ABSTRACT
During the mitochondrial permeability transition, a large channel in the inner mitochondrial membrane opens, leading to the loss of multiple mitochondrial solutes and cell death. Key triggers include excessive reactive oxygen species and mitochondrial calcium overload, factors implicated in neuronal and cardiac pathophysiology. Examining the differential behavior of mitochondrial Ca(2+) overload in Drosophila versus human cells allowed us to identify a gene, MCUR1, which, when expressed in Drosophila cells, conferred permeability transition sensitive to electrophoretic Ca(2+) uptake. Conversely, inhibiting MCUR1 in mammalian cells increased the Ca(2+) threshold for inducing permeability transition. The effect was specific to the permeability transition induced by Ca(2+), and such resistance to overload translated into improved cell survival. Thus, MCUR1 expression regulates the Ca(2+) threshold required for permeability transition.
Subject(s)
Calcium/metabolism , Membrane Proteins/metabolism , Mitochondrial Membranes/metabolism , Mitochondrial Proteins/metabolism , Amino Acid Sequence , Animals , Cyclophilins/genetics , Cyclophilins/metabolism , Drosophila/cytology , Drosophila/genetics , Drosophila/metabolism , Drosophila Proteins/genetics , Drosophila Proteins/metabolism , Fluoresceins/metabolism , Humans , Membrane Proteins/genetics , Mitochondrial Proteins/genetics , Molecular Sequence Data , Myocytes, Cardiac/cytology , Myocytes, Cardiac/metabolism , Permeability , Rats , Sequence Homology, Amino AcidABSTRACT
Physical activity is associated with beneficial adaptations in human and rodent metabolism. We studied over 50 complex traits before and after exercise intervention in middle-aged men and a panel of 100 diverse strains of female mice. Candidate gene analyses in three brain regions, muscle, liver, heart, and adipose tissue of mice indicate genetic drivers of clinically relevant traits, including volitional exercise volume, muscle metabolism, adiposity, and hepatic lipids. Although â¼33% of genes differentially expressed in skeletal muscle following the exercise intervention are similar in mice and humans independent of BMI, responsiveness of adipose tissue to exercise-stimulated weight loss appears controlled by species and underlying genotype. We leveraged genetic diversity to generate prediction models of metabolic trait responsiveness to volitional activity offering a framework for advancing personalized exercise prescription. The human and mouse data are publicly available via a user-friendly Web-based application to enhance data mining and hypothesis development.
Subject(s)
Adaptation, Physiological , Transcriptome , Male , Middle Aged , Humans , Female , Mice , Animals , Transcriptome/genetics , Obesity/metabolism , Acclimatization , Adipose Tissue/metabolism , Muscle, Skeletal/metabolismABSTRACT
Ion channels form the basis for cellular electrical signaling. Despite the scores of genetically identified ion channels selective for other monatomic ions, only one type of proton-selective ion channel has been found in eukaryotic cells. By comparative transcriptome analysis of mouse taste receptor cells, we identified Otopetrin1 (OTOP1), a protein required for development of gravity-sensing otoconia in the vestibular system, as forming a proton-selective ion channel. We found that murine OTOP1 is enriched in acid-detecting taste receptor cells and is required for their zinc-sensitive proton conductance. Two related murine genes, Otop2 and Otop3, and a Drosophila ortholog also encode proton channels. Evolutionary conservation of the gene family and its widespread tissue distribution suggest a broad role for proton channels in physiology and pathophysiology.