CDKN1B/p27 is localized in mitochondria and improves respiration-dependent processes in the cardiovascular system—New mode of action for caffeine

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.

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Effects of Dietary Supplements on Adaptations to Endurance Training

“…Caffeine can increase exogenous carbohydrate oxidation [168], possibly via greater intestinal absorption [169], and also increase AMPK activation via calciummediated protein phosphatase 2A activity [170]. Emerging research also points to a role for caffeine in improving mitochondrial respiration via its effects on mitochondrial p27 [171], suggesting the potential to work synergistically with SIT -the form of interval training that has been associated with the greatest improvements in mitochondrial respiration [172].…”

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“…In regard to the role of the interplay between caffeine and mitochondria in the cardiovascular system, Ale-Agha, et al recently established experimentally that caffeine acting jointly with mitochondrial cyclin-dependent kinase inhibitor 1B exerts protective effects against CVD [ 25 ]. However, although likely related to biochemical differences between ND2-237Leu and ND2-237Met in response to some compounds in coffee, the physiological mechanisms underlying the joint association of ND2-237 Leu/Met polymorphism and coffee consumption with serum chloride levels remains unknown.…”