Tissue-specific mitochondrial HIGD1C promotes oxygen sensitivity in carotid body chemoreceptors
Alba Timón-Gómez,
Alexandra L Scharr,
Nicholas Y Wong,
Erwin Ni,
Arijit Roy,
Min Liu,
Julisia Chau,
Jack L Lampert,
Homza Hireed,
Noah S Kim,
Masood Jan,
Alexander R Gupta,
Ryan W Day,
James M Gardner,
Richard JA Wilson,
Antoni Barrientos,
Andy J Chang
Affiliations
Alba Timón-Gómez
Department of Neurology, University of Miami, Miami, United States
Alexandra L Scharr
Department of Physiology and Cardiovascular Research Institute, University of California, San Francisco, San Francisco, United States
Nicholas Y Wong
Department of Physiology and Cardiovascular Research Institute, University of California, San Francisco, San Francisco, United States
Erwin Ni
Department of Physiology and Cardiovascular Research Institute, University of California, San Francisco, San Francisco, United States
Arijit Roy
Department of Physiology and Pharmacology, University of Calgary, Calgary, Canada; Hotchkiss Brain Institute, University of Calgary, Calgary, Canada; Alberta Children's Hospital Research Institute, University of Calgary, Calgary, Canada
Min Liu
Department of Physiology and Cardiovascular Research Institute, University of California, San Francisco, San Francisco, United States
Julisia Chau
Department of Physiology and Cardiovascular Research Institute, University of California, San Francisco, San Francisco, United States
Department of Physiology and Cardiovascular Research Institute, University of California, San Francisco, San Francisco, United States
Homza Hireed
Department of Physiology and Cardiovascular Research Institute, University of California, San Francisco, San Francisco, United States
Noah S Kim
Department of Physiology and Cardiovascular Research Institute, University of California, San Francisco, San Francisco, United States
Masood Jan
Department of Physiology and Cardiovascular Research Institute, University of California, San Francisco, San Francisco, United States
Alexander R Gupta
Department of Surgery, University of California, San Francisco, San Francisco, United States; Diabetes Center, University of California, San Francisco, San Francisco, United States
Ryan W Day
Department of Surgery, University of California, San Francisco, San Francisco, United States
James M Gardner
Department of Surgery, University of California, San Francisco, San Francisco, United States; Diabetes Center, University of California, San Francisco, San Francisco, United States
Department of Physiology and Pharmacology, University of Calgary, Calgary, Canada; Hotchkiss Brain Institute, University of Calgary, Calgary, Canada; Alberta Children's Hospital Research Institute, University of Calgary, Calgary, Canada
Mammalian carotid body arterial chemoreceptors function as an early warning system for hypoxia, triggering acute life-saving arousal and cardiorespiratory reflexes. To serve this role, carotid body glomus cells are highly sensitive to decreases in oxygen availability. While the mitochondria and plasma membrane signaling proteins have been implicated in oxygen sensing by glomus cells, the mechanism underlying their mitochondrial sensitivity to hypoxia compared to other cells is unknown. Here, we identify HIGD1C, a novel hypoxia-inducible gene domain factor isoform, as an electron transport chain complex IV-interacting protein that is almost exclusively expressed in the carotid body and is therefore not generally necessary for mitochondrial function. Importantly, HIGD1C is required for carotid body oxygen sensing and enhances complex IV sensitivity to hypoxia. Thus, we propose that HIGD1C promotes exquisite oxygen sensing by the carotid body, illustrating how specialized mitochondria can be used as sentinels of metabolic stress to elicit essential adaptive behaviors.
