Mobilization of adenine nucleotide translocators as molecular bases of the biochemical threshold effect observed in mitochondrial diseases.
ABSTRACT The existence of a biochemical threshold effect in the metabolic expression of oxidative phosphorylation deficiencies has considerable implications for the understanding of mitochondrial bioenergetics and the study of mitochondrial diseases. However, the molecular bases of this phenomenon remain unclear. We report here a new mechanism to explain this threshold effect, based on a reserve of enzymes not initially participating in the respiratory rate that can be activated either to respond to a flux increase or to compensate for a defect induced by a mutation. We show that this mobilization occurs through 1) the assembly of inactive adenine nucleotide translocator isoform 1 subunits into oligomeric active carriers or 2) conformational changes in the adenine nucleotide translocator isoform 1 in a permeability transition pore-like structure. We discuss how these transitions are sensitive to the steady state of oxidative phosphorylation functioning or tissue and analyze their consequences on the threshold effect.
Article: Mitoplasticity: Adaptation biology of the mitochondrion to the cellular redox state in physiology and carcinogenesis.[show abstract] [hide abstract]
ABSTRACT: Significance: Adaptation and transformation biology of the mitochondrion to redox status is an emerging domain of physiology and pathophysiology. Mitochondrial adaptations occur in response to accidental changes in cellular energy demand or supply while mitochondrial transformations are part of greater program of cell metamorphosis. The possible role of mitochondrial adaptations and transformations in pathogenesis remains unexplored and it has become critical to decipher the stimuli and the underlying molecular pathways. Recent Advances: Immediate activation of mitochondrial function was described during acute exercise, respiratory chain injury, ER stress, genotoxic stress or environmental toxic insults. Delayed adaptations of mitochondrial form, composition and functions were evidenced for persistent changes in redox status as observed in endurance training, in fibroblasts grown in presence of respiratory chain inhibitors or in absence of glucose, in the smooth muscle of patients with severe asthma or in the skeletal muscle of patients with a mitochondrial disease. Besides, mitochondrial transformations were observed in the course of human cell differentiation, during immune response activation, or in cells undergoing carcinogenesis. Critical Issues: Little is known on the signals and downstream pathways which govern mitochondrial adaptations and transformations. Few adaptative loops including redox sensors, kinases and transcription factors were deciphered, but their implication in physiology and pathology remains elusive. Future Directions: Mitoplasticity could play a protective role against aging, diabetes, cancer or neurodegenerative diseases. Research on adaptation and transformation could allow the design of innovative therapies, notably in cancer.Antioxidants & Redox Signaling 09/2012; · 8.20 Impact Factor