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PRKCE gene encoding protein kinase C-epsilon-Dual roles at sarcomeres and mitochondria in cardiomyocytes.

ABSTRACT: Protein kinase C-epsilon (PKC?) is an isoform of a large PKC family of enzymes that has a variety of functions in different cell types. Here we discuss two major roles of PKC? in cardiac muscle cells; specifically, its role in regulating cardiac muscle contraction via targeting the sarcomeric proteins, as well as modulating cardiac cell energy production and metabolism by targeting cardiac mitochondria. The importance of PKC? action is described within the context of intracellular localization, as substrate selectivity and specificity is achieved through spatiotemporal targeting of PKC?. Accordingly, the role of PKC? in regulating myocardial function in physiological and pathological states has been documented in both cardioprotection and cardiac hypertrophy.

SUBMITTER: Scruggs SB

PROVIDER: S-EPMC5366072 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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PRKCE gene encoding protein kinase C-epsilon-Dual roles at sarcomeres and mitochondria in cardiomyocytes.

Scruggs Sarah B SB Wang Ding D Ping Peipei P

Gene 20160613 1

Protein kinase C-epsilon (PKCε) is an isoform of a large PKC family of enzymes that has a variety of functions in different cell types. Here we discuss two major roles of PKCε in cardiac muscle cells; specifically, its role in regulating cardiac muscle contraction via targeting the sarcomeric proteins, as well as modulating cardiac cell energy production and metabolism by targeting cardiac mitochondria. The importance of PKCε action is described within the context of intracellular localization, ...[more]

PMID: 27312950

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Project description:In mammals there are at least 10 isoforms of diacylglycerol kinases (DGK). All catalyze the phosphorylation of diacylglycerol (DAG) to phosphatidic acid (PA). Among DGK isoforms, DGKε has several unique features. It is the only DGK isoform with specificity for a particular species of DAG, i.e., 1-stearoyl-2-arachidonoyl glycerol. The smallest of all known DGK isoforms, DGKε, is also the only DGK devoid of a regulatory domain. DGKε is the only DGK isoform that has a hydrophobic segment that is predicted to form a transmembrane helix. As the only membrane-bound, constitutively active DGK isoform with exquisite specificity for particular molecular species of DAG, the functional overlap between DGKε and other DGKs is predicted to be minimal. DGKε exhibits specificity for DAG containing the same acyl chains as those found in the lipid intermediates of the phosphatidylinositol-cycle. It has also been shown that DGKε affects the acyl chain composition of phosphatidylinositol in whole cells. It is thus likely that DGKε is responsible for catalyzing one step in the phosphatidylinositol-cycle. Steps of this cycle take place in both the plasma membrane and the endoplasmic reticulum membrane. DGKε is likely present in both of these membranes. DGKε is the only DGK isoform that is associated with a human disease. Indeed, recessive loss-of-function mutations in DGKε cause atypical hemolytic-uremic syndrome (aHUS). This condition is characterized by thrombosis in the small vessels of the kidney. It causes acute renal insufficiency in infancy and most patients develop end-stage renal failure before adulthood. Disease pathophysiology is poorly understood and there is no therapy. There are also data suggesting that DGKε may play a role in epilepsy and Huntington disease. Thus, DGKε has many unique molecular and biochemical properties when compared to all other DGK isoforms. DGKε homologs also contain a number of conserved sequence features that are distinctive characteristics of either the rodents or specific groups of primate homologs. How cells, tissues and organisms harness DGKε's catalytic prowess remains unclear. The discovery of DGKε's role in causing aHUS will hopefully boost efforts to unravel the mechanisms by which DGKε dysfunction causes disease.

Project description:Calcium transfer into the mitochondrial matrix during sarcoplasmic reticulum (SR) Ca2+ release is essential to boost energy production in ventricular cardiomyocytes (VCMs) and match increased metabolic demand. Mitochondria from female hearts exhibit lower mito-[Ca2+] and produce less reactive oxygen species (ROS) compared to males, without change in respiration capacity. We hypothesized that in female VCMs, more efficient electron transport chain (ETC) organization into supercomplexes offsets the deficit in mito-Ca2+ accumulation, thereby reducing ROS production and stress-induced intracellular Ca2+ mishandling. Experiments using mitochondria-targeted biosensors confirmed lower mito-ROS and mito-[Ca2+] in female rat VCMs challenged with β-adrenergic agonist isoproterenol compared to males. Biochemical studies revealed decreased mitochondria Ca2+ uniporter expression and increased supercomplex assembly in rat and human female ventricular tissues vs male. Importantly, western blot analysis showed higher expression levels of COX7RP, an estrogen-dependent supercomplex assembly factor in female heart tissues vs males. Furthermore, COX7RP was decreased in hearts from aged and ovariectomized female rats. COX7RP overexpression in male VCMs increased mitochondrial supercomplexes, reduced mito-ROS and spontaneous SR Ca2+ release in response to ISO. Conversely, shRNA-mediated knockdown of COX7RP in female VCMs reduced supercomplexes and increased mito-ROS, promoting intracellular Ca2+ mishandling. Compared to males, mitochondria in female VCMs exhibit higher ETC subunit incorporation into supercomplexes, supporting more efficient electron transport. Such organization coupled to lower levels of mito-[Ca2+] limits mito-ROS under stress conditions and lowers propensity to pro-arrhythmic spontaneous SR Ca2+ release. We conclude that sexual dimorphism in mito-Ca2+ handling and ETC organization may contribute to cardioprotection in healthy premenopausal females.

Dataset Information

PRKCE gene encoding protein kinase C-epsilon-Dual roles at sarcomeres and mitochondria in cardiomyocytes.

Publications

PRKCE gene encoding protein kinase C-epsilon-Dual roles at sarcomeres and mitochondria in cardiomyocytes.

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