Abstract
Mitochondria are not generated de novo but grow and divide adding newly synthesized constituents to preexisting mitochondrial compartments. Mitochondria have their own compact circular genome and multiprotein machineries that mediate replication, transcription, and translation. During the past two decades, the core components implicated in these processes have been identified, and several molecular mechanisms underlying mtDNA dynamics have been proposed. The ability to repair certain types of mtDNA lesions using BER, mismatch repair, and recombinational repair pathways has been also demonstrated, and several proteins implicated in these pathways have been identified.
The vast majority of mitochondrial proteins, including components of the OXPHOS machinery, is encoded by the nuclear genome, synthesized on cytosolic ribosomes, and imported through complex pathways. At least four major pathways are exploited for biogenesis of mitochondrial proteins, including the presequence pathway, the carrier protein pathway, the redox-regulated import pathway, and the β-barrel protein pathway. Biogenesis of the mitochondrial membranes relies on the highly coordinated synthesis, import, and assembly of proteins and phospholipids. However, in contrast to the biogenesis of mitochondrial proteins, the mechanisms of mitochondrial phospholipid biosynthesis and trafficking are much less characterized.
The coordinated expression of a subset of genes in the nucleus and mitochondria is orchestrated by the intricate network of transcription factors and cofactors. While nuclear-encoded mitochondrial factors TFAM, TFB1M, TFB2M, and mTERF govern mtDNA maintenance, respiratory factors NRF1 and NRF2, ERRs, PPARs, and PGC-1 transcriptional coactivators regulate expression of multiple OXPHOS subunits, FA transporter, and FA oxidation enzymes. The PGC-1 family members, PGC-1α, PGC-1β, and PRC, play a central role in integrating various signals and coordinating a variety of transcription factors to orchestrate mitochondrial biogenesis and respiratory function. A central role of the PGC-1 pathway in orchestrating energy metabolism in energy-demanding myocardium and the recent finding that it is downregulated in the failing heart suggest that this regulatory circuit could be a potential target for treatment of myocardial disorders. At present, many fundamental questions still remain unanswered regarding the molecular mechanisms of mitochondrial biogenesis to therapeutically target this process in the treatment of cardiovascular diseases.
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Marín-García, J. (2013). Mitochondrial Biogenesis. In: Mitochondria and Their Role in Cardiovascular Disease. Springer, Boston, MA. https://doi.org/10.1007/978-1-4614-4599-9_4
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