoded factors coordinately regulate mitochondrial mass and function in response to a host of energy and growth demands, including cellular metabolic stress, such as the constant production of reactive oxygen species (ROS). Dysregulation of mitochondrial function has broad implications for human disease including diabetes, heart failure, and neurodegeneration. Thus, there is a high level of interest in developing therapeutic strategies aimed at modulating the regulatory

Factors acting upon the mitochondrial genome

The transcription and translation of the mitochondrial genome is dependent upon a host of nucleus-encoded gene products (Figure 1; Box 1). Mitochondrial DNA (mtDNA) transcription requires a single RNA polymerase (POLRMT; see Glossary) that shares sequence similarity with yeast mitochondrial and T3/T7 bacteriophage polymerases, two stimulatory transcription factors (Tfam, TFB2M), and a termination factor (MTERF1) 1, 2. Transcription takes place bidirectionally from divergent promoters, termed

Integration of mitochondrial biogenic regulatory pathways: the PGC-1 coactivators

A major breakthrough in the understanding of how transcription factors controlling mitochondrial biogenesis are coregulated came with the discovery of PGC-1α. PGC-1α was first identified as a coactivator of the adipocyte-enriched nuclear receptor, PPARγ, in brown adipocytes [38]. PGC-1α is a member of a family of transcriptional coactivators that includes the closely related PGC-1β 39, 40 and more distant relative, PGC-1 related coactivator (PRC) [10]. All three PGC-1 members are characterized

Integration of mitochondrial biogenesis and metabolic signaling

The PGC-1 coactivators are dynamically regulated at the level of mRNA and protein expression in response to a variety of signaling pathways (e.g., AMPK, CaMK) involved in cellular growth, differentiation, and energy metabolism 2, 55. These include pathways that often converge on the CREB-dependent induction of PGC-1α gene transcription in response to cold exposure, nutrient deprivation, and exercise [56]. The importance of this response has been confirmed in PGC-1 knockout mice. Mice with

Concluding remarks

Regulatory factors encoded by the nuclear genome are essential to the control of mitochondrial biogenesis and function. The PGC-1 family of coactivators plays an integrative role in linking developmental and physiological signals to a key subset of transcription factors directing the coordinate expression of nuclear and mitochondrial genes. This regulatory circuitry plays a pivotal role in adjusting mitochondrial function to meet the changing energetic demands for cellular growth,

Disclosure statement

D.P.K. serves on the Scientific Advisory Boards for Johnson & Johnson, Pfizer, and Eli Lilly & Company.

Acknowledgments

This work was supported by National Institutes of Health grants (R01 DK045416, R01 HL058493, and R01 HL101189 to D.P.K.), and by a National Institute of General Medical Sciences grant (R01 GM32525-28 to R.C.S.). We wish to thank Teresa Leone for critical reading and Lorenzo Thomas for assistance in the preparation of the manuscript.

Glossary

AMP-activated protein kinase (AMPK)
an energy-sensing kinase that directly phosphorylates and enhances the activity of PGC-1.
Dimethyladenosine transferase 1, mitochondrial (Tfb1m)
a mitochondrial methyltransferase that dimethylates 12S rRNA and controls the stability or assembly of the mitochondrial ribosome.
Estrogen-related receptors (ERRs)
a family of orphan nuclear receptors that are involved in the regulation of virtually all aspects of mitochondrial function and biogenesis.
General control of

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