Nuclear transcription factors in mammalian mitochondria

Mammalian cells store genetic information in two cellular compartments: the nucleus and the mitochondria. Mitochondrial DNA is packaged, handled and inherited independently of the nuclear genome, and far less is known about the regulation of mitochondrial gene expression compared with that of nuclear genes. As the singular site of the generation of adenosine triphosphate (ATP) by oxidative phosphorylation in the eukaryotic cell, the regulation of mitochondrial functions are complex and must be tightly regulated to respond to cellular metabolic requirements [1,2]. The majority of proteins present in mitochondria are encoded and transcribed in the nucleus [3], but the mitochondrial genome encodes a handful of proteins crucial for the generation of ATP (Figure 1). These proteins are transcribed and translated in the mitochondrial matrix and do not enter the cytoplasm [4,5]. Because both the nuclear and the mitochondrial genomes contribute to the mitochondrial proteome, their regulatory coordination is critical to cell survival and energy homeostasis [6]. This coordination is complicated by the distinct packaging and environment of the two genomes (Box 1).The mitochondrion is the single cellular site of ATP generation via aerobic respiration, and metabolites such as dietary lipids and pyruvate, the metabolic product of glycolysis, are actively transported into mitochondria [79]. As the tricarboxylic acid cycle progresses within the mitochondrial matrix, a series of electron-transfer reactions, known collectively as the electron-transport chain, proceeds between large multiprotein complexes and small electron carriers within the inner membrane and matrix [5]. The resulting electrochemical gradient generates bioavailable ATP via a rotating inner-membrane ATPase, which couples proton flow down a proton gradient to the catalysis of the phosphorylation of ADP to ATP using inorganic phosphate [80].The mitochondrion is derived from a symbiotic α-proteobacterium [81], and so th