bims-cytox1 2022-09-11 papers

bims-cytox1

Biomed News

on Cytochrome oxidase subunit 1

Issue of 2022–09–11
six papers selected by
Gavin McStay, Liverpool John Moores University

Something old, something new, something borrowed, something blue: the anaerobic microbial ancestry of aerobic respiration.
Mitochondrial protein synthesis and the bioenergetic cost of neurodevelopment.
cAMP/PKA Signaling Modulates Mitochondrial Supercomplex Organization.
Mitochondrial respiratory complexes: Significance in human mitochondrial disorders and cancers.
Identification of COX4I2 as a hypoxia-associated gene acting through FGF1 to promote EMT and angiogenesis in CRC.
Mitochondrial DNA polymorphisms in COX1 affect the lifespan of Caenorhabditis elegans through nuclear gene dct-15.

Trends Microbiol. 2022 Sep 01. pii: S0966-842X(22)00218-9. [Epub ahead of print]

Something old, something new, something borrowed, something blue: the anaerobic microbial ancestry of aerobic respiration.

Jennifer B Glass, Claire E Elbon, Loren Dean Williams.

  Aerobic respiration evolved by bricolage, with modules cobbled together as microbial biochemistry coevolved with Earth's geochemistry. The mitochondrial electron transport chain represents a patchwork of respiratory modules inherited from microbial methanogenesis, iron oxidation, anoxygenic photosynthesis, and denitrification pathways, and preserves a biochemical record of Earth's redox environment over its four-billion-year history. Imprints of the anoxic early Earth are recognizable in Complex I's numerous iron-sulfur cofactors and vestigial binding sites for ferredoxin, nickel-iron, and molybdopterin, whereas the more recent advent of oxygen as a terminal electron acceptor necessitated use of heme and copper cofactors by Complex IV. Bricolage of respiratory complexes resulted in supercomplexes for improved electron transfer efficiency in some bacteria and archaea, and in many eukaryotes. Accessory subunits evolved to wrap mitochondrial supercomplexes for improved assembly and stability. Environmental microbes with 'fossil' proteins that are similar to ancestral forms of the respiratory complexes deserve further scrutiny and may reveal new insights on the evolution of aerobic respiration.

Keywords:  aerobic; anaerobic; electron transport chain; evolution; respiration

DOI:  https://doi.org/10.1016/j.tim.2022.08.006
iScience. 2022 Sep 16. 25(9): 104920

Mitochondrial protein synthesis and the bioenergetic cost of neurodevelopment.

Pernille Bülow, Anupam Patgiri, Victor Faundez.

  The human brain consumes five orders of magnitude more energy than the sun by unit of mass and time. This staggering bioenergetic cost serves mostly synaptic transmission and actin cytoskeleton dynamics. The peak of both brain bioenergetic demands and the age of onset for neurodevelopmental disorders is approximately 5 years of age. This correlation suggests that defects in the machinery that provides cellular energy would be causative and/or consequence of neurodevelopmental disorders. We explore this hypothesis from the perspective of the machinery required for the synthesis of the electron transport chain, an ATP-producing and NADH-consuming enzymatic cascade. The electron transport chain is constituted by nuclear- and mitochondrial-genome-encoded subunits. These subunits are synthesized by the 80S and the 55S ribosomes, which are segregated to the cytoplasm and the mitochondrial matrix, correspondingly. Mitochondrial protein synthesis by the 55S ribosome is the rate-limiting step in the synthesis of electron transport chain components, suggesting that mitochondrial protein synthesis is a bottleneck for tissues with high bionergetic demands. We discuss genetic defects in the human nuclear and mitochondrial genomes that affect these protein synthesis machineries and cause a phenotypic spectrum spanning autism spectrum disorders to neurodegeneration during neurodevelopment. We propose that dysregulated mitochondrial protein synthesis is a chief, yet understudied, causative mechanism of neurodevelopmental and behavioral disorders.

Keywords:  Biological Sciences; Cell Biology; Neuroscience

DOI:  https://doi.org/10.1016/j.isci.2022.104920
Int J Mol Sci. 2022 Aug 25. pii: 9655. [Epub ahead of print]23(17):

cAMP/PKA Signaling Modulates Mitochondrial Supercomplex Organization.

Anna Signorile, Consiglia Pacelli, Luigi Leonardo Palese, Arcangela Santeramo, Emilio Roca, Tiziana Cocco, Domenico De Rasmo.

  The oxidative phosphorylation (OXPHOS) system couples the transfer of electrons to oxygen with pumping of protons across the inner mitochondrial membrane, ensuring the ATP production. Evidence suggests that respiratory chain complexes may also assemble into supramolecular structures, called supercomplexes (SCs). The SCs appear to increase the efficiency/capacity of OXPHOS and reduce the reactive oxygen species (ROS) production, especially that which is produced by complex I. Studies suggest a mutual regulation between complex I and SCs, while SCs organization is important for complex I assembly/stability, complex I is involved in the supercomplex formation. Complex I is a pacemaker of the OXPHOS system, and it has been shown that the PKA-dependent phosphorylation of some of its subunits increases the activity of the complex, reducing the ROS production. In this work, using in ex vivo and in vitro models, we show that the activation of cAMP/PKA cascade resulted in an increase in SCs formation associated with an enhanced capacity of electron flux and ATP production rate. This is also associated with the phosphorylation of the NDUFS4 subunit of complex I. This aspect highlights the key role of complex I in cellular energy production.

Keywords:  NDUFS4; cAMP/PKA; complex I; mitochondria; mitochondrial supercomplexes

DOI:  https://doi.org/10.3390/ijms23179655
J Cell Physiol. 2022 Sep 08.

Mitochondrial respiratory complexes: Significance in human mitochondrial disorders and cancers.

Kunwar Somesh Vikramdeo, Sarabjeet Kour Sudan, Ajay P Singh, Seema Singh, Santanu Dasgupta.

  Mitochondria are pivotal organelles that govern cellular energy production through the oxidative phosphorylation system utilizing five respiratory complexes. In addition, mitochondria also contribute to various critical signaling pathways including apoptosis, damage-associated molecular patterns, calcium homeostasis, lipid, and amino acid biosynthesis. Among these diverse functions, the energy generation program oversee by mitochondria represents an immaculate orchestration and functional coordination between the mitochondria and nuclear encoded molecules. Perturbation in this program through respiratory complexes' alteration results in the manifestation of various mitochondrial disorders and malignancy, which is alarmingly becoming evident in the recent literature. Considering the clinical relevance and importance of this emerging medical problem, this review sheds light on the timing and nature of molecular alterations in various respiratory complexes and their functional consequences observed in various mitochondrial disorders and human cancers. Finally, we discussed how this wealth of information could be exploited and tailored to develop respiratory complex targeted personalized therapeutics and biomarkers for better management of various incurable human mitochondrial disorders and cancers.

Keywords:  ATP; cancer; genetic disorders; mitochondria; oxidative phosphorylation (OXPHOS); respiratory complexes

DOI:  https://doi.org/10.1002/jcp.30869
Cell Mol Biol Lett. 2022 Sep 05. 27(1): 76

Identification of COX4I2 as a hypoxia-associated gene acting through FGF1 to promote EMT and angiogenesis in CRC.

Jie-Pin Li, Yuan-Jie Liu, Shu-Hong Zeng, Hai-Jian Gao, Yu-Gen Chen, Xi Zou.

   BACKGROUND: Current evidence suggests that the hypoxic tumor microenvironment further aggravates tumor progression, leading to poor therapeutic outcomes. There is as yet no biomarker capable of evaluating the hypoxic state of the tumor. The cytochrome c oxidase (COX) subunit is crucial to the mitochondrial respiratory chain.
METHODS: We investigated the potential oncogenic role of COX subunit 4 isoform 2 gene (COX4I2) in colorectal cancer (CRC) by least absolute shrinkage and selection operator (LASSO) and COX regression analysis to examine whether COX4I2 overexpression can predict colorectal cancer (CRC) prognosis. The association of COX4I2 levels with clinical features and its biological actions were evaluated both in vitro and in vivo.
RESULTS: Our analysis showed that elevated COX4I2 levels were correlated with poor clinical outcomes. We also observed that that COX4I2 may be involved in epithelial-mesenchymal transition, activation of cancer-related fibroblasts and angiogenesis in relation to fibroblast growth factor 1.
CONCLUSIONS: The COX4I2 level may be a predictor of outcome in CRC and may represent a novel target for treatment development.

Keywords:  Angiogenesis; COX4I2; Cancer-associated fibroblasts; Colorectal cancer; Epithelial–mesenchymal transition; Fibroblast growth factor 1

DOI:  https://doi.org/10.1186/s11658-022-00380-2
Gene. 2022 Sep 02. pii: S0378-1119(22)00595-9. [Epub ahead of print] 146776

Mitochondrial DNA polymorphisms in COX1 affect the lifespan of Caenorhabditis elegans through nuclear gene dct-15.

Yao Zhu, Ying Li, Yuechen Wang, Liang Wang, Peng Shi, Xinze Du, Yingchun Zhang, Yuanjian Song, Zuobin Zhu.

Mutations in the mitochondrial DNA (mtDNA) are closely related to age and age-related complex diseases, but the exact regulatory mechanism of mtDNA natural variation or polymorphism and ageing remains unclear. Recently, nuclear genes that regulate mitochondrial functions and thereby influence ageing have been widely studied. In this study, the relationship between the retrograde communication from the mitochondria to the nucleus and its ultimate effect on ageing has been elucidated. This study found that the natural variations in COX1 of the mitochondria in the Caenorhabditis elegans population do not correlate with multiple phenotypes, except for a mild correlation with lifespan. After excluding the differences in the nuclear genome, the correlation between natural mitochondrial variation and lifespan increased significantly. Moreover, mtDNA variation downregulated the nuclear dct-15 gene expression, which consequently reduced the lifespan, development rate and motility of C. elegans. dct-15 mutations decreased mitochondria copy number but increased ATP content and mitochondrial ultrastructure. Thus, the results indicated that dct-15 interacted with the mitochondrial DNA polymorphisms in COX1 and is associated with ageing. Finally, bioinformatic analyses revealed that mtDNA variation regulated the structural constituent of the cuticle via dct-15 and suggested that the structural constituent of the cuticle could have an important role in the development and ageing processes. These results provide insights into the mtDNA mechanism that can alter the nuclear gene and thereby regulate ageing and ageing-related diseases.

DOI: https://doi.org/10.1016/j.gene.2022.146776