Transcriptional integration of mitochondrial biogenesis

Abstract

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.

Figure 1. Nuclear-encoded factors acting within mitochondria

Targeted gene disruptions in mice (knockouts) have helped define the functions of several nuclear genes encoding products that function within mitochondria (as described in the text) including: Tfam (orange spheres), binds the mtDNA at multiple sites and functions in both mtDNA maintenance and transcription initiation; Mterf3, functions as a negative regulator of mtDNA transcription; Tfb1m (red ellipse) and Mterf4 (green ellipse), participate in mitochondrial ribosome assembly. Tfb1m is a dimethyltransferase that catalyzes the adenine dimethylation of the small ribosomal RNA required for ribosome assembly and translation. Similarly, a complex containing Mterf4 and the rRNA methyltransferase, NSUN4 (blue ellipse), participates in the assembly of the large ribosomal subunit.

Figure 2. Control of mitochondrial biogenesis by PGC-1

Interaction between PGC-1 and specific transcription factors orchestrates major functions of mitochondria including fatty acid β-oxidation, the tricarboxylic acid cycle (TCA), mtDNA replication and oxidative phosphorylation and the electron transport chain (OxPhos/ETC) in addition to biogenesis of this organelle. PPARα interacts with its binding partner, the retinoid X receptor (RXR), to control the expression of many fatty acid β-oxidation enzymes. NRF-1 and NRF-2 contribute to the maintenance of mtDNA and the expression of multiple components of the ETC. ERR members regulate the expression of virtually all functions of the mitochondria including those shown here.

Figure 3. Proposed integration of energy-generating and antioxidant pathways by PGC-1α

PGC-1α is activated via post-transcriptional phosphorylation by AMPK or by deacetylation via SIRT1 in response to nutrient deprivation. Induction or activation of the coactivator can enhance mitochondrial biogenesis and oxidative function through the coactivation of multiple transcription factors involved in respiratory gene expression (see Figure 2). PGC-1α activation may also promote an antioxidant environment by coactivating ERRα to induce SIRT3, a mitochondrial sirtuin that has been implicated in ROS detoxification. In addition, AMPK promotes autophagy through direct phosphorylation of ULK1 or suppression of the TORC1 kinase complex. Inhibition of the TORC1 pathway also has been shown to have a negative effect on senescence. Increased autophagy, enhanced ROS detoxification and inhibition of TORC1 are all associated with health and longevity. Under conditions of caloric excess, SRC-3 induces GCN5 which inactivates PGC-1α through acetylation.

Figure 4. PRC response to growth and metabolic stress

Under normal growth conditions, PRC acts as an immediate early gene product that is transiently elevated upon the initiation of cell growth. The transient induction of PRC and other immediate early genes is an early event in the program leading to cell proliferation. Under conditions of severe stress, resulting from chemical uncoupling or energy starvation, PRC is induced constitutively in cultured cells as a dysregulated response. This latter response is a departure from its normal expression pattern and leads to the induction of a battery of genes associated with the chronic inflammatory response. The induction of this inflammatory response is thought to be adaptive at the cellular level but may be maladaptive at the organismal level and thus associated with a number of age-related diseases.