title: Regulation of mitochondrial function and cellular energy metabolism by protein kinase C-λ/ι: a novel mode of balancing pluripotency.
abstract: Pluripotent stem cells (PSCs) contain functionally immature mitochondria and rely upon high rates of glycolysis for their energy requirements. Thus, altered mitochondrial function and promotion of aerobic glycolysis are key to maintain and induce pluripotency. However, signaling mechanisms that regulate mitochondrial function and reprogram metabolic preferences in self-renewing versus differentiated PSC populations are poorly understood. Here, using murine embryonic stem cells (ESCs) as a model system, we demonstrate that atypical protein kinase C isoform, PKC lambda/iota (PKCλ/ι), is a key regulator of mitochondrial function in ESCs. Depletion of PKCλ/ι in ESCs maintains their pluripotent state as evident from germline offsprings. Interestingly, loss of PKCλ/ι in ESCs leads to impairment in mitochondrial maturation, organization, and a metabolic shift toward glycolysis under differentiating condition. Our mechanistic analyses indicate that a PKCλ/ι-hypoxia-inducible factor 1α-PGC1α axis regulates mitochondrial respiration and balances pluripotency in ESCs. We propose that PKCλ/ι could be a crucial regulator of mitochondrial function and energy metabolism in stem cells and other cellular contexts.
authors.affiliation: Department of Pathology & Laboratory Medicine, Kansas City, Kansas, USA.
authors.forename: Biraj
authors.initials: B
authors.lastname: Mahato
authors.forename: Pratik
authors.initials: P
authors.lastname: Home
authors.forename: Ganeshkumar
authors.initials: G
authors.lastname: Rajendran
authors.forename: Arindam
authors.initials: A
authors.lastname: Paul
authors.forename: Biswarup
authors.initials: B
authors.lastname: Saha
authors.forename: Avishek
authors.initials: A
authors.lastname: Ganguly
authors.forename: Soma
authors.initials: S
authors.lastname: Ray
authors.forename: Nairita
authors.initials: N
authors.lastname: Roy
authors.forename: Russell H
authors.initials: RH
authors.lastname: Swerdlow
authors.forename: Soumen
authors.initials: S
authors.lastname: Paul
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D053595:Embryonic Stem Cells / Q000378:metabolism*; D004734:Energy Metabolism / Q000502:physiology*; D006019:Glycolysis / Q000502:physiology; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism*; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D039904:Pluripotent Stem Cells / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D000099293:Protein Kinase C-lambda
chemical_list: D007527:Isoenzymes; D011493:Protein Kinase C; D000099293:Protein Kinase C-lambda
keywords: Embryonic stem cells; Energy metabolism; Mitochondria; PGC1α; Protein kinase C λ/ι