A fundamental function of mitochondria is to produce ATP through oxidative phosphorylation, thereby providing energy for the cellular activities. Mitochondria have their own genome, transcription and translation systems, but they also require proteins encoded by the nucleus [Cannino et al., 2007
]. Cytochrome c oxidase IV (COXIV) is a key nuclear-encoded protein within the electron transfer chain in mitochondria, and participates in ATP production. The alteration of COXIV protein levels is able to affect mitochondrial function. miR-338 is a brain-specific miRNA expressed in neuronal tissue [Kim et al., 2004
; Wienholds et al., 2005
]. The miR-338 has been shown to regulate the expression of COXIV. COXIV 3′UTR contains miR-338 target And enforced expression of miR-338 reduces COXIV mRNA as well as protein levels. On the contrary, inhibition of endogenous miR-338 by its specific antagomir results in an increase in COXIV mRNA and protein levels. Functional study revealed that the over expression of miR-338 can significantly reduce mitochondrial oxygen consumption, mitochondrial metabolic activity, and ATP production [Aschrafi et al., 2008
Glutaminase is important for mitochondrial metabolism and it converts glutamine to glutamate, which is further catabolized through the tricarboxylic acid cycle for the production of ATP or serves as the substrate for glutathione synthesis in mitochondria. The miR-23a and miR-23b (miR-23a/b) have been demonstrated to participate in targeting glutaminase [Gao et al., 2009
] and can directly repress glutaminase expression. Modulation of miR-23a/b through their antagomirs can affect glutaminase expression levels.
The miR-210, a miRNA significantly upregulated during hypoxic stress in many cell types [Corn, 2008
; Kulshreshtha et al., 2007
], is reported to be involved in repressing mitochondrial respiration and the associated downstream functions [Chan et al., 2009
; Favaro et al., 2010
]. For example, mitochondrial iron sulfur cluster homologue (ISCU) has been identified as a target of miR-210. Iron sulfur clusters are assembled in mitochondria by a complex series of chaperones and enzymes [Mühlenhoff and Lill, 2000
], which are then exported to the cytoplasm for assembling into the relevant functional protein [Rouault and Tong, 2008
; Tong and Rouault, 2000
]. A decrease in ISCU can influence the activity of enzymes requiring iron sulfur clusters. The miR-210 can repress the expression of ISCU by directly binding to ISCU 3′UTR. Both gain-and loss-of-function assays have demonstrated that miR-210 is necessary and sufficient for the downregulation of ISCU during hypoxia. Consequently, miR-210 is able to affect aconitase and the activity of mitochondrial complex.
Certain miRNAs are able to regulate insulin gene expression, biosynthesis and the secretion [Herrera et al., 2010
; Poy et al., 2004
; Xia et al., 2011
; Zampetaki et al., 2010
]. For example, miR-15a promotes insulin biosynthesis by inhibiting the expression of endogenous uncoupling-protein 2 (UCP-2) in mouse β-cells. The UCP-2 is a member of the mitochondrial inner membrane carrier family of proteins and it facilitates uncoupling of oxygen consumption [Bordone et al., 2006
; Bouillaud et al., 1985
]. The miR-15a regulates oxygen consumption and ATP generation through targeting UCP-2. Mitochondrial dysfunction is related to insulin resistance [Cheng et al., 2009
; Kim et al., 2008
; Lowell and Shulman, 2005
], but the underlying mechanism is not fully understood. A recent report shows that miR-126 is actively involved in insulin resistance by targeting insulin receptor substrate-1 (IRS-1) [Ryu et al., 2011
]. Thus, miRNAs can be considered as a target for developing effective treatment for diabetes.
Interestingly, miR-696 regulates fatty acid oxidation capacity and mitochondrial biogenesis through targeting peroxisome proliferator-activated receptor gamma co activator 1-alpha (PGC-1α) [Aoi et al., 2010
]. The PGC-1α promotes aerobic metabolism and mitochondrial biogenesis in skeletal muscle [Puigserver et al., 1998
; Wu et al., 2002
; Wu et al., 1999
]. Both the fatty acid oxidation and mtDNA content are reduced by miR-696 over expression but increased upon transfection of its inhibitor.