title: Regulation of metabolism in individual mitochondria during excitation-contraction coupling.
abstract: The heart is an excitable organ that undergoes spontaneous force generation and relaxation cycles driven by excitation-contraction (EC) coupling. A fraction of the oscillating cytosolic Ca(2+) during each heartbeat is taken up by mitochondria to stimulate mitochondrial metabolism, the major source of energy in the heart. Whether the mitochondrial metabolism is regulated individually during EC coupling and whether this heterogeneous regulation bears any physiological or pathological relevance have not been studied. Here, we developed a novel approach to determine the regulation of individual mitochondrial metabolism during cardiac EC coupling. Through monitoring superoxide flashes, which are stochastic and bursting superoxide production events arising from increased metabolism in individual mitochondria, we found that EC coupling stimulated the metabolism in individual mitochondria as indicated by significantly increased superoxide flash activity during electrical stimulation of the cultured intact myocytes or perfused heart. Mechanistically, cytosolic calcium transients promoted individual mitochondria to take up calcium via mitochondrial calcium uniporter, which subsequently triggered transient opening of the permeability transition pore and stimulated metabolism and bursting superoxide flash in that mitochondrion. The bursting superoxide, in turn, promoted local calcium release. In the early stage of heart failure, EC coupling regulation of superoxide flashes was compromised. This study highlights the heterogeneity in the regulation of cardiac mitochondrial metabolism, which may contribute to local redox signaling.
authors.affiliation: Mitochondria and Metabolism Center, Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, WA 98109, USA.
authors.forename: Guohua
authors.initials: G
authors.lastname: Gong
authors.affiliation: Mitochondria and Metabolism Center, Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, WA 98109, USA; Department of Neurology, Second Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, China.
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Liu
authors.affiliation: Mitochondria and Metabolism Center, Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, WA 98109, USA. Electronic address: wangwang@u.washington.edu.
authors.forename: Wang
authors.initials: W
authors.lastname: Wang
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004734:Energy Metabolism; D056966:Excitation Contraction Coupling; D005260:Female; D057809:HEK293 Cells; D006333:Heart Failure / Q000378:metabolism; D006801:Humans; D008822:Mice, Transgenic; D008929:Mitochondria, Heart / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism; D017207:Rats, Sprague-Dawley
keywords: Excitation–contraction coupling; Mitochondrial calcium uptake; Mitochondrial metabolism; Permeability transition pore; Superoxide flash