10:58am Tuesday 15 October 2019

Researchers Discover Mechanism Linked to Cellular Respiration

The system involves a heme-mediated oxygen sensing mechanism that also was found to regulate the mitochondrial respiratory chain’s function as the powerhouse of the cell.

Led by senior author Antoni Barrientos, Ph.D., associate professor of neurology and biochemistry and molecular biology, the researchers discovered that the activity of a conserved yeast cytochrome c oxidase translational activator and assembly factor is regulated by heme B, defining a homeostatic mechanism that links the formation and activity of the respiratory chain to the availability of oxygen via the oxygen-regulated heme biosynthetic pathway.

Their study, “A Heme-Sensing Mechanism in the Translational Regulation of Mitochondrial Cytochrome c Oxidase Biogenesis,” described the first case of heme-mediated oxygen sensing in mitochondria, defined as the “powerhouse” because it generates most of the cell’s energy supply in the form of adenosine triphosphate.

“We have discovered that a conserved translational activator and cytochrome c oxidase assembly factor, termed Mss51, is a heme-binding protein,” Barrientos explained. “Mss51 contains two Cysteine-Proline-X (CPX) heme regulatory motifs that are important for heme binding and efficient performance of Mss51 functions.”

Heme binding to proteins is essential for many cellular and organismal functions involving oxygen sensing and use. Hemoglobin in blood, for example, is a heme binding protein. Since the regulation of globin production is dependent on heme availability, if heme concentration is low, it will remain inactive, thus preventing the accumulation of globins.

The team also found evidence that heme could play a regulatory role in Mss51 functions.

Mss51 is a mitochondrial translational activator specific for Cox1 synthesis. Cox1 is a catalytic subunit of cytochrome c oxidase, the last enzyme of the mitochondrial respiratory chain, where oxygen is reduced to water during the process of cellular respiration. Because heme biosynthesis requires oxygen, Mss51 senses oxygen through heme-binding to facilitate the formation of cytochrome c oxidase.

In mammals, CPX motifs are present, for example, in the transcriptional repressor Bach1, which regulates globin expression, and in the HRI kinase which coordinates globin protein synthesis and heme availability in reticulocytes, immature red blood cells that make up about one percent of the red cells in the human body.

Although heme has been shown to play roles in regulation of nuclear gene expression (both transcription and translation), the possible roles of heme in regulating mitochondrial gene expression are largely unexplored.

“Our results are relevant to the coordination of mitochondrial respiratory chain formation and aerobic energy production across evolution, from yeast to higher organisms including humans,” Barrientos said.

Barrientos and his team concluded that by binding heme B, Mss51 could sense oxygen levels (required for heme biosynthesis) to modulate the synthesis of a mitochondrial DNA-encoded protein and its subsequent assembly into cytochrome c oxidase, the major oxygen-consuming mitochondrial enzyme essential for aerobic energy production.

Co-authors on the study are Iliana C. Soto, Ph.D., post-doctoral associate, and Flavia Fontanesi, Ph.D., associate research scientist, both from the Department of Neurology, Richard Myers, Ph.D., associate professor of biochemistry and molecular biology, and Patrice Hamel, Ph.D., associate professor of molecular genetics and molecular and cellular biochemistry at The Ohio State University.

University of Miami

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