Nuclear activators and coactivators in mammalian mitochondrial biogenesis

Abstract

The biogenesis of mitochondria requires the expression of a large number of genes, most of which reside in the nuclear genome. The protein-coding capacity of mtDNA is limited to 13 respiratory subunits necessitating that nuclear regulatory factors play an important role in governing nucleo-mitochondrial interactions. Two classes of nuclear transcriptional regulators implicated in mitochondrial biogenesis have emerged in recent years. The first includes DNA-binding transcription factors, typified by nuclear respiratory factor (NRF)-1, NRF-2 and others, that act on known nuclear genes that specify mitochondrial functions. A second, more recently defined class, includes nuclear coactivators typified by PGC-1 and related family members (PRC and PGC-1β). These molecules do not bind DNA but rather work through their interactions with DNA-bound transcription factors to regulate gene expression. An important feature of these coactivators is that their expression is responsive to physiological signals mediating thermogenesis, cell proliferation and gluconeogenesis. Thus, they have the ability to integrate the action of multiple transcription factors in orchestrating programs of gene expression essential to cellular energetics. The interplay of these nuclear factors appears to be a major determinant in regulating the biogenesis of mitochondria.

Introduction

Mitochondria are best known for their role in the generation of ATP from metabolic fuels through oxidative phosphorylation (reviewed in [1], [2]). Fats and sugars are oxidized to acetyl CoA which is converted, via the citric acid cycle in the mitochondrial matrix, to NADH and FADH₂. These strong reducing agents donate electrons to the respiratory chain resulting in the establishment of an electrochemical gradient of protons across the mitochondrial inner membrane. This gradient is generated by the vectorial pumping of protons during sequential electron transfer to a series of carriers of increasing redox potential. Three multisubunit respiratory complexes, I, III and IV, are imbedded in the mitochondrial inner membrane and serve as the sites of proton pumping from the matrix. In addition, complex V, comprised of an ATPase coupled to an inner membrane proton channel, can dissipate the proton gradient in the synthesis of ATP or hydrolyze ATP to maintain the gradient. A unique feature of this system is that all four of the complexes involved in proton pumping and ATP synthesis are comprised of protein subunits encoded by both nuclear and mitochondrial genes.

Mitochondria have their own genetic system comprised of a circular DNA genome, the enzymes and cofactors required for its transcription and replication as well as the protein synthetic machinery necessary for the translation of mitochondrial mRNAs (reviewed in [1], [3], [4]. However, mitochondria are semiautonomous organelles in that the entire protein-coding capacity of mtDNA is limited to 13 subunits of respiratory complexes I, III, IV and V with the remainder of the genome encoding ribosomal and transfer RNAs. Thus, mitochondria rely upon nuclear genes for the majority of the 100 or so respiratory subunits and for the machinery required for the maintenance, replication and expression of mtDNA. In addition, all other gene products such as those comprising mitochondrial enzyme systems, for example enzymes involved in pyruvate and fatty acid oxidation, and those required for the import and assembly of the respiratory apparatus, are encoded by nuclear genes.

Mitochondrial content and respiratory capacity vary according to specific demands for respiratory energy, and the abundance of mitochondria can be modulated in response to physiological conditions. Muscle mitochondria proliferate in response to exercise training [5] and electrical stimulation [6], and thyroid hormones increase metabolic rate and mitochondrial enzyme levels in multiple tissues [7]. The proliferation of mitochondria also occurs in the brown fat of rodents during adaptive thermogenesis. This coincides with the activation and induction of UCP-1, an uncoupling protein that dissipates the proton gradient to produce heat as a response to cold exposure [8]. Mitochondrial biogenesis is also regulated during pre- and postnatal development. Massive amplification of mtDNA occurs during oogenesis [9] and these genomes are distributed among the cells of the early embryo until the blastocyst stage when embryonic mtDNA replication is initiated [10], [11]. At birth, the production of mitochondria and respiratory enzymes is induced through both transcriptional and posttranscriptional mechanisms as the neonate adapts to extrauterine life [12], [13]. Finally, in certain mitochondrial diseases, defective mitochondria proliferate in diseased muscle fibers giving rise to ragged red fibers that are a diagnostic indicator [14]. Presumably, this proliferation is a nuclear response to mtDNA mutations that lead to deficiencies in ATP production. The underlying molecular mechanisms governing these regulatory phenomena are poorly understood at the molecular level.

This review will focus on recent advances pertaining to the nuclear regulatory proteins that control the expression of the respiratory apparatus in mammalian cells. Two classes of these molecules have been defined in recent years. The first consists of DNA-binding transcription factors. These proteins bind the promoters of nuclear genes that contribute both directly and indirectly to respiratory chain expression and function. The second class of nuclear regulators includes more recently defined transcriptional coactivators. These regulatory proteins do not bind DNA but exert their effects on gene expression through their interactions with transcription factors and other coactivators. New evidence supports the conclusion that the control of mitochondrial biogenesis results from the interplay of these two classes of nuclear factors.