Mitochondrial biogenesis and turnover

Abstract

Mitochondrial biogenesis is a complex process involving the coordinated expression of mitochondrial and nuclear genes, the import of the products of the latter into the organelle and turnover. The mechanisms associated with these events have been intensively studied in the last 20 years and our understanding of their details is much improved. Mitochondrial biogenesis requires the participation of calcium signaling that activates a series of calcium-dependent protein kinases that in turn activate transcription factors and coactivators such as PGC-1alpha that regulates the expression of genes coding for mitochondrial components. In addition, mitochondrial biogenesis involves the balance of mitochondrial fission-fusion. Mitochondrial malfunction or defects in any of the many pathways involved in mitochondrial biogenesis can lead to degenerative diseases and possibly play an important part in aging.

Figure 1. Structure and expression of the human mitochondrial DNA

The 16,569 bp human mtDNA (panel A) showing 13 protein coding genes as well as 2 rRNA- and 22 tRNA-coding genes. Genes coding for subunits of complex I (ND1-ND6), complex III (Cyt b), complex IV (COX I-COX III) and complex V (A8 and A6) are shown by different colors. The insert on panel A illustrates one of the mechanisms proposed for mtDNA replication. It also shows a consensus model of polycyctronic transcription, including the approximately binding sites for the mitochondrial RNA polymerase, the mitochondrial transcription factor TFAM, the RNA processing enzyme RNAse MRP and the transcription termination factor mTERF. The origins of replication for the H- and L- (OH and OL) strands are also shown. The structure of the regulatory D-loop region is shown in panel B, including the approximate position of the conserved sequence boxes believed to play a role in replication and RNA primer processing. It also shows the location of the two hypervariable regions (HSV1 and HSV2) commonly used for evolutionary studies.

Figure 2. Protein import into mitochondria

Nuclear encoded proteins are imported into mitochondria by different pathways depending on their final destination. Matrix proteins, synthesized as precursors containing a targeting sequence in the amino terminus are translocated through TOM and TIM23-Hsp70/Mge1 complexes and once in the matrix the targeting sequence is cleaved by mitochondrial proteases to render the mature form. Inner membrane proteins are translocated by TOM and TIM23 but get arrested in the latter, transferred laterally into the membrane and have their targeting sequence cleaved. Other inner membrane proteins are imported into the matrix by TOM and TIM23 and inserted into the inner membrane with the help of Oxa1. In addition, very hydrophobic inner membrane proteins with even number of transmembrane domains are translocated through TOM, then passed to TIM22 via small Tim proteins and inserted into the membrane. Intermembrane space (IMS) proteins are transported via TOM-TIM23 and laterally transferred to inner membrane, where the presequence is cleaved and the protein is released into the intermembrane space. Other IMS proteins are translocated through the TOM complex and then folded in the intermembrane space with the help of Mia40 and Erv1 chaperones. Outer membrane proteins are translocated through the TOM complex, guided by the small Tim proteins to the TOB/SAM complex and inserted into the membrane. See text for more details.

Figure 3. Calcium signaling participating in Mitochondrial Biogenesis

Extracellular stimuli such as nutrient deprivation, changes in temperature or exercise increase intracellular concentrations of calcium that stimulates different kinases (depending on the stimuli) that can activate transcription by stimulating specific transcription factors (e.g. CREB). Certain kinases also activate the transcriptional coactivator PGC-1α by directly phosphorylating it or by activating its transcription. PGC-1α stimulates transcription factors such as nuclear respiratory factor NRF1 and NRF2 to activate transcription of several mitochondrial genes including proteins necessary for transcription and replication of mtDNA, proteins of the electron transport chain, mitochondrial protein import, TCA cycle and β-oxidation of fatty acids that will lead to mitochondrial biogenesis.

Figure 4. Mitochondrial Fission and Fusion

In yeast, mitochondria fission involves the action of Dmn1, that can self assemble into polymeric spirals and is recruited into the mitochondrial membrane by Fis1 and Mdv1. Dmn1 polymers wrap around the organelle and constrict the membrane until fission occurs. In humans, Drp1 and hFis1 are the homologs of Dmn1 and Fis1 whereas no homolog of Mdv1 has been found yet. Mitochondrial fusion involves the interaction of Fzo1/Ugo1 molecules located in the outer membrane of two mitochondria until outer membrane fuses, and then inner membrane fusion occurs through the interaction of Mgm1 molecules. In mammals, there are two homologs of Fzo1, the mitofusins 1 and 2 (Mfn1 and Mfn2) whereas the homolog of Mgm1 is OPA1. MIM, mitochondrial inner membrane: MOM, mitochondrial outer membrane. See text for more details. The cartoon is based on models described in reference [80].