Most cited article - PubMed ID 31652072
TMEM70 facilitates biogenesis of mammalian ATP synthase by promoting subunit c incorporation into the rotor structure of the enzyme
Disorders of ATP synthase, the key enzyme in mitochondrial energy supply, belong to the most severe metabolic diseases, manifesting as early-onset mitochondrial encephalo-cardiomyopathies. Since ATP synthase subunits are encoded by both mitochondrial and nuclear DNA, pathogenic variants can be found in either genome. In addition, the biogenesis of ATP synthase requires several assembly factors, some of which are also hotspots for pathogenic variants. While variants of MT-ATP6 and TMEM70 represent the most common cases of mitochondrial and nuclear DNA mutations respectively, the advent of next-generation sequencing has revealed new pathogenic variants in a number of structural genes and TMEM70, sometimes with truly peculiar genetics. Here we present a systematic review of the reported cases and discuss biochemical mechanisms, through which they are affecting ATP synthase. We explore how the knowledge of pathophysiology can improve our understanding of enzyme biogenesis and function. Keywords: Mitochondrial diseases o ATP synthase o Nuclear DNA o Mitochondrial DNA o TMEM70.
- MeSH
- Phenotype * MeSH
- Humans MeSH
- Membrane Proteins genetics metabolism MeSH
- DNA, Mitochondrial genetics MeSH
- Mitochondrial Diseases genetics enzymology MeSH
- Mitochondrial Proteins genetics metabolism MeSH
- Mitochondrial Proton-Translocating ATPases * genetics metabolism MeSH
- Mitochondria enzymology genetics MeSH
- Mutation MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Systematic Review MeSH
- Names of Substances
- Membrane Proteins MeSH
- DNA, Mitochondrial MeSH
- Mitochondrial Proteins MeSH
- Mitochondrial Proton-Translocating ATPases * MeSH
- TMEM70 protein, human MeSH Browser
Individual complexes of the mitochondrial oxidative phosphorylation system (OXPHOS) are not linked solely by their function; they also share dependencies at the maintenance/assembly level, where one complex depends on the presence of a different individual complex. Despite the relevance of this "interdependence" behavior for mitochondrial diseases, its true nature remains elusive. To understand the mechanism that can explain this phenomenon, we examined the consequences of the aberration of different OXPHOS complexes in human cells. We demonstrate here that the complete disruption of each of the OXPHOS complexes resulted in a decrease in the complex I (cI) level and that the major reason for this is linked to the downregulation of mitochondrial ribosomal proteins. We conclude that the secondary cI defect is due to mitochondrial protein synthesis attenuation, while the responsible signaling pathways could differ based on the origin of the OXPHOS defect.
- Keywords
- Biochemistry, Cell biology, Molecular biology,
- Publication type
- Journal Article MeSH
Life manifests as growth, movement or heat production that occurs thanks to the energy accepted from the outside environment. The basis of energy transduction attracted the Czech researchers since the beginning of the 20th century. It further accelerated after World War II, when the new Institute of Physiology was established in 1954. When it was found that energy is stored in the form of adenosine triphosphate (ATP) that can be used by numerous reactions as energy source and is produced in the process called oxidative phosphorylation localized in mitochondria, the investigation focused on this cellular organelle. Although the Czech scientists had to overcome various obstacles including Communist party leadership, driven by curiosity, boldness, and enthusiasm, they characterized broad spectrum of mitochondrial properties in different tissues in (patho)physiological conditions in collaboration with many world-known laboratories. The current review summarizes the contribution of the Czech scientists to the bioenergetic and mitochondrial research in the global context. Keywords: Mitochondria, Bioenergetics, Chemiosmotic coupling.
- MeSH
- Biomedical Research history trends MeSH
- History, 20th Century MeSH
- History, 21st Century MeSH
- Energy Metabolism * MeSH
- Humans MeSH
- Mitochondria * metabolism MeSH
- Animals MeSH
- Check Tag
- History, 20th Century MeSH
- History, 21st Century MeSH
- Humans MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Historical Article MeSH
- Review MeSH
- Geographicals
- Czech Republic MeSH
Mutations of the TMEM70 gene disrupt the biogenesis of the ATP synthase and represent the most frequent cause of autosomal recessive encephalo-cardio-myopathy with neonatal onset. Patient tissues show isolated defects in the ATP synthase, leading to the impaired mitochondrial synthesis of ATP and insufficient energy provision. In the current study, we tested the efficiency of gene complementation by using a transgenic rescue approach in spontaneously hypertensive rats with the targeted Tmem70 gene (SHR-Tmem70ko/ko), which leads to embryonic lethality. We generated SHR-Tmem70ko/ko knockout rats expressing the Tmem70 wild-type transgene (SHR-Tmem70ko/ko,tg/tg) under the control of the EF-1α universal promoter. Transgenic rescue resulted in viable animals that showed the variable expression of the Tmem70 transgene across the range of tissues and only minor differences in terms of the growth parameters. The TMEM70 protein was restored to 16-49% of the controls in the liver and heart, which was sufficient for the full biochemical complementation of ATP synthase biogenesis as well as for mitochondrial energetic function in the liver. In the heart, we observed partial biochemical complementation, especially in SHR-Tmem70ko/ko,tg/0 hemizygotes. As a result, this led to a minor impairment in left ventricle function. Overall, the transgenic rescue of Tmem70 in SHR-Tmem70ko/ko knockout rats resulted in the efficient complementation of ATP synthase deficiency and thus in the successful genetic treatment of an otherwise fatal mitochondrial disorder.
- Keywords
- ATP synthase deficiency, TMEM70 factor, gene therapy, mitochondria disease, transgenic rescue,
- Publication type
- Journal Article MeSH
Eukaryotic cells arose ~1.5 billion years ago, with the endomembrane system a central feature, facilitating evolution of intracellular compartments. Endomembranes include the nuclear envelope (NE) dividing the cytoplasm and nucleoplasm. The NE possesses universal features: a double lipid bilayer membrane, nuclear pore complexes (NPCs), and continuity with the endoplasmic reticulum, indicating common evolutionary origin. However, levels of specialization between lineages remains unclear, despite distinct mechanisms underpinning various nuclear activities. Several distinct modes of molecular evolution facilitate organellar diversification and to understand which apply to the NE, we exploited proteomic datasets of purified nuclear envelopes from model systems for comparative analysis. We find enrichment of core nuclear functions amongst the widely conserved proteins to be less numerous than lineage-specific cohorts, but enriched in core nuclear functions. This, together with consideration of additional evidence, suggests that, despite a common origin, the NE has evolved as a highly diverse organelle with significant lineage-specific functionality.
