New Study Identifies a Mitochondrial Mechanism Controlling Blood Oxygen Sensing in the Carotid Body

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A team led by Antoni Barrientos, Ph.D., professor in the Department of Neurology and the Department of Biochemistry and Molecular Biology at the University of Miami Miller School of Medicine, and Andy Chang, assistant professor in the University of California San Francisco School of Medicine’s Department of Physiology and its Cardiovascular Research Institute, has uncovered fundamental mitochondrial mechanisms underlying the sensing of changes in arterial blood oxygen levels at the carotid body, a sensory organ, to regulate the respiratory and cardiovascular systems. Findings of the study were recently published in the journal eLife.

Antoni Barrientos, Ph.D., of the Miller School (left) and Andy Chang, Ph.D., of the University of California San Francisco

The research was supported by a grant from the National Institutes of Health to Dr. Barrientos. Alba Timón-Gómez, Ph.D., an associate scientist in the Barrientos lab, was the first author of the collaborative study. Dr. Timón-Gómez received a development grant from the Muscular Dystrophy Association to support her research work.

The carotid body (CB) is the major chemoreceptor for blood oxygen in the control of ventilation in mammals, contributing to physiological adaptation to high altitude, pregnancy, and exercise, and its hyperactivity is linked to chronic conditions such as sleep-disorder breathing, hypertension, chronic heart failure, airway constriction, and metabolic syndrome

Upon acute hypoxia, potassium channels on CB glomus cells are inhibited, causing membrane depolarization to trigger calcium influx and neurotransmitter release that stimulates afferent nerves. A longstanding model proposes that the CB senses hypoxia through atypical mitochondrial electron transport chain (ETC) metabolism ETC is more sensitive to decreases in oxygen than other tissues. This model is supported by observations that in glomus cells, the terminal ETC enzyme, known as cytochrome c oxidase or complex IV, contains a subunit isoform (COX4i2) typical of lungs and is expressed in other tissues under hypoxia. However, this protein alone cannot explain oxygen sensitivity, and therefore the fundamental mechanism of oxygen sensing has remained unknown.

A Novel Discovery

Now, the researchers have identified HIGD1C, a novel hypoxia-inducible gene domain factor isoform, as an ETC complex IV-interacting protein, highly and selectively expressed in glomus cells, which mediates acute oxygen sensing by the CB. During cellular respiration, oxygen binds to the catalytic center of cytochrome c oxidase and is reduced to water. Defects in cytochrome c oxidase are among the most frequent cause of mitochondrial disorders such as severe cardio- and encephalopathies.

The paper, titled “Tissue-specific mitochondrial HIGD1C promotes oxygen sensitivity in carotid body chemoreceptors,” clarifies key aspects of how the cytochrome c oxidase enzyme activity is modulated by HIGD1C in response to changing oxygen levels.

“Determining how HIGD1C and other atypical complex IV proteins expressed in the CB work together to confer exquisite oxygen sensing to the ETC will help us better understand how these proteins contribute to physiological function and disease and allow us to potentially target them to treat chronic illnesses characterized by CB dysfunction,” said Dr. Barrientos. “We have demonstrated that HIGD1C negatively regulates oxygen consumption by mitochondrial complex IV and acts with the hypoxia-induced subunit COX4i2 to enhance the sensitivity of cytochrome c oxidase to hypoxia, constituting an essential component of mitochondrial oxygen sensing in the CB “

Two Decades of Research

The Barrientos lab has been working for 20 years to understand how the mitochondrial cytochrome c oxidase enzyme is assembled. The process is complicated because cytochrome c oxidase is formed by 14 protein subunits — three of which form the catalytic center of the enzyme and are encoded in the mitochondrial genome, and the rest of which are encoded in the nuclear genome. Assembling all these proteins to form the full enzyme is arduous. Over the years, the Barrientos laboratory has contributed to identifying protein chaperones that help with the process, from inserting the metal groups in the catalytic core to bringing the more than 35 proteins together to form the complex. Among them, his group recently characterized the human hypoxia-inducible gene domain family proteins HIGD1A and HIGD2A, involved in the assembly of isolated and supercomplexed cytochrome c oxidase.

“The group led by Andy Chang at UCSF used whole-genome expression data from RNAseq to uncover genes encoding putative mitochondrial proteins that are overexpressed in the mouse CB compared to the adrenal medulla. They discovered that HIGD1C and COX4i2 were highly expressed. They generated a HIGD1C knockout mouse that lost CB sensory and metabolic responses to hypoxia.” Dr. Barrientos said. HIGD1C is almost exclusively expressed in glomus cells.

“Given our experience with the characterization of HIGD proteins, Andy contacted us to collaborate in deciphering the key role of HIGD1C in oxygen sensing,” Dr. Barrientos said. “We have performed studies in cultured cells to demonstrate that HIGD1C is a mitochondrial protein that negatively regulates oxygen consumption by complex IV and acts with the hypoxia-induced complex IV subunit COX4i2 to enhance the sensitivity of the enzyme to hypoxia, constituting an essential component of mitochondrial oxygen sensing in the CB.”

There is growing appreciation that mitochondrial complex IV contains subunits that are tissue-specific and/or regulated by development, physiological changes (hypoxia and low glucose), and diseases (i.e., ischemia/reperfusion injury and sepsis).

“In addition to the CB, HIGD1C is expressed in kidney proximal tubules. Compared to other nephron segments, the proximal tubules have the highest oxygen demand, exhibit greater ETC sensitivity to hypoxia, and are most susceptible to ischemia/reperfusion injury. The kidney will be the target of future studies by our groups,” Dr. Barrientos said. “We speculate that HIGD1C modulates ETC activity in multiple oxygen-sensitive cell types to match oxygen utilization to physiological function.”