Transcriptional regulatory circuits controlling mitochondrial biogenesis and function

We are witnessing a period of renewed interest in the biology of the mitochondrion. The mitochondrion serves a critical function in the maintenance of cellular energy stores, thermogenesis, and apoptosis. Moreover, alterations in mitochondrial function contribute to several inherited and acquired human diseases and the aging process. This review summarizes our understanding of the transcriptional regulatory mechanisms involved in the biogenesis and energy metabolic function of mitochondria in higher organisms.

The mitochondrial genome

A defining feature of eukaryotic cells is that they contain nuclear and mitochondrial genomes sequestered into distinct subcellular compartments. The mitochondrial genetic system is comprised of a circular DNA genome (mtDNA, ∼16.5 kb in vertebrates; Fig. 1), the enzymes required for its transcription and replication, and the protein synthetic machinery necessary for the translation of 13 mitochondrial mRNAs (for review, see Garesse and Vallejo 2001). These mRNAs, which account for the entire protein-coding capacity of mtDNA, encode essential subunits of respiratory complexes I, III, IV, and V. The extrusion of protons through complexes I, III, and IV is coupled to the sequential transfer of electrons to a series of carriers of increasing redox potential resulting in an electrochemical proton gradient across the inner membrane. Complex V, comprised of an ATPase coupled to an inner membrane proton channel, can dissipate the proton gradient in the synthesis of ATP or can couple proton pumping to ATP hydrolysis to maintain the gradient. mtDNA also encodes for two ribosomal and 22 transfer RNAs, required for translation by mitoribosomes within the matrix.