Abstract
We show that the cyclin-dependent kinase inhibitor 1B (CDKN1B)/p27, previously known as a cell cycle inhibitor, is also localized within mitochondria. The migratory capacity of endothelial cells, which need intact mitochondria, is completely dependent on mitochondrial p27. Mitochondrial p27 improves mitochondrial membrane potential, increases adenosine triphosphate (ATP) content, and is required for the promigratory effect of caffeine. Domain mapping of p27 revealed that the N-terminus and C-terminus are required for those improvements. Further analysis of those regions revealed that the translocation of p27 into the mitochondria and its promigratory activity depend on serine 10 and threonine 187. In addition, mitochondrial p27 protects cardiomyocytes against apoptosis. Moreover, mitochondrial p27 is necessary and sufficient for cardiac myofibroblast differentiation. In addition, p27 deficiency and aging decrease respiration in heart mitochondria. Caffeine does not increase respiration in p27-deficient animals, whereas aged mice display improvement after 10 days of caffeine in drinking water. Moreover, caffeine induces transcriptome changes in a p27-dependent manner, affecting mostly genes relevant for mitochondrial processes. Caffeine also reduces infarct size after myocardial infarction in prediabetic mice and increases mitochondrial p27. Our data characterize mitochondrial p27 as a common denominator that improves mitochondria-dependent processes and define an increase in mitochondrial p27 as a new mode of action of caffeine.
Highlights
The cyclin-dependent kinase inhibitor 1B (CDKN1B), known as p27, was initially discovered as a nuclear-localized cell cycle inhibitor [1]
The protein p27 is a nuclear cell cycle inhibitor that can be shuttled to the cytoplasm to inactivate its inhibitory role, and this mechanism is thought to be used by cancer cells to unlock cell cycle arrest
We find that p27 is required for migration of endothelial cells by enhancing mitochondrial functions and that caffeine concentrations reached after consumption of 4 cups of coffee induce its translocation into mitochondria
Summary
The cyclin-dependent kinase inhibitor 1B (CDKN1B), known as p27, was initially discovered as a nuclear-localized cell cycle inhibitor [1]. Its promigratory effect was independent of its cell cycle arrest functions but rather required serine 10 phosphorylation–dependent nuclear export and a C-terminal scatter domain [4]. It was suggested that knockout of a cell cycle inhibitor like p27 could be beneficial in the experimental setup of myocardial infarction. This was based on the reasoning that myocardial infarction leads to loss of cells in the heart and that enhanced proliferation of cells in p27-deficient mice may result in smaller infarct size and reduced mortality; exactly the opposite was observed [5,6]. Over the last several years, it has become evident that functional mitochondria, in cardiomyocytes and in endothelial cells [7,8] and in cardiac fibroblasts [9], are required for proper functionality of those cells and are essential for protective actions in cardiovascular diseases
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