Maintenance and Expression of Mammalian Mitochondrial DNA

Abstract

Mammalian mitochondrial DNA (mtDNA) encodes 13 proteins that are essential for the function of the oxidative phosphorylation system, which is composed of four respiratory-chain complexes and adenosine triphosphate (ATP) synthase. Remarkably, the maintenance and expression of mtDNA depend on the mitochondrial import of hundreds of nuclear-encoded proteins that control genome maintenance, replication, transcription, RNA maturation, and mitochondrial translation. The importance of this complex regulatory system is underscored by the identification of numerous mutations of nuclear genes that impair mtDNA maintenance and expression at different levels, causing human mitochondrial diseases with pleiotropic clinical manifestations. The basic scientific understanding of the mechanisms controlling mtDNA function has progressed considerably during the past few years, thanks to advances in biochemistry, genetics, and structural biology. The challenges for the future will be to understand how mtDNA maintenance and expression are regulated and to what extent direct intramitochondrial cross talk between different processes, such as transcription and translation, is important.

Differential contribution of the mitochondrial translation pathway to the survival of diffuse large B-cell lymphoma subsets

“…These analyses indicated higher expression across several classes of mitochondrial translation proteins, including mitochondrial elongation factors (TUFM (Tu translation elongation factor, mitochondrial) and GFM1 (G elongation factor, mitochondrial, 1)), mitochondrial ribosomal proteins (mitochondrial ribosomal protein (MRP) S5, S7, S9, S16, S22, S25, L12, and L46), and proteins in charge of mitochondrial tRNA synthesis and function (DARS2 (aspartyl-tRNA synthetase 2), YARS2 (tyrosyl-tRNA synthetase 2), and PUS1 (pseudouridylate synthase 1); Figures 1a and b; Table 1). The enrichment in mtDNA-encoded ETC subunits and mitochondrial translation proteins in OxPhos-DLBCLs is further consistent with higher expression of proteins involved in mtDNA maintenance (SSBP1 (single-stranded DNA-binding protein 1)) and transcription (TFAM (mitochondrial transcription factor A) and LRPPRC (leucine-rich pentatricopeptide repeat containing protein)) in this DLBCL subtype 18,28 ( Figure 1f; Table 1; Supplementary Table 2).…”

“…Except for complex II (succinate dehydrogenase), the protein constituents of the ETC complexes are encoded by two independently transcribed and translated genomes; nuclear and mitochondrial. 18,19 The mitochondrial DNA (mtDNA) encodes 13 subunits contributing to complexes I, III, IV, and V, 22 transfer RNAs, and 2 ribosomal RNAs. The mechanism for decoding the mitochondrial genome requires nuclear-encoded factors, including ribosomes, translation initiation, and elongation factors, and tRNA synthetases that are distinct from the cytoplasmic counterparts dedicated to translation of nuclear transcripts.…”

The GTPase domain of gamma-tubulin is required for normal mitochondrial function and spatial organization

“…We found that in the crude mitochondria fraction of γTubulin sh-MCF10A cells, reduced protein levels of γ-tubulin had enhanced the protein levels of the mitochondrial-specific DNA polymerase gamma 29 as the cells progressed through S-phase (Fig. 6f), which provides us with a potential molecular mechanism accounting for the observed rise in mtDNA.…”

“…Both the nuclear compartment and the mitochondria contain chromatin and a double membrane, so accordingly, γ-tubulin associates to both compartments. Taking into consideration that the maintenance and expression of mtDNA depends on the mitochondrial import of many nuclear-encoded proteins that control mitochondrial function 29 , we hypothesize that the accumulation of γ-strings at the nuclear and mitochondrial membranes may connect the cytosolic and DNA-associated γ-tubulin pools. This association may establish a path for transport of proteins to the mitochondria 29 and for converting cytosolic signals into a gene response 5, 14, 36 .…”

Mechanism of Transcription Anti-termination in Human Mitochondria

“…In human mitochondria, the process of replication of mtDNA is directly linked to transcription (Asin-Cayuela and Gustafsson, 2007; Gustafsson et al, 2016). In the absence of a dedicated mitochondrial primase, replication primers are generated by the mitochondrial RNA polymerase (mtRNAP), a single subunit enzyme that resembles phage RNAPs (Gustafsson et al, 2016; Phillips et al, 2017; Ringel et al, 2011; Wanrooij et al, 2008).…”